STRESS RESILIENCE

MOLECULAR AND BEHAVIORAL ASPECTS

Edited by

ALON CHEN

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This book is dedicated in loving memory of Wylie W. Vale, a founder of mechanistic stress research and to whom I am forever indebted for his endless inspiration and encouragement. “Resilience is critical in all things. Grit and zest are qualities most predictive of success.”

Wylie W. Vale (1941e2012)

v

Elisabeth B. Binder Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; Department of Psychiatry and Behavioral Sciences and Department of Psychology, Emory University School of Medicine, Atlanta, GA, United States

Tracy L. Bale Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, United States; Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, United States

Tallie Z. Baram Department of Anatomy/ Neurobiology, University of California-Irvine, Irvine, CA, United States; Department of Pe- diatrics, University of California-Irvine, Irvine, CA, United States

David André Barrière Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France; Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospi- talier Sainte-Anne, Paris, France

Jessica L. Bolton Department of Anatomy/ Neurobiology, University of California-Irvine, Irvine, CA, United States; Department of Pe- diatrics, University of California-Irvine, Irvine, CA, United States

Mallory E. Bowers Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Dennis S. Charney Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Alon Chen Department of Stress Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Matthew Cranshaw University of Miami, Miller School of Medicine, Miami, FL, United States

John F. Cryan Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, University College Cork, Cork, Ireland

E. Ron de Kloet Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

Jan M. Deussing Department of Stress Neuro- biology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany

Olivia Engmann Laboratory of Neuro- epigenetics, Brain Research Institute, Medical faculty of the University of Zurich and Institute for Neuroscience, Department of Health Science and Technology, ETH Zurich, Switzerland

C. Neill Epperson Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, United States

Edward Ganz Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/ 3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal

Jakob Hartmann McLean Hospital e Harvard Medical School, Mailman Research Center, Neurobiology of Fear Laboratory, Belmont, MA, United States

Marloes J.A.G. Henckens Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands

James P. Herman Department of Pharmacology and System Physiology, University of Cincin- nati, Cincinnati, OH, United States

Contributors

 

xi

xii CONTRIBUTORS

Matthew N. Hill Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

S.B. Hill Division of Depression and Anxiety, McLean Hospital; Department of Psychiatry, Harvard Medical School, Belmont, MA, United States

Brian M. Iacoviello Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Discovery and Translational Research, Click Therapeutics, Inc., New York, NY, United States

Orna Issler Nash Family Department of Neu- roscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Thérèse M. Jay Physiopathologie des Maladies Psychiatriques, UMR_S 894 Inserm, Centre de Psychiatrie et Neurosciences, Paris, France; Faculté de Médecine Paris Descartes, Service Hospitalo-Universitaire, Centre Hospitalier Sainte-Anne, Paris, France

Marian Joëls Department of Translational Neu- roscience, UMC Utrecht Brain Center, Univer- sity Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands; University of Groningen/University Medical Center Gro- ningen, Groningen, The Netherlands

C.D. King Division of Depression and Anxiety, McLean Hospital; Department of Psychiatry, Harvard Medical School, Belmont, MA, United States

Stafford L. Lightman Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, United Kingdom

Ekaterina Likhtik Hunter College, The Gradu- ate Center, City University of New York, New York, NY, United States

Zachary S. Lorsch Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States

David M. Lyons Department of Psychiatry and Behavioral Sciences, Stanford University, Stan- ford, CA, United States

Ricardo Magalhães Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/ 3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal

Isabelle M. Mansuy Laboratory of Neuro- epigenetics, Brain Research Institute, Medical faculty of the University of Zurich and Institute for Neuroscience, Department of Health Science and Technology, ETH Zurich, Switzerland

Bruce S. McEwen Alfred E. Mirsky Professor Head, Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rock- efeller University, New York, NY, United States

Sébastien Mériaux Neurospin, JOLIOT, CEA, Gif-sur-Yvette, France

Laia Morató Laboratory of Behavioral Genetics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

Kathleen E. Morrison Department of Pharma- cology, University of Maryland School of Med- icine, Baltimore, MD, United States; Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, United States

Iris Müller Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von- Guericke University Magdeburg, Magdeburg, Germany; Department of Psychological Sci- ences, Purdue University, Indianapolis, IN, United States

Charles B. Nemeroff Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, Miami, FL, United States

Eric J. Nestler Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Olivia F. O’Leary Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; APC Microbiome Institute, Univer- sity College Cork, Cork, Ireland

Lilia Papst Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

Sachin Patel Departments of Psychiatry and Behavioral Sciences, Pharmacology, Molecular Physiology & Biophysics, and The Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, United States

Rony Paz Weizmann Institute of Science, Rehovot, Israel

K.J. Ressler Division of Depression and Anxi- ety, McLean Hospital; Department of Psychia- try, Harvard Medical School, Belmont, MA, United States

Gal Richter-Levin Department of Psychology, University of Haifa, Haifa, Israel; Sagol Department of Neurobiology, University of Haifa, Haifa, Israel; The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa, Israel

Mariana Rodrigues Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/ 3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal; Algoritmi Centre, University of Minho, Braga, Portugal

Carmen Sandi Laboratory of Behavioral Genetics, Brain Mind Institute, École Poly- technique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

R. Angela Sarabdjitsingh Department of Trans- lational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands

Alan F. Schatzberg Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

Mathias V. Schmidt Max Planck Institute of Psychiatry, Munich, Germany

A.V. Seligowski Division of Depression and Anxiety, McLean Hospital; Department of Psychiatry, Harvard Medical School, Belmont, MA, United States

Annabel K. Short Department of Anatomy/ Neurobiology, University of California-Irvine, Irvine, CA, United States; Department of Pe- diatrics, University of California-Irvine, Irvine, CA, United States

Nuno Sousa Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B’s, PT Government Associate Laboratory, Braga/ Guimarães, Portugal

Francesca Spiga Bristol Medical School: Trans- lational Health Sciences, University of Bristol, Bristol, United Kingdom

Oliver Stork Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences, Magdeburg, Germany

Shariful A. Syed Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, Miami, FL, United States

Kuldeep Tripathi Sagol Department of Neuro- biology, University of Haifa, Haifa, Israel

Christiaan H. Vinkers VU University Medical Center, Amsterdam, The Netherlands

A.P. Wingo Division of Depression and Anxi- ety, McLean Hospital; Department of Psychia- try, Harvard Medical School, Belmont, MA, United States

Rachel Yehuda Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Mental Health Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, United States; Department of Neu- roscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States

CONTRIBUTORS xiii

About the editor

Prof. Alon Chen is President-Elect of the Weizmann Institute of Science and will begin his term on December 1, 2019. He was Head of the Department of Neurobiology from 2016 to 19. He is also a Director and Scientific Member at the Max Planck Institute of Psychiatry, Munich, Germany, and serves as the Head of the Max Planck SocietydWeizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. He is an adjunct professor at the Medical School of the Ludwig Maximilian University, Munich.

Prof. Chen received a BSc in Biological Studies, with distinction,
from Ben-Gurion University in 1995, and a PhD from the Weiz-
mann Institute of Science in 2001 (Direct PhD Program, with
distinction). During his PhD studies, Prof. Chen also received an
MBA from Ben-Gurion University. He was a postdoctoral fellow at
the Salk Institute for Biological Studies in California, where he started researching stress. In 2005, he joined the faculty of the Weizmann Institute, in the Department of Neurobiology. At the Weizmann Institute, he is the incumbent of the Vera and John Schwartz Family Profes- sorial Chair.

Prof. Chen’s research focuses on the neurobiology of stress, particularly the mechanisms by which the brain regulates the response to stressful challenges and how this response is linked to psychiatric disorders. The collective long-term goal of his research is to elucidate the pathways and mechanisms by which stressors are perceived, processed, and transduced into neuroendocrine and behavioral responses under healthy and pathological conditions.

His laboratory has made significant discoveries in this field, including fundamental as- pects of the organism’s stress response and actions that link specific stress-related genes, epigenetic mechanisms, and brain circuits with anxiety disorders, depression, eating disor- ders, and the metabolic syndrome. Prof. Chen and his team use both genetic mouse models and human patients to ultimately create the scientific groundwork for therapeutic in- terventions to treat stress-related behavioral and physiological disorders.

Prof. Chen is known for his excellent communication and interpersonal skills, strong leadership aptitude, and the ability to identify opportunities and to convert challenges into innovative solutions.

  

xv

“It is not stress that kills us, it is our reaction to it.” Hans Selye (1907e1982)

Given that exposure to stressful life ex- periences is often unavoidable, understand- ing what makes individuals resilient to stress and how resilience can be built is of great interest and constitutes an integral part of preventive and therapeutic efforts. Since pro- resilient molecular and cellular mechanisms can counteract the deleterious effects of stressful challenges or trauma, a better un- derstanding of resilience promoting factors and processes, as well as inter-individual differences in resilience is needed. Conse- quently, this understanding could pave the way for new clinical interventions for stress- related psychopathologies including anxiety, depression and post-traumatic stress disor- der (PTSD).

To date, the field of stress neurobiology has largely recognized stress resilience as simply the absence of any psychopathology after an extremely stressful event or chronic stress exposure. This book aims to provide a broader and comprehensive overview of stress resilience and presents it rather as a highly complex process of effective and adaptive coping to diverse stressful or trau- matic stimuli; a continuum of adjustable physiological and behavioral changes that shows a large inter-individual variation and can change over time. World-leading scien- tists and psychiatrists, working in the newly emerging field of stress resilience, present and discuss the diverse biological and envi- ronmental factors that shape and determine

an individual’s response to stressful stimuli, manifested with a susceptible or resilient outcome.

Both humans and animals show notable variability in their responses to stressful challenges. In some individuals, a major acute insult or chronic stressor triggers abnormal behavioral and physiological re- sponses and precipitates the onset of psy- chiatric disease, while in most others, the same stressors have little to no effect. This phenomenon of individual resistance to stressors has been broadly termed stress resilience. Commonly, stress resilience, which is essential for good health and well- being, refers to the individual’s ability to retain a set of adaptive characteristics that enable coping and recovery from stressful challenges or trauma or even enable one to thrive as result of this process.

The collective and pivotal aim of the or- ganism’s response to stressors is the main- tenance of homeostasis in the presence of real or perceived challenges. This process requires numerous adaptive responses involving changes in the central nervous and neuroendocrine systems. When a situation is perceived as stressful, the brain activates many neuronal circuits, linking centers involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand posed by the threat. However, the details of the pathways by which the brain translates stressful stimuli into the final, integrated biological response are only partially

Preface

 

xvii

xviii PREFACE

understood. Nevertheless, there is extensive evidence showing that inappropriate regu- lation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and path- ophysiology of an array of physiological and behavioral disorders. Previously, most research focused on understanding what positions an individual at greater risk for developing stress-related disorders, but more recently the focus has shifted to those individuals who do not develop significant psychopathology following stress, and who are typically referred to as being resilient.

In several animal models and in human studies, resilience is associated with rapid activation of the stress response and its effi- cient termination. It is further characterized by the capacity to constrain stress-induced increases in corticotropin-releasing factor (CRF) and cortisol through an elaborate negative feedback system. Stress mediators, such as noradrenaline, the CRF family of neuropeptides, endocannabinoids or corti- costerone/cortisol, are of obvious signifi- cance for understanding the mechanism of resilience. A proper balance in signaling cascades that regulate physiological re- sponses and behavioral adaptation to a stressor is key in understanding the mecha- nisms of resilience. Thus, for optimal resil- ience, the sympathetic and parasympathetic nervous system, the pro- and anti- inflammatory cytokines, and the activating and inhibiting arms of the hypothalamic- pituitary-adrenal (HPA) axis need to be in balance.

Resilience may be demonstrated by resis- tance to the negative effects of stressful challenges or by recovery to a normal state of functioning more quickly than expected following a stressful event. As such, it is important to distinguish between resistance to, and recovery from, stressful events, as these outcomes may involve distinct brain

regions, neurochemical processes, and unique biomarkers.

Some consider stress resilience to be a pre- existing personality trait, independent of risk exposure. Trait characteristics and assess- ments suggest that cognitive capabilities, personality, and neurobiological factors work alongside environmental factors to make certain individuals more or less resil- ient. Experiences that are emotionally stress- ful but not traumatic promote coping and build resilience since they are known to enhance learning and memory mechanisms, and can be used in therapeutic settings to foster recovery and resilience. Thus, rather than just a lack of significant psychological symptoms, we can also define resilience by the specific mechanisms that help to reduce one’s risk of developing such symptoms. For example, while there is no single genetic marker that predicts the development of PTSD following trauma, there do appear to be biological markers, mechanisms, and pro- cesses that help buffer the effects of trauma.

The unique characteristics of resilient in- dividuals have gained substantial interest in recent years, and growing efforts in animal models have attempted to unravel the mo- lecular and cellular mechanisms that under- lie this phenomenon. These animal studies have identified changes in several molecules, pathways and circuits, which involve mul- tiple brain regions. While some molecular pathways identified in resilience overlap with those regulated in the opposite direc- tion in stress susceptibility, others are unique to stress-resilient individuals. Again, this suggests that the molecular and cellular basis of resilience is not merely the absence of susceptibility, but rather active and adaptive processes, with genetic, epigenetic, tran- scriptional, cellular and circuit ebased mechanisms playing important roles in mediating the behavioral and physiological response to stressful challenges.

In addition to the neurobiological factors associated with resilience, psychosocial fac- tors are thought to play a critical role. These factors comprise cognitive and behavioral traits such as optimism, cognitive flexibility, active coping skills, social support networks, physical activity, and a personal moral com- pass. Resilience promoting factors include having caring and supportive relationships, good communication and problem-solving skills, and the ability to manage strong feel- ings and impulses.

The mechanisms underlying resilience may be primed early on in life by the inter- play of environmental factors, including the quality of care-giving and the degree of adversity experienced, together with genetic factors that impact the regulation of the stress response, which in turn may influence the development of brain circuits relevant for emotion regulation.

Stress habituation, which involves prior exposure to manageable stressors, reduces the behavioral and physiological responses to later stressors. Prior exposure to stressors increases the sense of control of stressful situations, and through desensitization re- duces the amount of negative emotions experienced when confronted with these situations again, i.e., it teaches one how to respond to stressors more effectively.

A predisposition to emotional and cogni- tive disorders originates early in life. The concepts of gene-environment interactions, and the importance of early-life experience for later resilience or vulnerability, have been demonstrated in both animal models and human populations. Early-life experience can modulate vulnerability vs. resilience to emotional and cognitive disorders in adult- hood. This suggests that early-life is a particularly sensitive period, during which beneficial or adverse events can cause a later propensity towards stress resilience or vulnerability. Most early-life experiences are

generated from signals received from the primary caregiver, and perturbations in these signals can program stress-related be- haviors. These caregiver signals cause lasting changes in brain circuitry and function, including in networks associated with learning and memory, and with emotional and stress responses. Underlying these changes in brain circuits are transcriptional and epigenetic mechanisms. These molecular changes set in motion a signaling cascade that can determine an individual’s resilience or vulnerability to stress later on in life.

The interaction of genetic factors with environmental stressors shapes the devel- oping brain towards susceptibility or resil- ience. By studying gene-environment interactions, we can gain understanding of resilience mechanisms and information on relevant molecular and cellular mechanisms, brain circuits and behavioral strategies. A detailed map of gene-environment in- teractions in large longitudinal cohorts with repeated biological, neuroimaging, behav- ioral and symptomatic measures may allow us to dissect mechanisms of resilience at different developmental stages or even across generations and suggest strategies for enhancing resilience.

From studies in animal models, a wide range of molecular and cellular changes have been associated with stress resilience. In particular, studies have identified resilient- specific changes at the levels of RNA, pro- tein, chromatin, and DNA, all of which can have an impact on neuronal function and affect circuit-level interactions within the brain. Many studies of resilience to date have examined effects on candidate genes or mo- lecular pathways known to be perturbed in stress-susceptible animals or in humans with depression. However, an increasing number of studies are the result of unbiased genome- wide profiling approaches. Such approaches, when combined with advanced systems

PREFACE xix

xx PREFACE

biology and bioinformatics analysis, have the potential to reveal novel regulators of stress resilience. For these cases, in vivo validation is essential to provide causal evi- dence that a given target molecule is indeed pro-resilient.

In this book, we also touch on the growing evidence of the interplay between the peripheral system and the brain in the context of stress resilience. We suggest po- tential mechanisms and treatment ap- proaches for stress-related disorders, which extend beyond the brain, and therefore our focus should not be limited to targeting CNS mechanisms.

Another important aspect of resilience is the role that sex plays, as many psychiatric disorders are both linked to exposure to stressful life events and are sex-biased in symptomology or prevalence. There are profound sex differences in stress-induced psychiatric disorders, with females being more likely than males to develop these diseases. However, most of the mechanistic studies to date have focused exclusively on males. Sex is a key factor in determining when an individual might be vulnerable to stress, what type of stress is likely to produce long-term negative consequences, and in which behavioral domains the stress- induced dysfunction will manifest.

Although the last decade has been very fruitful in terms of elaborating the molecular and cellular changes that define stress resil- ience, additional mechanistic studies are still greatly needed. The molecular basis of stress resilience is complex, with numerous brain regions and enumerable molecular, biochemical and cellular mediators involved. Although resilience appears to restore control-like behavior, multiple studies point

to active processes occurring at the molecu- lar and cellular levels, which compensate for, bypass, or overcome the harmful effects of stressors. Delineating the complex in- teractions between the genetic, epigenetic, and environmental factors promoting stress resilience is essential for understanding this complex phenomenon, and will allow the development of preventative therapeutic approaches that aim to enhance, build or train resilience in at-risk populations.

As outlined and discussed throughout the book, stress resilience is a highly complex process of adaptive coping to diverse stressful or traumatic stimuli; it is a contin- uum of physiological and behavioral modi- fications that shows large inter-individual variation and can change over time. Considering the frequency and range of stressors and traumatic experiences humans can face, it is essential to recognize the fac- tors that contribute to resilience versus other outcomes, including the emergence of psy- chiatric disorders. Understanding these fac- tors will help us to promote resilience in individuals before they encounter stress or trauma, and can inform us on the best treatment for individuals facing stress or struggling with trauma. This book aims to describe this complex phenomenon and present the latest knowledge on the molec- ular and behavioral aspects of stress resilience.

Alon Chen, Vera and John Schwartz Family Professorial Chair Weizmann Institute of Science, Rehovot, Israel and Max Planck Institute of Psychiatry, Munich, Germany

Acknowledgments

I would like to profoundly thank my colleagues in the field of stress research who selflessly agreed to contribute to this book and without whom this book would not have been possible. Many thanks go to Jessica Keverne for her support in editing. I would also like to thank the graphic design team at the Weizmann Institute of Science, especially Tali Wiesel for the cover image and Ishai Sher, Genia Brodsky and Keren Katzav for their dedicated work on refor- matting the chapter figures. Finally, my thanks go to the team at Elsevier for bringing the book from a concept into print.

 

xxi

CHAPTER

1

A life-course, epigenetic perspective

on resilience in brain and body

Bruce S. McEwen

Alfred E. Mirsky Professor Head, Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, United States

Introduction

Resilience can be defined as “the ability to achieve a successful outcome in the face of adversity.” Understanding what this means in biological terms requires an understanding of “epigenetics,” as it is now applied to gene-environment interactions as well as the realiza- tion that the brain and body are continually changing as the life course proceeds and that one cannot simply “roll back the clock.” Moreover, positive and negative events during the life course, including events before conception and during gestation, can have long-term effects. Furthermore, the plasticity of the adult as well as developing brain provides the ability of experiences to change trajectories in a positive or negative direction. The mediators of this plasticity include not only endogenous neurotransmitters and neuromodulators but also mechanisms involving the cell surface, the cell nucleus, and mitochondria, along with circu- lating steroid and metabolic hormones. Two-way interactions between brain and body are of paramount significance, and the concepts of allostasis and allostatic load emphasize that the same mediators that promote adaptation in a biphasic and nonlinear manner can also promote pathophysiology when they are overused or dysregulated among themselves.

We begin by considering the meaning of “stress” and the concepts of allostasis and allo- static load before introducing brain adaptive plasticity and epigenetics and how they produce adaptive as well as maladaptive plasticity. Studies of gene expression show that the brain is continually changing and that one cannot “roll back the clock.” Moreover, experiences can have lasting positive influences as in successful attachment or lasting negative influences as in early life abuse and neglect or traumatic events that cause PTSD. This raises the issue of interventions where we now must refer to “resilience” rather than “reversal” in describing what appears to be “recovery” and must therefore think about the process as a “redirection” of a trajectory in more positive direction.

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00001-X 1 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

2 1. A life-course, epigenetic perspective on resilience in brain and body What is stress?

“Stress” is a widely used and ambiguous word and so this chapter will use the following classifications of types of stress: good stress, tolerable stress, and toxic stress.

See http://developingchild.harvard.edu/library/reports_and_working_papers/policy_ framework/ for paper related to toxic stress.

“Good stress” is a term used in popular language to refer to the experience of rising to a challenge, taking a risk, and feeling rewarded by an often-positive outcome. A related term is “eustress.” Good self-esteem and good impulse control and decision-making capability, all functions of a healthy architecture of the brain, are important here! Even adverse outcomes can be “growth experiences” for individuals with such positive, adaptive characteristics that promote resilience in the face of adversity.

“Tolerable stress” refers to those situations where bad things happen, but the individual with healthy brain architecture is able to cope, often with the aid of family, friends, and other individuals who provide support. These adverse outcomes can be “growth experiences” for individuals with such positive, adaptive characteristics and support systems that promote resilience. Here, “distress” refers to the uncomfortable feeling related to the nature of the stressor and the degree to which the individual feels a lack of ability to influence or control the stressor (Lazarus and Folkman, 1984; Diez Roux and Mair, 2010; Theall et al., 2013).

Finally, “toxic stress” refers to the situation in which bad things happen to an individual who has limited support and who may also have brain architecture that reflects effects of adverse early life events that have impaired the development of good impulse control and judgment and adequate self-esteem. Here, the degree and/or duration of “distress” may be greater. With toxic stress, the inability to cope is likely to have adverse effects on behavior and physiology, and this will result in a higher degree of allostatic overload, as will be explained later in this chapter.

Definition of stress, allostasis, and allostatic load

In spite of the further definitions of types of stress, the word “stress” is still an ambiguous term and has connotations that make it less useful in understanding how the body handles events that are stressful. Insight into these processes can lead to a better understanding of how best to intervene, a topic that will be discussed at the end of this chapter. There are two sides to this story: on the one hand, the body responds to almost any event or challenge, whether or not we call it “stress,” by releasing chemical mediatorsdfor example, catecholamines that increase heart rate and blood pressuredand helps us cope with the situation; on the other hand, chronic elevation of these same mediatorsdfor example, chron- ically increased heart rate and blood pressuredproduces a chronic wear and tear on the cardiovascular system that can result, over time, in disorders such as strokes and heart attacks. For this reason, the term “allostasis” was introduced by Sterling and Eyer in 1988 to refer to the active process by which the body responds to daily events and maintains homeostasis (allostasis literally means “achieving stability through change”). Since chronically increased allostasis can lead to disease, we introduced the term “allostatic load or overload” to refer to the wear and tear that results from either too much stress or the

 

 

Protection and damage as the two sides of the response to experiences 3

FIGURE 1.1 Central role of the brain in allostasis and the behavioral and physiological response to stressors. Modified from McEwen, B.S. 1998. Protective and damaging effects of stress mediators. The New England Journal of Medicine 338, 171e179, with permission.

inefficient management of allostasis, for example, not turning off the response when it is no longer needed. Other forms of allostatic load involve not turning on an adequate response in the first place or not habituating to the recurrence of the same stressor and thus dampening the allostatic response (McEwen, 1998). See Fig. 1.1.

Protection and damage as the two sides of the response to experiences

Protection via allostasis and wear and tear on the body and brain via allostatic load/over- load are the two contrasting sides of the physiology involved in defending the body against the challenges of daily life. Besides adrenalin and noradrenalin, there are many mediators that participate in allostasis, and they are linked together in a network of regulation that is nonlinear, meaning that each mediator has the ability to regulate the activity of the other mediators, sometimes in a biphasic manner (McEwen, 2006). Glucocorticoid produced by the adrenal cortex in response to ACTH from the pituitary gland is the other major “stress hormone.” Pro- and antiinflammatory cytokines are produced by many cells in the body, and they regulate each other and are, in turn, regulated by glucocorticoids and cate- cholamines. Whereas catecholamines can increase proinflammatory cytokine production, glucocorticoids are known to inhibit this production. And yet, there are exceptionsd proinflammatory effects of glucocorticoids that depend on dose and cell or tissue type (Dinkel et al., 2003; Frank et al., 2012). The parasympathetic nervous system also plays an important regulatory role in this nonlinear network of allostasis, as it generally opposes

 

4 1. A life-course, epigenetic perspective on resilience in brain and body

the sympathetic nervous system and, for example, slows the heart and also has antiinflam- matory effects (Borovikova et al., 2000; Sloan et al., 2007).

What this nonlinearity and interaction among mediators means is that when any one mediator is increased or decreased, there are compensatory changes in the other mediators that depend on time course and level of change of each of the mediators. Unfortunately, we cannot measure all components of this system simultaneously, and we must, therefore, rely on measurements of only a few of them in any one study. Yet the nonlinearity must be kept in mind in interpreting the results.

A good example of the biphasic actions of stress, that is, “protection versus damage,” is in the immune system, in which an acute stressor activates an acquired immune response via mediation by catecholamines and glucocorticoids and locally produced immune mediators; yet, a chronic exposure to the same stressor over several weeks has the opposite effect and results in immune suppression (Dhabhar, 2009; Dhabhar et al., 2012). Acute stresseinduced immune enhancement is good for enhancing immunization, fighting an infection, or repair- ing a wound, but it is deleterious to health for an autoimmune condition such as psoriasis or Krohn’s disease. On the other hand, immune suppression is good in the case of an auto- immune disorder and deleterious for fighting an infection or repairing a wound. In an immune sensitive skin cancer, acute stress is effective in inhibiting tumor progression, whereas chronic stress exacerbates progression (Dhabhar et al., 2010; Saul et al., 2005).

Other experiences such as loneliness and social isolation (Cacioppo et al., 2011) or living in an ugly, noisy, or chaotic environment (Evans and Wachs, 2010) alter these same mediators and can lead to allostatic load and overload (Evans et al., 2007) (see Table 1.1). The same applies to poor or inadequate sleep and circadian disruption as in jet lag and shift work (McEwen and Karatsoreos, 2015). Other health-damaging behaviors also contribute to allostatic load/overload, including smoking, alcohol in excess, diet and amount of food, and lack of physical activity (Seeman et al., 2010).

Finally, because the mediators of allostasis and allostatic load/overload affect virtually the whole body at the same time, it should not be surprising that there is poly- or multimorbidity

TABLE 1.1 Conditions/experiences that “get under the skin” and dysregulate physiology.

All have effects whether or not called “stress” Loneliness
Lack of social support
Circadian disruption: jet lag, shift work

Ugly, noise, polluted neighborhood; lack of green space

Health behaviors

Lack of physical activity
Diet: quality and quantity of food Sleep
Alcohol
Smoking

    

 

Brain as the central organ of allostasis and allostatic load/overload 5

of diseases and disorders (Tomasdottir et al., 2015). For example, the association of diabetes and insulin resistance with depression and increased risk for dementia points to a common pathophysiology in which inflammation and glutamatergic hyperactivity play a key role (Rasgon and McEwen, 2016).

Brain as the central organ of allostasis and allostatic load/overload Plasticity and vulnerability of the hippocampus

The hippocampus was the first higher brain center that was recognized as a target of adrenal steroids (McEwen et al., 1968), and it has figured prominently as a gateway to our understanding of how stress impacts neural architecture and behavior in adult as well as developing brains. The hippocampus expresses both type I mineralocorticoid (MR) and type II glucocorticoid (GR) receptors (Reul and DeKloet, 1985), and these receptors mediate a biphasic response to adrenal steroids in the CA1 region, although only facilitation in the dentate gyrus (Joels, 2006). Yet, the hippocampus, nevertheless, shows a diminished excitability in the absence of adrenal steroids (Margineanu et al., 1994). Other brain regions, such as the paraventricular nucleus, lacking in MR but having GR, show a monophasic nega- tive response to increasing glucocorticoid levels (Joels, 2006). Adrenal steroids exert biphasic effects on excitability of hippocampal neurons in terms of long-term potentiation and primed burst potentiation (Diamond et al., 1992; Pavlides et al., 1994, 1995a,b) and show parallel biphasic effects on memory (Pugh et al., 1997; Okuda et al., 2004).

A form of structural plasticity is the remodeling of dendrites in the hippocampus, as well as in the amygdala and prefrontal cortex (McEwen and Gianaros, 2011). In hippocampus, chronic restraint stress (CRS), daily for 21 days, causes retraction and simplification of dendrites in the CA3 region of the hippocampus (McEwen, 1999; Sousa et al., 2000). Such dendritic reorganization is found in both dominant and subordinate rats undergoing adaptation to psychosocial stress in the visible burrow system, and it is independent of adrenal size (McKittrick et al., 2000). It also occurs in psychosocial stress in intruder tree shrews in a residentdintruder paradigm, with a time course of 28 days (Magarinos et al., 1996), a procedure that does not cause a loss of pyramidal neurons in the hippocampus (Vollmann-Honsdorf et al., 1997).

The mossy fiber input to the CA3 region in the stratum lucidum appears to drive the den- dritic remodeling, leading to the retraction of the apical dendrites above this input (McEwen, 1999). Moreover, the thorny excrescence giant spines, on which the mossy fiber terminals form their synapses, show stress-induced modifications (Stewart et al., 2005). And the number of active synaptic zones between thorny excrescences and mossy fiber terminals is rapidly modulated during hibernation and recovery from the hibernating state (Magarinos et al., 2006). The thorny excrescences are not the only spines affected by CRS. Dendritic spines also show remodeling, with increased spine density reported after CRS on apical dendrites of CA3 neurons (Sunanda Rao and Raju, 1995) and decreased spine density reported for CA1 pyramidal neurons (Magarinos et al., 2010). Indeed the entire mossy fiber-thorny excrescence complex decreases in volume with stress and increases in volume with environmental enrichment (Stewart et al., 2005).

 

6 1. A life-course, epigenetic perspective on resilience in brain and body
TABLE 1.2 Cell surface and nucleocytoplasmic interaction that are necessary/permissive for remodeling.

PSA-NCAMdcell surface “antistickiness” (Sandi, Rutishauser, McCall, Weil) Endonuclease N removes PSA from NCAM; dendrite expansion
Facilitate plasticity but also limits it
Cell adhesion molecules: neuroligin-2; nectin-3 (van der Kooij, Sandi) Chronic stress disrupts neuroligin-neurexin interaction

Chronic stress reduces nectin-3 via MMP9 protease

Nuclear pore complex NUP-62 (Kinoshita . Kohtz) Reduction leads to dendrite shrinkage
Possibly due to nuclear cytoplasmic communication

Exploration of the underlying mechanism for this remodeling of dendrites and synapses reveals that it is not adrenal size nor presumed amount of physiological stress per se that determines dendritic remodeling, but rather a complex set of other factors that modulate neuronal structure (McEwen, 1999). Indeed, after repeated stress, dendritic remodeling recovers (Conrad et al., 1999), and in species of mammals that hibernate, dendritic remodel- ing is a reversible process and occurs within hours of the onset of hibernation in European hamsters and ground squirrels, and it is also reversible within hours of wakening of the animals from torpor (Magarinos et al., 2006; Popov and Bocharova, 1992; Popov et al., 1992; Arendt et al., 2003). Along with data on posttranslational modification of cytoskeletal proteins (Table 1.2), this implies that reorganization of the cytoskeleton is taking place rapidly and reversibly (Arendt et al., 2003) and that changes in dendrite length and branching are not damage but a form of adaptive structural plasticity.

Cellular processes involved in structural plasticity

The neuronal surface, cytoskeleton, and nuclear envelope are each implicated in the mech- anisms of stress-induced retraction and expansion of dendrites and synapse turnover. The polysialylated form of neural cell adhesion molecule (PSA-NCAM) is expressed in the CA3 and DG region of the hippocampus and is believed to denote the capacity for adaptive structural plasticity in many parts of the CNS (Seki and Arai, 1999; Rutishauser, 2008; Theodosis et al., 1999). Repeated stress causes retraction of CA3 hippocampal dendrites accompanied by a modest increase in PSA-NCAM expression, possibly the result of gluco- corticoid mediation (Pham et al., 2003). Using EndoN to remove PSA from NCAM, Sandi (2004) reported impairment of consolidation of contextual fear conditioning. Using the same treatment, we reported considerable expansion of the dendritic tree in both CA3 and CA1 and a marked increase in excitotoxicity and damage to CA3 neurons; repeated stress still caused some dendrite retraction after PSA removal (McCall et al., 2013). Thus, although PSA-NCAM is a facilitator of plasticity, the PSA moiety appears to also limit the extent of dendritic growth and yet is not necessary for dendritic retraction under stress (see Table 1.2).

      

 

Brain as the central organ of allostasis and allostatic load/overload 7

Two other classes of cell adhesion molecules are reported to change with chronic stress, with behavioral consequences. Neuroligins (NLGNs) are important for proper synaptic formation and functioning and are critical regulators of the balance between neural excitation/inhibition (E/I), and CRS reduced hippocampal NLGN-2 levels, in association with reduced sociability and increased aggression (van der Kooij et al., 2014a; Wood et al., 2003). This occurred along with a reduction of NLGN-2 expression throughout the hippo- campus, detectable in different layers of the CA1, CA3, and DG subfields. Intrahippocampal administration of neurolide-2 that interferes with the interaction between NLGN-2 and neurexin led to reduced sociability and increased aggression, thus mimicking effects of chronic stress (van der Kooij et al., 2014a).

CRS also increases activity of matrix metalloproteinase-9 (MMP-9) in the CA1. MMP-9 carries out proteolytic processing of another cell adhesion molecule, nectin-3. Chronic stress reduced nectin-3 in the perisynaptic CA1, but not in the CA3, with consequences for social exploration, social recognition, and a CA1-dependent cognitive task. Implicated in this is a stress-related increase in extracellular glutamate and NMDA receptor mediation of MMP-9 (van der Kooij et al., 2014b). These findings are reminiscent of the CA1-specific effects of tissue plasminogen activator, mediating stress effects on spine density in CA1 (Pawlak et al., 2005) (see Table 1.2).

Actin polymerization plays a key role in filopodial extension and spine synapse formation as well as plasticity within the synapse itself (Matus et al., 2000), and cytoskeletal remodeling is an important factor in the effects of stress and other environmental manipulations. Hiber- nation in European hamsters and ground squirrels results in rapid retraction of dendrites of CA3 pyramidal neurons and equally rapid expansion when hibernation torpor is reversed (Magarinos et al., 2006; Popov et al., 1992). The retraction of dendrites is accompanied by increases in a soluble phosphorylated form of tau that may indicate disruption of the cyto- skeleton, which permits the dendrite shortening and possible protection from excitotoxicity; at the same time, PSA-NCAM expression is lost during hibernation torpor reducing the capacity for plasticity (Arendt et al., 2003). This model highlights the important role that tau plays in normal cytoskeletal function, a fact that should be emphasized when attempting to understand its role in pathology (Morris et al., 2011) (see Table 1.2).

Even though dendrite retraction and regrowth would appear to involve a reversible depolymerization and repolymerization of the cytoskeleton, there are other processes that point to the importance of nuclear factors. A recent example is the unexpected role of a cell nuclear pore complex protein, NUP-62, in the stress-induced dendritic remodeling in the CA3 region of hippocampus (Kinoshita et al., 2014). First identified as a gene that was downregulated in the prefrontal cortex of depressed patients (Tochigi et al., 2008), NUP-62 was also found to be reduced in response to chronic stress in CA3 neurons of rodents (Kinoshita et al., 2014). Importantly, the levels of other nuclear pore complex genes were unchanged with chronic stress, supporting the specificity of its role in stress remodeling. Subsequent in vitro studies confirmed that the downregulation of NUP-62 is associated with dendritic retraction, and this effect is regulated at the molecular level by NUP-62 phosphorylation at a PYK2 site, which results in its retention in the cytoplasm (Kinoshita et al., 2014). A role of NUP-62 in maintaining chromatin structure for tran- scription is suggested as well as in nucleocytoplasmic transport (Kinoshita et al., 2014) (see Table 1.2).

 

8 1. A life-course, epigenetic perspective on resilience in brain and body Extension of stress effects to amygdala and prefrontal cortex

Besides the hippocampus, the amygdala and prefrontal cortex are targets of stress and display structural plasticity after both acute and chronic stress. Neurons in the basolateral amygdala (BLA) expand dendrites after chronic immobilization stress and increase spine density (Vyas et al., 2002), whereas neurons in medial amygdala show reduced spine density after chronic stress (Bennur et al., 2007). The latter changes are dependent on tissue plasmin- ogen activator released by CRF (Matys et al., 2004), based on a tPA-ko mouse, whereas stress effects in BLA are not so dependent (Bennur et al., 2007). These stress-induced changes are accompanied by increases in anxiety-like behavior (Vyas et al., 2002; Pawlak et al., 2003) and suggest that stress causes a reorganization and dysfunction of circuits within the amygdala. Indeed, the medial amygdala is quite different and shows not only spine loss but also dendrite retraction after CRS, and this may underlie impaired social interactions of chronically stressed animals (Lau et al., 2017).

Glucocorticoids and excitatory amino acids are involved in the mechanism for dendritic expansion in the BLA with chronic stress, along with BDNF (Lakshminarasimhan and Chattarji, 2012; McEwen and Chattarji, 2007) and, indeed, a single bolus of corticosterone mimics the effects of 10 days of chronic immobilization to cause BLA dendrite expansion (Mitra and Sapolsky, 2008). Overexpression of BDNF in mice increases dendritic length in both CA3 and BLA and occludes the effects of chronic stress to decrease dendritic branching in CA3 and increase it in BLA (Govindarajan et al., 2006). Without such overexpression, chronic stress causes a downregulation of BDNF in CA3 hippocampus and an upregulation of BDNF in the BLA, and the effect in BLA persists 21 days poststress, whereas that in CA3 has normalized (Lakshminarasimhan and Chattarji, 2012); moreover, acute stress with a 10- day delay, which causes BLA to develop increased anxiety and increased density of spines in BLA neurons (Mitra et al., 2005), caused BDNF expression to rise and stay elevated for 10 days, whereas that in CA3 fell after acute stress but did so only transiently (Lakshminar- asimhan and Chattarji, 2012). Corticosterone levels increased after both acute and chronic stress and remained elevated after chronic, but not after acute stress.

Although some of the immediate consequences of stressdelevated glucocorticoids and glutamatedare similar in amygdala and hippocampus, they lead to contrasting patterns of BDNF expression and structural plasticity (see Table 1.3). This implies that signaling mechanisms more downstream of the initial changes in glucocorticoids and glutamate, but upstream of BDNF, may hold the key to the differential impact of stress in these brain areas. Importantly, BDNF infusion into the hippocampus of stressed rodents helped to protect against the deleterious effects of stress despite high levels of circulating corticosterone. This suggests that BDNF could be a final point of convergence for the stress-induced effects in the hippocampus. BDNF-mediated signaling is involved in stress response, but the direction and nature of signaling is region specific and stress specific and is influenced by epigenetic modifications along with posttranslational modifications (Gray et al., 2013; Lakshminarasimhan and Chattarji, 2012).

Concurrently, with changes in the amygdala, neurons in the medial prefrontal cortex show reversible dendritic shrinkage after chronic stress (Radley et al., 2004, 2005), with spine loss (Radley et al., 2008), that can be inhibited by blocking NMDA receptors (Martin and Wellman, 2011), similar to stress-induced atrophy of neurons in the CA3 hippocampus (see above).

 

Brain as the central organ of allostasis and allostatic load/overload 9 TABLE 1.3 Secreted signaling molecules that are necessary/permissive for remodeling.

BDNF – Brain-derived neurotrophic factor (Francis Lee, Shona Chattarji) – Facilitator of plasticity or growth; floor and ceiling

CRF – Corticotropin-releasing factor (Tallie Baram and colleagues) – Downregulates thin spines via RhoA signaling

tPA – Tissue plasminogen activator (Sid Strickland, Robert Pawlak, Tomas Matys) – Required for stress-induced spine loss in CA1 hippocampus and medial amygdala – CRF regulates tPA release

Lipocalin-2 – Secreted protein (Robert Pawlak) – Acute stress induces lipocalin-2 – Lipocalin-2 ko increases neuronal excitability and anxiety

Endocannabinoids (Hill, Holmes, Hillard, Gorzalka) – Induced via glucocorticoids – Regulate emotionality and HPA habituation and shut off – Buffer against stress induced remodeling

This chronic stresseinduced atrophy is associated with deficits in executive function and cogni- tive flexibility (Liston et al., 2006; Dias-Ferreira et al., 2009), and the stressors that cause this to happen also include circadian disruption (Karatsoreos et al., 2011). Although medial prefrontal cortical neurons show atrophy with chronic stress, neurons in the orbitofrontal cortex show hypertrophy (Liston et al., 2006) similar to what happens in the BLA (Vyas et al., 2002). The consequences of these changes are increased anxiety and increased vigilance, both adaptive traits in a dangerous environment.

Other mediators of structural plasticity

In addition to glucocorticoids, excitatory amino acids, BDNF, and tPA, other secreted signaling molecules play an important role in the remodeling of neural tissue during stress (see Table 1.3). Corticotropin-releasing factor (CRF), which is better known for its role in governing secretion of ACTH and glucocorticoids, plays a key role in stress-induced dendritic remodeling in the CA1 region of the hippocampus (Pawlak et al., 2005; Chen et al., 2006). Linking CRF with tPA discussed above, there is evidence that in the amygdala tPA release is stimulated by CRF (Matys et al., 2004). Similarly, lipocalin-2 is a novel modulator of spine plasticity with different effects in amygdala and hippocampus (Mucha et al., 2011; Skrzypiec et al., 2013). Acute stress increases lipocalin-2 levels, and lipocalin-2 downregulates mush- room spines and generally inhibits actin motility in hippocampus. Remarkably, deletion of lipocalin-2 increases neuronal excitability and anxiety, and, in amygdala, the absence of lipocalin-2 increases the basal number of spines and prevents a stress-induced increase in spine density (Mucha et al., 2011; Skrzypiec et al., 2013).

Endocannabinoids are another class of signaling molecules that importantly regulate mul- tiple aspects of the stress response. In addition to contributing to the termination (Hill et al., 2011a) of the acute response to stress, as well as habituation to repeated stress (Hill et al., 2010), endocannabinoids also appear to be important for the regulation of structural plasticity under conditions of repeated stress. For example, cannabinoid 1 (CB1) receptoredeficient

 

 

10 1. A life-course, epigenetic perspective on resilience in brain and body

mice exhibit reductions in prefrontal cortical dendritic length and complexity, while having enhanced and more complex dendritic arbors within the BLA, which parallels the effects of chronic stress (Lee et al., 2014; Hill et al., 2011b). More importantly, chronic stress and corti- costerone treatment are both known to impair endocannabinoid signaling at multiple levels, through both a downregulation of the CB1 receptor (Hill et al., 2005) and a reduction in the levels of the endocannabinoid, anandamide, mediated by an increase in its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) (Hill et al., 2013; Bowles et al., 2012).

Given the parallels between genetic deletion of the CB1 receptor and the ability of chronic stress to impair endocannabinoid signaling, it is interesting to note that elevating ananda- mide/CB1 receptor signaling, through genetic or pharmacological impairment of FAAH, retards the ability of chronic stress to produce dendritic hypertrophy in the BLA as well as concomitant changes in emotional behavior (Hill et al., 2013; Lomazzo et al., 2015; Bortolato et al., 2007; Rossi et al., 2010; Gunduz-Cinar et al., 2013). Collectively, these data indicate that endocannabinoid signaling buffers against many of the effects of stress and appears to be important for limiting the effects of chronic stress on structural plasticity within these identified limbic circuits. At a mechanistic level, this is likely due to the ability of CB1 receptor signaling to gate glutamatergic release, as it has been shown that CB1 receptoredeficient mice exhibit greater changes in glutamatergic signaling and excitotoxicity within the PFC following chronic stress (Zoppi et al., 2011). Moreover, similar to the protective effects of CB1 receptor activation identified within the amygdala, administration of a CB1 receptor agonist during repeated stress can reduce the increase in glutamatergic signaling, the induc- tion of proinflammatory cytokines, and lipid peroxidation within the PFC (Zoppi et al., 2011). As such, the release of endocannabinoids during stress may temper changes in structural plasticity by limiting the magnitude of glutamate release in response to stress, and under con- ditions of chronic stress, when this system becomes compromised, the loss of this endogenous buffer facilitates excess glutamate release and the ensuing changes in dendritic morphology. Linking this model with the previously described factors, it is interesting to note that in addition to promoting tPA release, CRF has also been found to induce anandamide hydro- lysis by FAAH (Gray et al., 2015), suggesting the possibility that CRF could act as an orchestrator of multiple signaling molecules, all of which converge in structural changes within the brain following chronic stress.

Glucocorticoids as key players in PTSD vulnerability

Recent studies have suggested that blood-based biomarkers may be able to predict aspects of brain signaling associated with trauma-related effects in both males and females, specif- ically with respect to convergence onto GR signaling pathways. After a predator- scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., “PTSD-like”) and resilient (i.e., minimally affected) phenotypes on the basis of their per- formance on a variety of behavioral measures (Daskalakis et al., 2014). Using genome-wide expression profiling in blood, amygdala, and hippocampus, glucocorticoid signaling was the only convergent pathway associated with individual differences in susceptibility.

 

Lessons of an ever-changing brain from gene expression 11

Moreover, corticosterone treatment 1 h after PSS exposure prevented anxiety and hyper- arousal 7 days later in both sexes, consistent with prior findings in the same as well as in another PTSD animal model (Zohar et al., 2011; Rao et al., 2012), confirming GR involvement in sequelae of traumatic stress.

Sex differences

Animal models of stress effects on the brain show that females and males response differently to acute and chronic stressors because of developmental factors involving both epigenetic effects of hormones along with genes in the sex chromosomes themselves (McCarthy and Arnold, 2011). One of the important discoveries of the past several decades is that sex hormones have effects throughout the brain. Indeed, sexually mature female rats do not show dendritic retraction from CRS in hippocampus (Galea et al., 1997) although chronic stress over puberty of immature male and female rats produces qualitatively similar structural plasticity in hippocampus, amygdala, and prefrontal cortex (Eiland et al., 2012). Chronically stressed adult female rats actually show enhanced memory function, whereas chronically stressed males are impaired (Luine, 2002).

Sex differences in the brain are subtle but widespread (McEwen and Milner, 2017) and yet males and females do many things equally well: for example, in human subjects, taking tests on empathy, men and women do equally well, but the brain activation patterns during the tests show different brain regions are activated (Derntl et al., 2010). This is reminiscent of an animal model study in which, despite no overall sex differences in fear conditioning freezing behavior, the neural processes underlying successful or failed extinction maintenance are sex specific (Gruene et al., 2015). Given other work showing sex differences in stress-induced structural plasticity in prefrontal cortex projections to amygdala and other cortical areas (Shansky et al., 2010), these findings are relevant not only to sex differences in fear conditioning and extinction but also, according to Gruene et al., “also to exposure-based clinical therapies, which are similar in premise to fear extinction and which are primarily used to treat disorders that are more common in women than in men” (Gruene et al., 2015).

Lessons of an ever-changing brain from gene expression

The hippocampus has been an important gateway to understanding the effects of gluco- corticoids and stress on gene expression. Recent advances in technology have allowed for high-throughput analysis of gene expression changes in response to stress (Rubin et al., 2014). For example, microarray analysis of whole hippocampus after acute and chronic stress, as well as recovery from stress in mice, has revealed a number of insights surrounding stress-induced neuroplasticity (Gray et al., 2014). Although acute stress and chronic stress modulate a core set of genes, there are numerous expression changes that are exclusive to each condition, highlighting how the duration and intensity of stress alters reactivity.

 

 

12 1. A life-course, epigenetic perspective on resilience in brain and body

Furthermore, corticosterone injections did not yield the same expression profile as acute stress, suggesting that in vivo stressors are able to activate a diverse set of pathways inde- pendent of GR activation. Finally, characterization of expression profiles after an extended recovery from chronic stress (21d) revealed that, despite a normalization of anxiety-related behaviors, recovery did not represent a return to the stress-naïve baseline but rather represented a new state in which reactivity to a novel stressor produced a unique expression profile (Gray et al., 2014). Studies in rats have also confirmed that gene expression profiles can vary significantly from the immediate end of stress (1 h) to 24 h after the end of stress (Wang et al., 2010) and that chronic stress can alter the transcriptional response to an acute corticosterone injection in dentate gyrus (Datson et al., 2013). These studies demonstrate that a history of stress exposure can have a lasting impact on future stress reactivity and hippocampal function. Many of the genes identified as changed after chronic stress by Datson and DeKloet are known epigenetic regulators, providing one possible mechanism underlying the persistent alterations in the expression response beyond the end of stress exposure.

Epigenetics: two meanings that are both important for prevention and treatment

“Epigenetics” now refers to events “above the genome” that regulate expression of genetic information without altering the DNA sequence. Besides the CpG methylation (Szyf et al., 2005), other mechanisms include histone modifications that repress or activate chromatin unfolding (Allfrey, 1970) and the actions of noncoding RNAs (Mehler, 2008), as well as transpo- sons and retrotransposons (Griffiths and Hunter, 2014) and RNA editing (Mehler and Mattick, 2007). Again, the hippocampus is providing important information. For example, Reul and colleagues have shown that the forced swimming-induced behavioral immobility response requires histone H3 phosphoacetylation and c-Fos induction in distinct dentate granule neurons through recruitment of the NMDA/ERK/MSK 1/2 pathway (Chandramohan et al., 2008).

Another histone mark changed in hippocampus, most prominently in the dentate gyrus, is the dramatic induction by an acute restraint stress of trimethylation of lysine 9 on histone H3, which is associated with repression of a number of retrotransposon elements and reduction of the coding and noncoding RNA normally produced by the repressed DNA (Hunter et al., 2009). This repression is lost with repeated stress, suggesting the possibility that those retrotransposon elements may impair genomic stability under conditions of chronic stress (Hunter et al., 2015).

A current practical application is the search for rapidly acting antidepressants because classical antidepressants work very slowly and are not effective on every depressed indi- vidual. Epigenetic processes are likely involved in the chronic relapsing nature of major depression, the strikingly higher incidence of depression in women after puberty, the high discordance rates between monozygotic twins, as well as the individual responsivity to stress that precipitates mood-related behaviors in susceptible individuals. In the course of these studies, we are learning more about epigenetic mechanisms that connect EAA function

 

Individual differences and experiences throughout the life course 13

with neural remodeling and stress-related behavior. The identification of the fast antidepres- sant effects of ketamine, an NMDA receptor blocker, has resulted in a paradigm shift toward the discovery of a new generation of rapidly acting antidepressants (Li et al., 2010).

Recently, our laboratory and other groups have found that the naturally occurring compound acetyl-L-carnitine (LAC) shows fast antidepressant efficacy in genetic and envi- ronmentally induced animal models of depression through the epigenetic modulation of the metabotropic glutamate receptor, mGlu2, in the hippocampus (Nasca et al., 2013; Cuccurazzu et al., 2013). mGlu2 is known to exert an inhibitory tone on glutamate release from synapses, and pharmacological modulators for this receptor are under clinical development to treat stress-related mood disorders, such as anxiety and depression (Nicoletti et al., 2015). Using the same animal models, 14 days of treatment with the tricyclic antidepressant clomipramine were needed to promote antidepressant responses, which disappeared when the treatment was stopped. In contrast, LAC antidepressant effects were still evident after 2 weeks of drug withdrawal (Nasca et al., 2013). The persistent effects of LAC suggested the involvement of stable molecular adaptations that may be reflected at the level of histone modifications in controlling mGlu2 transcription in the hippocampus. Indeed, LAC increases levels of mGlu2 receptors by acetylation of the histone H3K27 among other mechanisms (discussed below).

These findings support previous studies that have shown that histone deacetylase (HDAC) inhibitors, given intraperitoneally, normalize gene expression profiles in vulnerable brain regions, such as hippocampus, amygdala, and nucleus accumbens, to promote fast anti- depressant responses following stress (Covington et al., 2011; Tsankova et al., 2006). The use of agents such as LAC that act on histone remodeling to regulate transcription of the mGlu2 gene offers alternative and complementary strategies to ketamine and HDACs’ inhibitors with safer profiles and lower potential for drug dependence (Nicoletti et al., 2015).

Individual differences and experiences throughout the life course

In the course of this work, we have become aware of individual differences among inbred mice and rats (Cavigelli and McClintock, 2003; Miller et al., 2012; Freund et al., 2013). Using a simple light-dark test to rapidly screen naïve mice (Nasca et al., 2015), we found that a subset of mice shows elevated hippocampal MR levels and that this baseline difference makes those mice with higher MR show greater stress-induced reduction in mGlu2 accompanied by more anxiety and depressive-like behaviors. How MR activation does this is not yet clear, but it activates a mechanism that is opposite to that of LAC, which has been shown to use the acetyltransferase P300 to acetylate lysine 27 on histone H3 (Nasca et al., 2013). Likewise, the nature of the experiences of the animals that develop higher MR is also not yet known but may involve maternal care and stressors in the neonatal nesting environment (Francis et al., 1999). The epigenetic allostasis model points to a developmental origin of individual differences in the responses to stress and implies that unknown early-life epigenetic influences program each individual to different trajectories of behavioral and physiological responses to later stressful life events. In line with this model, previous studies have also associated increased hippocampal MR levels in juvenile animals with anxiety-like behavior in adulthood (Brydges et al., 2014; Korte et al., 1995).

 

14 1. A life-course, epigenetic perspective on resilience in brain and body Early-life experiences

Early-life experiences carry an even greater weight in terms of how an individual reacts to new situations. Early-life physical and sexual abuse carries with it a lifelong burden of behavioral and pathophysiological problems (Felitti et al., 1998). Cold and uncaring families produce long-lasting emotional problems in children (Repetti et al., 2002). Some of these effects are seen on brain structure and function and in the risk for later depression and post- traumatic stress disorder (Shonkoff et al., 2009). One of the biological consequences of early life adversity is the prolonged elevation of inflammatory cytokines as well as poor dental health, obesity, elevated blood pressure in children and young adults (Danese and McEwen, 2012). Harsh language is among the components of early-life adversity and has been shown to increase inflammatory markers (Miller and Chen, 2010).

The physical environment makes a huge difference, with crowding, noise, and ugliness, along with physical danger, which are a major contributor to allostatic overload both during development and throughout adult life (Diez Roux and Mair, 2010; Chang et al., 2009; Evans et al., 2005).

Animal models have been useful in providing insights into behavioral and physiological mechanisms. Individual differences in anxiety-like behaviors are evident (Cavigelli and McClintock, 2003; Nasca et al., 2015). Early-life maternal care in rodents is a powerful deter- minant of lifelong emotional reactivity and stress hormone reactivity, and increases in both are associated with earlier cognitive decline and a shorter life span (Meaney et al., 1991). Effects of early maternal care are transmitted across generations by the subsequent behavior of the female offspring, as they become mothers, and methylation of DNA on key genes appears to play a role in this epigenetic transmission (Francis et al., 1999; Meaney and Szyf, 2005). Yet, the mother is not the sole determinant of offspring emotional and physical development but rather modulates it by her behavior toward the infant, particularly in the immediate aftermath of infant experiences of novelty inside or outside of the home cage (Tang et al., 2014).

Furthermore, in rodents, abuse of the young is associated with an attachment, rather than an avoidance, of the abusive mother, an effect that increases the chances that the infant can continue to obtain food and other support until weaning (Moriceau and Sullivan, 2006). Moreover, other conditions that affect the rearing process can also affect emotionality in offspring. For example, uncertainty in the food supply for rhesus monkey mothers leads to increased emotionality in offspring and possibly an earlier onset of obesity and diabetes (Coplan et al., 2001; Kaufman et al., 2007).

Besides the important role of the social and physical environment and experiences of individuals in the health outcomes, genetic factors also play an important role. Different alleles of commonly occurring genes determine how individuals will respond to experiences. For example, the short form of the serotonin transporter is associated with a number of conditions such as alcoholism, and individuals who have this allele are more vulnerable to respond to stressful experiences by developing depressive illness (Caspi et al., 2003; Spinelli et al., 2012). In childhood, individuals with an allele of the monoamine oxidase A gene are more vulnerable to abuse in childhood and more likely to themselves become abusers and to show antisocial behaviors compared with individuals with another commonly occurring

 

References 15

allele (Caspi et al., 2002). Nevertheless, in a positive, nurturing environment, as formulated by Suomi and by Tom Boyce and colleagues (Suomi, 2006; Obradovic et al., 2010; Boyce and Ellis, 2005), these same alleles may lead to successful outcomes, which has led them to be called “reactive or context-sensitive alleles” rather than “bad genes.”

Intervention

For prevention and treatment, in the spirit of integrative medicine, it is important to let the “wisdom of the body” prevail and to focus upon strategies that center around the use of targeted behavioral therapies along with treatments, including pharmaceutical agents, that “open up windows of plasticity” in the brain and facilitate the efficacy of the behavioral interventions (McEwen, 2012). This is because a major challenge throughout the life course is to find ways of redirecting future behavior and physiology in more positive and healthy directions (Halfon et al., 2014). In keeping with the original definition of epigenetics (Waddington, 1942) as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage (e.g., think about a fertilized frog or human egg which look similar and what happens as each develop!), we do not mean “reversibility” as in “rolling back the developmental clock” but rather “redirection” as well as “resilience,” which can be defined as “achieving a successful outcome in the face of adversity.”

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CHAPTER

2

Cognitive and behavioral components of resilience to stress

Brian M. Iacoviello1, 2, Dennis S. Charney1 1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY,

United States; 2Discovery and Translational Research, Click Therapeutics, Inc., New York, NY, United States

Resilience: one of many possible responses to stress or trauma

Stress and trauma can affect individuals in very different ways. On the one hand, studies have shown strong associations between a history of trauma exposure and the presence of psychiatric disorders. The most severe manifestations are often posttraumatic stress disorder (PTSD), depressive disorders, and substance use disorders. However, most times, stress or trauma exposure does not result in psychiatric disorders. A large study of a community sample estimated an approximately 9% risk of developing PTSD after trauma (Breslau et al., 1998). Clearly, some individuals exhibit a remarkable ability to endure great stress, torture, trauma, or disaster; we describe these individuals as “resilient.” Resilience refers to possessing a set of adaptive characteristics that enable an individual to cope with and recover from (or even thrive after) stress or trauma. Considering the range of stresses and traumatic experiences humans can face, the factors that contribute to resilience versus other outcomes including the emergence of psychiatric disorders are important to understand. Understanding these factors can help promote resilience in individuals before they even encounter stress or trauma and can inform the treatment of individuals struggling with stress or trauma.

A set of psychosocial factors that appear to contribute to resilience after trauma exposure have been identified through anecdotal evidence from interviews with resilient individuals and research evidence from studies of trauma and disaster survivors. These factors comprise cognitive and behavioral components (see Table 2.1 for a description of the factors and their components), where cognitive components concern people’s patterns of thinking or core beliefs and behavioral components concern patterns of action or activity. In support of this conceptualization, a factor analysis of the items on a widely used tool used to assess resil- ience, the Connor-Davidson Resilience Scale (Connor and Davidson, 2003), suggests five

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00002-1 23 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

24

2. Cognitive and behavioral components of resilience to stress

TABLE 2.1

Factor

Optimism Cognitive flexibility

Active coping skills (vs. passive)

Physical health

Social support network

Personal moral compass

Cognitive and behavioral components of psychosocial factors associated with resilience.

 

Cognitive

Components Behavioral

  

Maintain positive expectancies for the future.

Reappraise, reframe, and assimilate stress/trauma.
Accept stress/trauma and failure as ingredients for growth.

Minimize continued appraisal of threat. Maintain positive self-regard.

Thinking one is “connected” versus alone. Adaptive, positive core beliefs; religious or

spiritual beliefs; sense of purpose in life.

Actively seek help and resources; face your fears.

Physical activity and exercise.

Maintain a social support network. Connect with a resilient role model.

Altruistic behavior.

factors underlie resilience, which the authors described as: (1) tenacity and a sense of personal competence; (2) tolerance of negative affect and acceptance of the strengthening effects of stress; (3) acceptance of change and cultivating secure relationships; (4) sense of control; and (5) spiritual influences. Factors 1, 2, 3, and 4 include cognitive components: thinking patterns and core beliefs that lead one to believe they can endure. Factors 1 and 3 also include behavioral components: being active and engaged in one’s response to stress or traumatic situations and actively cultivating relationships and social support networks. Factor 5, spiritual influences, comprises both cognitive and behavioral componentsdfor example, maintaining spiritual or religious beliefs as a cognitive component and seeking out opportu- nities for altruistic behavior as a behavioral component. There are also neurobiological factors associated with resilience, including genetic factors, neurochemical systems involved in the stress response, and the functioning of specific neural networks (Charney, 2004; Feder et al., 2009) although these are beyond the scope of this chapter. Here we describe the psychosocial factors that contribute to resilience, organized into cognitive and behavioral components, along with recommendations for cultivating these factors.

Cognitive and behavioral components of the psychosocial factors associated with resilience

Optimism

Optimism comprises primarily cognitive elements. Optimism means maintaining positive expectancies for future events or outcomes (Carver et al., 2010). Optimism has typically been considered a personality dimension, suggesting it is likely more of a trait than a state charac- teristic. However, an individual’s degree of optimism can shift over time or across situations.

 

Cognitive and behavioral components of the psychosocial factors associated with resilience 25

Optimism has been associated with self-reported well-being among long-term breast cancer survivors (Carver et al., 2005), psychological adjustment during a life transition (Brissette et al., 2002), and reduced PTSD symptom severity after an earthquake (Ahmad et al., 2010). When encountering adversity, maintaining optimism for the future can buoy ones spirit and provide the stamina to endure, but optimism alone is not sufficient to foster resilience. James Stockdale, the highest-ranking naval officer held as a prisoner of war in Vietnam, was known for his resilience to this situation and provides insight regarding the role of optimism in resilience when he was asked “Who did not make it out of Vietnam?”

Oh, that’s easy, the optimists. Oh, they were the ones who said, ‘We’re going to be out by Christmas.’ And Christmas would come, and Christmas would go. Then they’d say, ‘We’re going to be out by Easter.’ And Easter would come, and Easter would go. And then Thanksgiving, and then it would be Christmas again. And they died of a broken heart. Collins, (2014)

Cognitive flexibility

Stockdale’s response illuminates another factor that is important for resilience: cognitive flexibility. Cognitive flexibility refers to the ability to reappraise one’s perception and experi- ence, instead of being rigid in one’s perception. Reappraisal involves finding meaning and positivity in a situation, as well as acknowledging the negative or painful aspects. Reevaluating stressful or traumatic experiences can alter their perceived value or meaning. If one can learn to reframe thoughts about a traumatic event, assimilating these into their memories and beliefs about the event, one may be able to accept and eventually recover. Acceptance and assimilation of a traumatic experience into one’s life narrative involves acknowledging that experiences with stress or trauma can provide opportunities for growth, even when there is pain or distress. Optimism and cognitive flexibility can work in tandem; together they can enable an individual to maintain faith that they will endure while also accepting the harsh reality they face.

Active coping skills and a strong social support network

Active coping skills involve both cognitive and behavioral components. Active rather than passive coping skills are often employed by resilient individualsdthey act to promote their own resilience. The cognitive component includes mindfulness for thoughts about situations and actively minimizing the appraisal of threat to avoid becoming consumed by fear. The behavioral component includes efforts to create positive statements about oneself, facing one’s fears instead of avoiding them, and efforts to seek the help and support of others. This is also related to another factor for promoting resilience, maintaining a strong social support network. Very few can “go it alone,” and resilient examples often acknowledge the invaluable social support around them. Close relationships can convey considerable emotional strength to an individual, and perceiving an available “safety net” can encourage acting in one’s own interest when confronting or recovering from stressful or traumatic situations. Recent studies of PTSD in returning Iraq/Afghanistan war veterans support this. One study found that PTSD was associated with greater relationship impairment, reduced social support, and impaired social functioning. Importantly, these social impair- ments were not simply consequences of PTSD. Reduced social support from the community

 

26 2. Cognitive and behavioral components of resilience to stress

and reduced availability of secure relationships appeared to mediate associations between PTSD and poor social functioning (Tsai et al., 2012). In another study, being in a relationship, having fewer psychosocial difficulties, and reporting greater perceptions of control and family support were all associated with resilience (Pietrzak and Southwick, 2011). Moreover, the presence of robust social support can influence one’s thinking about themselves and their worlds in a positive way. This can help protect against developing hopelessness and other negative psychological outcomes (Panzarella et al., 2006). Taken together, effective social support can engender strength to face fear and trauma and can minimize the experience of hopelessness while encouraging active coping.

Physical activity

Physical activity is primarily a behavioral factor. Attending to one’s physical health can help promote resilience. Physical exercise improves physical hardiness and increases strength and stamina, which can increase the chances of survival in traumatic situations. Physical exercise results in positive effects on mood and self-esteem (Scully et al., 1998), as well as aspects of cognition and brain function (Hillman et al., 2008). Maintaining aware- ness of one’s physical hardiness during a traumatic situation can contribute to mental forti- tude to endure. Improved mood and increased self-esteem resulting from physical exercise can also facilitate establishing and nurturing social relationships, which are important for promoting resilience.

A personal moral compass

Embracing a personal moral compass involves both cognitive and behavioral factors. The cognitive component involves developing a set of values and holding a strong set of positive core beliefs about oneself and one’s role in their world. Studies have shown that hopelessness and depression can result when individuals maintain negative beliefs regarding the stability (persisting over time), globality (affecting different areas of one’s life), and internality (associ- ation with one’s own personal characteristics) of the negative life events that they encounter (Alloy et al., 1997). On the other hand, maintaining positive beliefs results in adaptive thinking, can help prevent the development of hopelessness, and encourages resilience.

Observing one’s own behavior can also contribute to one’s beliefs about themselves and their worlds. Engaging in altruistic behavior toward others can result in positive self-beliefs and can be a factor that promotes resilience in the face of stress. Thus, altruism is an important behavioral component of embracing a personal moral compass, and it has been strongly associated with resilience in children and adults (Southwick et al., 2005; Leontopoulou, 2010). Altruistic behavior helps others but confers a sense of community and connectedness for the altruistic individual, which can also contribute to perceived meaning and purpose in life. In a study of primary care patients, purpose in life was a key factor associated with resilience and recovery from illness (Alim et al., 2008), and in a study of earthquake survivors, purpose in life was associated with reduced PTSD and depressive symptoms (Feder et al., 2013).

For many, faith in conjunction with religion or spirituality is an important component of a personal moral compass. Religion or spirituality provide opportunities to gain understanding

 

Cultivating psychosocial factors to promote resilience 27

of questions about life and personal meaning. This can be particularly relevant in times of stress or trauma, when it can be hard to find positive meaning or value in the situation. How- ever, doing so can aid in generating a healthy perspective of a traumatic situation and, accordingly, contribute to resilience. In fact, positive religious coping is associated with healthier physical and mental outcomes after surviving disaster (Smith et al., 2000) and in medically ill patients (Pargament et al., 2004). A large metaanalysis investigating the associ- ation between religious coping and psychological adjustment to stress found positive reli- gious coping to have a moderate association with positive psychological adjustment (Ano and Vasconcelles, 2005).

Cultivating psychosocial factors to promote resilience Encourage optimism, attend to pessimism, and aspire for flexibility

Optimistic attitudes can be hard to cultivate during times of stress or trauma. In those times, others can be relied upon to hold onto and convey optimism. Find someone who is able to express hope that the patient’s symptoms can improve or who can cite research and personal experience that things can get better. A positive attitude expressed by another can go a long way in encouraging some hope in the patient and can motivate them to continue to try. Unlike optimistic attitudes, negative or hopeless attitudes seem easy to develop during times of distress. Particularly, negative or hopeless attitudes should be addressed when encountered. Attend to common cognitive distortions (Burns, 1989) that underlie anxious and depressed thinking such as all or nothing thinking, overgeneralizing, disqualifying the positive, jumping to conclusions, catastrophizing, excessive “should” statements, and personalizing. Studies have also shown that hopelessness can stem from maintaining rigid and negative beliefs regarding the stability, globality, and internality of the life events that are encountered (Alloy et al., 1997), so maintaining relatively positive beliefs can result in more adaptive thinking, preventing the development of hopelessness and encouraging resilience.

There are many anecdotal examples of the power of optimism and cognitive flexibility. As a general example, consider the history of runners attempting to “break the 4-minute mile,” which means running a full 1-mile in under 4 min. This is a story of what can happen when the “impossible” becomes seen as “possible” or what can happen with optimism and cognitive flexibility. Until 1954, runners, physiologists, and medical doctors believed that it was impos- sible for a human body to naturally achieve the speed necessary to run 1 mile in under 4 min (approximately 15 miles per hour). This belief was crystallized over many, many years in which no runner achieved the feat despite many trying. As long as the feat was believed to be impossible, there was no success at breaking through the 4-minute mile. Then, in the 1950s, some runners began to challenge the belief that it was humanely impossible to break a 4-minute mile. Without any evidence to support them, they decided to be cognitively flexible and optimistic and committed to the belief that it was possible for a human to run a 4-minute mile. They then set out to prove it. With the help of some fellow runners and teammates to pace him, on May 6, 1954, a British runner named Roger Bannister became the first human to break a 4-minute mile (he ran it in 3:59.4). Just the one example of a human breaking the 4-minute mile was all that was needed to challenge the belief that it was “impossible”; now

 

28 2. Cognitive and behavioral components of resilience to stress

this was something that was possible in the mind of runners. This optimistic shift in belief then enabled what was previously seen as impossible, and other runners miraculously began to accomplish the same feat. Just 2 months after Bannister first broke the 4-minute mile, he and an Australian runner named John Landy both ran 1 mile in under 4 minutes in the 1954 British Empire and Commonwealth Games. In the past 50 years, the mile record has been lowered numerous times, by approximately 17 s in total. As long as breaking the 4-minute mile was believed to be impossible, despite best efforts, it was not achieved; once it was believed to be possible, runners began to accomplish the feat. Cognitive flexibility and optimism facilitated a shift in belief that enabled the accomplishment for runners after Bannister.

Face your fears

The initial, knee-jerk reaction to a fear- or anxiety-inducing situation is often to try as hard as we can to avoid it, to minimize the amount of fear or anxiety we experience. However, fear is a normal human experience, as it is intended to inform us about potential dangers in our environment. Listening to fear can help identify potential dangers, but it is also important to recognize that avoidance should not be the automatic reaction to fear. Some psychiatric disorders are characterized by nonacceptance of fear and maladaptive efforts to avoid fear, anxiety, or uncertainty (e.g., Hayes et al., 1996). Accepting fear and anxiety as part of the normal human experience, and pushing oneself to face fears instead of avoiding them, can help promote resilience. Stress inoculation, which involves deliberate prior exposure to manageable stressors, reduces the behavioral and physiological responses to later stressors (Meichenbaum, 1996). Prior exposure to stressors increases one’s sense of control and mastery of stressful situations and through desensitization reduces the amount of anxiety experienced when confronted with these situations, enabling one to learn to respond to stressors more adaptively. Facing one’s fears provides an opportunity for stress inoculation, learning to cope with fear actively and adaptively, and even strengthening self-esteem.

Connect with a resilient role model

When searching for a resilient role model, seek someone who has survived adversity, disaster, or trauma. Or, resilient role models can be found in support groups or other groups of individuals who have encountered similar stresses or traumas. Modeling of behavior is a powerful method to learn new behavior(s), and so a resilient role model can help cultivate resilience-promoting characteristics via modeling and internalizing the experience of resilience. For example, role models who have successfully navigated a stress- ful life event might be able to teach cognitive flexibility by relaying their own experience of acceptance, reappraisal, and assimilation of traumatic experiences. Relaying their own unique story of cognitive flexibility can help normalize the difficulty and also provide hope for success. These role models can become a part of a social support network, providing opportunities to model other relevant behaviors including active coping skills and the search for purpose in life. Ideally a resilient role model will function as a coach would, focusing the learner on skills to practice and strengthen, using themselves and their own success as a real-life example to learn from.

 

Cultivating psychosocial factors to promote resilience 29 Form and maintain a supportive social network

Since “few can go-it-alone,” having a social support network in place, on which one can rely during trauma or stress, can mean the difference between resilient outcomes versus the development of psychopathology. Social relations contribute to emotional strength, and social support can influence one’s beliefs about themselves and their worlds (Panzarella et al., 2006), which can facilitate optimism and positive self-regard. Supportive social networks also encourage active and adaptive coping behavior. For example, minimizing the appraisal of threat and acting in one’s own best interest are easier if a safety net is perceived in their social networks. These networks can involve friends, family, coworkers, spiritual advisors, mentors, role models, and others. Nurturing these relationships to establish support networks can be invaluable in promoting resilience.

Attend to physical health and well-being

Establishing a physical exercise regimen and/or ensuring regular physical activity can have a number of benefits. Physical exercise contributes to physical hardiness and, practically speaking, the ability to survive in certain situations. Physical activity is known to contribute to improved mood and self-esteem (Scully et al., 1998) as well as aspects of cognition and brain function (Hillman et al., 2008). Physical exercise has not only physical health benefits but also mental health benefits. Physical activity prior to stress or trauma can increase self-esteem and optimism about the chances for survival. During stressful times, physical activity can improve mood and cognitive capacities for emotion regulation. Even after the stress or trauma has ended, physical exercise can still affect resilience, as physical activity can improve mood, emotion regulation, cognitive flexibility, etc., which can facilitate resilient outcomes. The key is to establish a physical exercise regimen with some regularity and to stick to it.

Attend to your personal moral compass; identify and foster your character strengths

Attending to your personal moral compass involves developing and holding a set of core beliefs about yourself and your role in the world that are positive or adaptive. Being able to answer the question “who am I and what do I stand for?” with a set of beliefs about yourself is indicative of a strong personal moral compass. Being mindful for thoughts about yourself and your world is the first step in attending to your personal moral compass, and making sure that the beliefs that you hold are healthy and adaptive is key. This can involve chal- lenging or reframing any core beliefs that are unhealthy, maladaptive, or generally negative, and practicing holding onto healthier, more adaptive ones. Spiritual or religious beliefs, including belief in a higher power, and spiritual or religious activities can also help guide your moral compass and should be pursued. As our own behaviors can also shape our beliefs about ourselves, engaging in behaviors that help others can influence our core beliefs in a positive direction. Seek opportunities to help others or better the world, or engage in behaviors that highlight your positive characteristics and strengths.

We all have our relative strengths and weaknesses. Character strengths can include extroversion, emotion regulation capabilities, openness to new experience, and stress

 

30 2. Cognitive and behavioral components of resilience to stress

(or fear) tolerance and can be leveraged to cultivate the psychosocial factors that will promote resilience. For example, extroversion can help establish and nurture a supportive social network. Openness to new experiences can be relied on for stress inoculation and practicing facing one’s fears. The key is to learn to recognize our character strengths and engage them when confronting stressful situations. Identifying character strengths can also help identify relative weaknesses, which can then be honed and strengthened. Modifying a character strength or weakness typically involves training regularly and rigorously, as change requires systematic and disciplined activity. Commit to training in multiple areas and commit to a training regimen with enough frequency of practice to yield success.

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CHAPTER

3

Resilience as a process instead

of a trait

David M. Lyons, Alan F. Schatzberg

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States

Introduction

Stress resilience is crucial for health and well-being, but commonly accepted conceptual frameworks for resilience research have not yet emerged (Aburn et al., 2016; Johnston et al., 2015). Trait perspectives suggest that cognitive capabilities, personality characteristics, and neurobiological factors work along with environmental assets to make certain individ- uals resilient (Feder et al., 2009; Johnson, Panagioti, Bass, Ramsey and Harrison, 2017; Kalisch et al., 2015; Ungar, 2015). Process perspectives instead suggest that coping with stress builds resilience through learning and memory mechanisms (DiCorcia and Tronick, 2011; Lee et al., 2016a; Lyons et al., 2009). Experiences that are emotionally stressful but not traumatic promote coping and stress resilience by tagging learned information for memory consolida- tion (Bergado et al., 2011; Dunsmoor et al., 2015; Sotgiu and Mormont, 2008). Emotional experiences are known to enhance learning and memory mechanisms (Cahill and McGaugh, 1998; LaBar and Cabeza, 2006; Lisman et al., 2011). Emotional learning and memory are adaptive (Cosmides and Tooby, 2013) and often utilized in therapeutic settings to foster recovery and resilience (Lane et al., 2015).

Variously described in studies of humans as inoculating, steeling, or toughening (Dienstbier, 1989; Garmezy et al., 1984; Russo et al., 2012; Rutter, 2013), the notion that learning to cope with stress builds resilience is supported by nonhuman primate research. In natural and seminatural conditions, squirrel monkey mothers and other group members periodically leave newly weaned offspring beginning at 3e6 months of age to forage for food on their own (Lyons et al., 1998). At this stage of development, offspring are approx- imately half their adult body size. Initially, brief mother-infant separations studied in controlled experimental conditions elicit distress peep calls and increase plasma levels of the stress hormone cortisol with partial habituation of these measures observed over

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00003-3 33 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

34 3. Learning to cope builds resilience

repeated separations (Coe et al., 1983; Hennessy, 1986). Later in life, monkeys exposed to intermittent separations show fewer behavioral indications of anxiety, diminished stress levels of cortisol, and enhanced glucocorticoid feedback regulation of the hypothalamic- pituitary-adrenal (HPA) axis compared with monkeys not exposed to intermittent separa- tions (Levine and Mody, 2003; Lyons et al., 1999; Lyons, Parker and Schatzberg, 2010b; Parker et al., 2004; Parker et al., 2006). Similar examples have been reported for human chil- dren learning to cope with everyday stress (DiCorcia and Tronick, 2011), separation stress (Poulton et al., 2001), family stress (Hagan et al., 2014), work-related stress (Mortimer and Staff, 2004), and other diverse stressful life events (Boyce and Chesterman, 1990).

Learning to cope is not, of course, limited to sensitive or critical periods in primate postnatal development. Learning to cope with intermittent stress increases adult monkey hippocampal neurogenesis and enhances the expression of genes involved in cell prolifera- tion and survival (Lyons et al., 2010a). Learning to cope also protects adult monkeys against subsequent stress-induced deficits in behavior on tests of emotionality and diminishes the HPA axis neuroendocrine stress response (Lee et al., 2014). Adult humans who survive earthquakes or floods subsequently respond to natural disasters with diminished anxiety (Norris and Murrell, 1988) and less depressed affect (Knight et al., 2000) compared with inex- perienced survivors. Since learning can never be directly observed (Staddon, 2016), learning to cope is unavoidably inferred from behavior change.

Here we describe studies of learning to cope and resilience in mice. Instead of screening for the presence of traits that occur in resilient individuals or the absence of vulnerability to stress (Feder et al., 2009; Russo et al., 2012), we focus on learning to cope with stress and the process of building resilience. Considering resilience as a process implies that it can be modified and improved in people with or without preexisting psychopathologies (Waugh and Koster, 2015). Humans may more closely resemble various nonhuman primates, but the availability of research tools for dissecting causal pathways that link behavior and brain is much greater in mice compared with monkeys (Gerits and Vanduffel, 2013; Huang and Zeng, 2013). Therefore, mouse models offer essential opportunities to bridge the gap between basic and applied resilience research.

Learning-to-cope training

Learning-to-cope sessions of training were designed for mice on the basis of evidence that mild but not minimal nor severe stress exposure provides opportunities to learn, practice, and improve coping as described by U-shaped functions (Russo et al., 2012; Sapolsky, 2015; Seery et al., 2010). In addition to the qualities or intensities of stress exposure, temporal aspects differentially contribute to vulnerability versus resilience. Chronic severe stress leads to vulnerability (Brosschot, 2010; Charney and Manji, 2004; Duman, 2009), whereas intermit- tent stress exposures interspersed with undisturbed periods of recovery provide repeated opportunities to learn, practice, and improve coping with subsequent gains in stress resilience (DiCorcia and Tronick, 2011; Lyons et al., 2010b).

For studies of learning to cope in mice, we modified a protocol commonly used to inves- tigate severe social stress. Instead of direct or continuous exposure to an aggressive, same- sex, social stranger (Golden et al., 2011), learning-to-cope sessions of training are conducted

 

Learning to cope inferred from hormones and behavior 35

every other day for 15 min behind a mesh-screen barrier in the cage of a reproductively expe- rienced, same-sex, resident stranger (Brockhurst et al., 2015). Immediately after each training session, subjects are returned to their home cage to allow ample time for recovery and consol- idation of memory in familiar undisturbed conditions.

Resident strangers are housed individually to promote defense behavior, and their prior reproductive experiences enhance same-sex aggression (Ferrari et al., 1996; Miczek et al., 2001; Palanza et al., 1996). Male resident mice attack same-sex intruders more often than do female residents, but females engage one another in similar levels of agonistic behavior compared with same-sex interactions of male mice (Clipperton-Allen et al., 2011). Agonistic behavior of female mice includes acts of aggression aimed at establishing social dominance instead of attacks to evict same-sex intruders. Attacks are salient but not necessary for learning-to-cope training because we employ a mesh-screen barrier to prevent all attacks as well as all physical injuries while allowing noncontact social interaction.

Learning to cope inferred from hormones and behavior

Learning-to-cope sessions of training in mice subsequently diminish immobility as a mea- sure of behavioral despair on tail-suspension tests (Brockhurst et al., 2015). Tail suspension elicits neuroendocrine stress responses (S. B. Johnson et al., 2016), and diminished immobility is thought to reflect active coping with tail-suspension stress. Learning-to-cope training also diminishes subsequent freezing in the open field as a measure of anxiety-like behavior and decreases exploration latencies for novel and familiar objects (Brockhurst et al., 2015). Less freezing, shorter latencies, and diminished immobility do not reflect nonspecific activity insofar as learning-to-cope training does not increase locomotor activity (Brockhurst et al., 2015). Greater effect sizes are observed for novel compared with familiar object-exploration latencies, but object recognition memory is not required to show learning-to-cope training effects on this behavioral test. Learning-to-cope main effects in mice are significant across novel and familiar object-exploration latencies (Brockhurst et al., 2015). Shorter latencies reflect enhanced curiosity, and curiosity has been associated with stress coping and resilience in humans (Denneson et al., 2017) and nonhuman primates (Parker et al., 2007).

Initially, we reported learning-to-cope training effects for male mice (Fig. 3.1) and recently confirmed nearly identical effects in female mice (Lyons et al., 2018). Comparable findings in male and female monkeys (Lee et al., 2014, 2016b; Lyons et al., 2010a) support the hypothesis that learning-to-cope training is mediated by conserved neural mechanisms. Convergent re- sults in monkeys and mice also minimize false-positive findings and enhance translational relevance (Ciesielski et al., 2014). Translation has commanded considerable attention because of recent uncertainties about generalization across different species given inevitable biological variation, the use of diverse experimental manipulations, and various ways to operationalize complex outcomes of interest (Institute of Medicine, 2013). Reproducibility across distinct models that utilize different species and both sexes helps to ensure that observed outcomes generalize to broader contexts.

The hypothesis that learning to cope with stress builds resilience is further supported by human psychotherapies. Intermittent exposure to mildly stressful situations is a feature of stress inoculation training for people who work in conditions where performance in the

 

36 3. Learning to cope builds resilience

FIGURE 3.1 Learning to cope inferred from behavior. Learning-to-cope training subsequently decreases (A) immobility on tail-suspension tests, (B) freezing in the open field, and (C) exploration latencies for novel (Nov) and familiar (Fam) objects (mean ` SEM, n 1⁄4 12 mice per treatment, *P < .05). Adapted with permission from “Stress inoculation modeled in mice”, by Brockhurst, J., Cheleuitte-Nieves, C., Buckmaster, C.L., Schatzberg, A.F., Lyons, D.M., 2015. Stress inoculation modeled in mice. Translational Psychiatry 5, e537. Copyright 2015 by Nature Publishing Group.

face of adversity is required, for example, medical and military personnel, police, firefighters, and rescue workers (Meichenbaum and Novaco, 1985; Saunders et al., 1996; Stetz et al., 2007). Exposure psychotherapies likewise train people to imagine a graded series of stress-inducing situations and encourage interaction with stressors in vivo (McNally, 2007). These procedures promote learning (Craske et al., 2008) and provide opportunities to practice acquired coping skills (Serino et al., 2014).

Animal models of exposure psychotherapies often focus on learned extinction of condi- tioned fear (Milad and Quirk, 2012). Extinction occurs when a conditioned stimulus (CS) that was previously paired with an unconditioned stimulus (US) is repeatedly presented on its own. Repeated presentation of the CS alone results in new learning and subsequent inhibition of the conditioned fear response (Milad and Quirk, 2012). Far less researched, but of equal importance, are indications that repeated presentation of the US alone also inhibits conditioned fear responses by devaluing or reducing the impact of the US through a process called US habituation (Rauhut et al., 2001; Storsve et al., 2010).

Inhibitory effects of CS extinction do not generalize to contexts that differ from those in which CS extinction learning occurred (Bouton, 2002; Rauhut et al., 2001). Context specificity limits the utility of animal models for exposure psychotherapies based on CS extinction (Craske et al., 2008; McNally, 2007). In contrast, certain models of US habituation are minimally responsive to modulation by contextual cues (Churchill et al., 1987; Evans and Hammond, 1983; Grissom et al., 2007; Hall and Honey, 1989; Jordan et al., 2000; Nyhuis et al., 2010; Rauhut et al., 2001). In this regard, US habituation resembles aspects of learning to cope.

Learning-to-cope training effects generalize in mice to various test contexts as exemplified by diminished immobility during tail suspension, less freezing in the open field, and

 

Neurobiology of learning to cope 37

decreased object-exploration latencies (Fig. 3.1). Glucocorticoid stress hormone responses to repeated restraint are also diminished by learning-to-cope training compared with no-training controls (Fig. 3.2). Learning to cope is stressful, however, insofar as repeated training sessions increase glucocorticoids without habituation (Fig. 3.3). Learning to cope does not therefore represent habituation as a form of nonassociative learning and appears to reflect associative learning and memory inferred from behavior change.

Neurobiology of learning to cope

In an unbiased search for neural markers of learning to cope, we discovered increased stargazin (also called TARP gamma-2 or CACNG2) expression in anterior cingulate cortex of monkeys (Lee et al., 2016a). The anterior cingulate cortex is involved in learning, remote memory, cognitive control, emotion, and HPA axis regulation (Etkin et al., 2011; Herman, 2013; Ochsner et al., 2012; Wang et al., 2012; Weible, 2013). Stargazin regulates AMPA receptor trafficking (Chen et al., 2000; Jackson and Nicoll, 2011; Vandenberghe et al., 2005) by interact- ing with scaffold proteins of the postsynaptic density (Bats et al., 2007). AMPA receptor traf- ficking plays a key role in synaptic plasticity as a mechanism for learning (Huganir and Nicoll, 2013) viewed functionally in terms of behavior change. Eyeblink conditioning, for example, increases stargazin in male rat cerebellum (Kim and Thompson, 2011), and we found that learning-to-cope training increases stargazin in the anterior cingulate cortex of monkeys (Lee et al., 2016a). Results from monkeys were therefore tested for reproducibility in mice.

Brain tissues were collected from mice that were or were not behaviorally tested for emotionality after learning-to-cope training or the no-training control (Lee et al., 2016a).

FIGURE 3.2 Learning to cope diminishes subsequent stress hormone responses to repeated restraint. Tail vein plasma corticosterone levels in undisturbed home cage baseline conditions (Base) and immediately after the first, third, and seventh restraint-stress test sessions (mean ` SEM, n 1⁄4 8 mice per treatment, *P < .01). Adapted with permission from “Stress inoculation modeled in mice”, by Brockhurst, J., Cheleuitte-Nieves, C., Buckmaster, C.L., Schatzberg, A.F., Lyons, D.M., 2015. Stress inoculation modeled in mice. Translational Psychiatry 5, e537. Copyright 2015 by Nature Publishing Group.

 

 

38 3. Learning to cope builds resilience

FIGURE 3.3 Learning to cope is stressful. Tail vein plasma corticosterone levels in undisturbed home cage baseline conditions (Base) and immediately after the 1st, 3rd, 7th, and 11th learning-to-cope training sessions (mean ` SEM, n 1⁄4 8 mice, *P < .01 Fishers protected t-tests relative to Base). Adapted with permission from “Stress inoculation modeled in mice”, by Brockhurst, J., Cheleuitte-Nieves, C., Buckmaster, C.L., Schatzberg, A.F., Lyons, D.M., 2015. Stress inoculation modeled in mice. Translational Psychiatry 5, e537. Copyright 2015 by Nature Publishing Group.

Training main effects for anterior cingulate cortex stargazin in mice were discerned, but neither the behavioral testing main effect nor behavioral testing-by-training interaction was significant (Fig. 3.4). Results indicate that increased stargazin is caused by learning-to-cope training rather than subsequent behavioral testing. Increased stargazin appears to be selective for the anterior cingulate cortex insofar as no change in stargazin was observed in hippocam- pus or amygdala (Lee et al., 2016a).

FIGURE 3.4 Increased stargazin is caused by learning-to-cope training rather than subsequent behavioral testing. Anterior cingulate cortex stargazin in mice randomized to learning-to-cope training versus the no-training control. Mice from each training treatment were exposed or not to subsequent behavioral testing for emotionality (N 1⁄4 11e12 mice; mean ` SEM; *P 1⁄4 .016). Adapted with permission from “Learning to cope with stress modulates anterior cingulate cortex stargazin expression in monkeys and mice”, by Lee, A.G., Capanzana, R., Brockhurst, J., Cheng, M. Y., Buckmaster, C.L., Absher, D., Schatzberg, A.F., Lyons, D.M., 2016a. Learning to cope with stress modulates anterior cingulate cortex stargazin expression in monkeys and mice. Neurobiology of Learning and Memory 131, 95e100. Copyright 2016 by Elsevier.

 

Neurobiology of learning to cope 39

As evidence of learning-to-cope training effects distinct from stress exposures per se, increased stargazin in the anterior cingulate cortex correlates inversely with diminished emotionality in mice (Lee et al., 2016a). Specifically, increased stargazin in the anterior cingulate cortex correlates with diminished object-exploration latencies and with dimin- ished immobility on tail-suspension tests. Increased stargazin did not correlate with freezing in the open field, and stargazin was not measured in mice monitored for cortico- sterone in response to repeated restraint stress.

Array data from the anterior cingulate cortex of monkeys also indicate that increased stargazin induced by learning-to-cope training correlates with increased AMPA receptor subunit GluA1 (Fig. 3.5). Synaptic delivery of GluA1 is enhanced by stargazin in vitro (Chen et al., 2003; Tomita et al., 2007) and is a well-known correlate of learning and memory in vivo (Kessels and Malinow, 2009; Mitsushima et al., 2011; Rumpel et al., 2005). AMPA receptor neurotransmission in the anterior cingulate cortex is required for learning in rats (Wang et al., 2012), and GluA1 is increased in mice that learned to cope with stress inferred from diminished neuroendocrine measures (Schmidt et al., 2010). Diminished neuroendo- crine stress responses in monkeys that we previously described elsewhere (Lyons et al., 2007) were reanalyzed and found to correlate with increased GluA1 in the anterior cingulate cortex (Fig. 3.5).

Synaptic AMPA receptor trafficking as a correlate of learning is modulated by dopamine acting in concert with other signaling molecules (Ouyang et al., 2017; Tritsch and Sabatini, 2012; Wolf, 2010). Dopaminergic projections to corticolimbic regions are known to be activated by aversive or stressful events (Holly and Miczek, 2016). Therefore, we hypothe- size that learning-to-cope training activates dopaminergic projections to enhance AMPA receptor trafficking in the anterior cingulate cortex as a mechanism of synaptic plasticity for learning to facilitate the process of building stress resilience.

FIGURE 3.5 Increased anterior cingulate cortex GluA1 in monkeys correlates with (A) increased stargazin (r 1⁄4 0.85, P 1⁄4 .0004) and with (B) diminished adrenocorticotropic hormone (ACTH) measured immediately after restraint stress (r 1⁄4 0.71, P 1⁄4 .009). Monkeys trained to cope (circles) express higher levels of GluA1 (P 1⁄4 .04) and stargazin (P 1⁄4 .03) compared with no-training controls (squares). Diminished ACTH responses to restraint stress in monkeys trained to cope are nearly significantly different from controls (P 1⁄4 .11).

 

40 3. Learning to cope builds resilience Limitations

Our findings should be interpreted along with potential limitations. Both learning-to-cope training and subsequent testing were conducted after onset of lights-on, and this schedule may have altered circadian aspects of emotionality. Training and testing also both required transfer of mice from their home cage into new environments. Studies of repeated cage transfers alone are needed, but contextual differences between training and testing generally enhance behavioral and neuroendocrine measures of arousal (Bouton et al., 2006; Herman, 2013) instead of producing observed reductions in emotion- ality. More broadly, the particular experiences that promote learning-to-cope training and resilience in mice are unknown, but experiential details gleaned from mice will probably not translate to humans. Therefore, we focus on neurobiology instead of dissecting experi- ential details. Lastly, the pursuit of convergent evidence in mice and monkeys may enhance translational relevance (Ciesielski et al., 2014), but this approach also increases the risk of falsely disregarding species differences as negative or unimportant results.

Conclusions

Our findings suggest a new framework for stress resilience research. In addition to inves- tigating how severe stress damages behavior and brain (Charney and Manji, 2004; Duman, 2009), we propose a complementary approach focused on learning to cope with stress and the process of building resilience. Mechanisms of learning to cope identified in animal models may provide novel targets for new treatments of stress disorders in humans. Pharmacological facilitation of coping shifts attention from neuropathology to consider neural mechanisms that mediate coping as targets for building stress resilience. Although not fully complete, this framework supersedes narrower views that regard stress as solely destructive and over- look its broader role in behavior, neurobiology, and human mental health.

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CHAPTER

4

The brain mineralocorticoid

receptor: a resilience factor for

psychopathology?

R. Angela Sarabdjitsingh1, E. Ron de Kloet2, Marian Joëls1, 3,

Christiaan H. Vinkers4
1Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical

Center Utrecht, University of Utrecht, Utrecht, The Netherlands; 2Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; 3University of Groningen/University Medical Center Groningen, Groningen, The Netherlands; 4VU University Medical Center, Amsterdam, The Netherlands

The brain mineralocorticoid receptor

Individuals need to adapt to a continuously changing internal and external environment to survive. Threats subjectively experienced in a changing environment, that is, stress, give rise to a response that is highly conserved among mammals. The stress response involves, among other things, a rapid activation of the locus coeruleus noradrenergic network and the its pe- ripheral sympathetic adrenomedullar system resulting in increased circulating levels of adrenaline, and a slightly later activation of the hypothalamus-pituitary-adrenal (HPA) axis, which causes secretion of cortisol and/or corticosterone from the adrenal cortex, on top of the natural ultradian corticosteroid secretion pattern (Lightman and Conway-Campbell, 2010). These stress-induced waves of (nor)adrenaline and corticosteroids reach many organs including the brain, though with different kinetic properties: at least in rodents, corticosteroid hormones reach brain cells with a delay of 20 min compared with noradrenaline (Reul and De Kloet, 1985; Reul et al., 2015). The extent to which brain cells respond to these waves of hormones depends on many factors; for instance, corticosteroids’ access to the brain and neurons (and hence their response) depends on the expression of p-glycoproteins on epithelial or neural cells (Karssen et al., 2001; Pariante, 2008).

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00004-5 45 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

46 4. The brain mineralocorticoid receptor: a resilience factor for psychopathology?

A major factor determining exactly how neurons respond to waves of hormones is the availability of receptors, e.g., for (nor)adrenaline and corticosteroids. Multiple adrenoceptor subtypes are involved in the stress response, but a particularly prominent role is played by the b-adrenoceptor (De Quervain et al., 2017). Corticosterone and cortisol bind to two receptor types in the brain (de Kloet et al., 2005), that is, the high-affinity mineralocorticoid receptor (MR), in a limited number of limbic areas and motor nuclei; and the lower-affinity, more ubiquitously expressed glucocorticoid receptor (GR). Importantly, most MRs in brain differ from MRs in epithelial cells in kidney tubules, the bladder, intes- tines, salivary glands, and vascular endothelial cells, which all are aldosterone selective. Aldosterone selectivity in these cells primarily results from the activity of 11b-hydroxysteroid dehydrogenase type 2 (HSD-2), which converts the bioactive glucocorticoids to their 11-keto inactive congeners, thus allowing access of the less prevalent hormone aldosterone. In the brain, aldosterone-selective MRs do occur; they are localized in the nucleus tractus solitarii (NTS), some discrete cell groups in the medial amygdala and hypothalamus, and in the circumventricular organs (Geerling and Loewy, 2009; de Kloet and Joëls, 2017). The aldosterone-selective MR is involved in salt appetite, autonomous outflow, and volume regulation. However, most MR-expressing cells in the forebrain express 11b-HSD1 rather than 11b-HSD2, which actually regenerates bioactive glucocorticoids (Chapman et al., 2013) and therefore primarily bind the more abundant hormones corticosterone/cortisol rather than aldosterone.

Mineralocorticoid receptor activation and neuronal activity

At the single cell level, the response to a stress-induced surge of noradrenaline and cor- ticosteroids very much depends on the cellular expression pattern of receptors. With regard to corticosteroids, cells abundantly expressing both receptor types, such as hippocampal CA1 cells, show MR mediated effects that are generally found to be opposite from those mediated by GR (Joels et al., 2012). Activation of the high-affinity MR (already achieved with low doses of corticosteroids) is gradually counteracted by activation of the lower- affinity GR. In the majority of brain cells, however, GR is expressed at a substantially higher level than MR, which most likely results in a linear dose dependency (Joëls, 2006). Dentate granule cells (and possibly CA3 hippocampal cells) are an exception to these response patterns, because in these cells MR-mediated actions are efficiently induced, whereas GR-mediated actions are less effective, which causes a sigmoid dose-dependency curve.

The brain’s response after stress is thus a composite of regional effects, partially dependent on the MR relative to GR expression. In addition to these regional differences, temporal aspects also play a role in the response to stress. Both MR and GR are located intracellularly and upon activation translocate to the nucleus, where they bind to response elements in 1%e2% of all genes (Datson et al., 2008; Gray et al., 2017). They act as slow transcriptional regulators, an effect that is fine-tuned by locally expressed cofactors (Zalachoras et al., 2013). However, over the past years, it has become increasingly evident that MR and GR can also mediate rapid nongenomic actions (Joels et al., 2012; Jiang et al., 2014). Most likely, this involves the same pool of receptors of which a small part moves to the vicinity of the plasma membrane and there mediates rapid effects (Karst et al., 2005), although convincing proof lacks to date.

 

Mineralocorticoid receptors and cognitive function in rodents 47

In the hippocampus and amygdala, areas that play an important role in the etiology of depression, MR induces rapid effects on glutamate transmission with an apparent lower affinity than the gene-mediated actions, rendering the rapid effects relevance during the stress response (Karst et al., 2005, 2010). Rapid MR effects occur in a time window where b-adrenoceptors are also active. Synergistic effects between the two hormones have been described, for example, in the dentate gyrus (Joels et al., 2012). A more complex interaction might take place in the basolateral amygdala (BLA). Here, rapid corticosteroid actions strongly depend on the recent stress history of the organism; that is, recent exposure of BLA neurons to either noradrenaline or corticosterone causes opposite effects to those seen in “naïve” BLA cells, a phenomenon called metaplasticity (Karst et al., 2010). Waves of the b-adrenoceptor agonist isoproterenol and corticosterone revealed BLA responses ranging from a transient excitation followed by inhibition (with low hormone concentrations, as seen during very mild stress) to prolonged excitatory responsesdinduced by very high doses of the hormones, as may occur during severe stress (see Fig. 4.1; Karst and Joëls, 2016). All in all, the stress response in the brain forms a composite of regionally and temporally diverse responses, depending on the local concentration of noradrenaline, corticosterone and their receptors.

Mineralocorticoid receptors and cognitive function in rodents

MR and GR are both widely expressed in brain areas that are important for learning and memory processes and promote behavioral adaptation in a distinct yet highly coordinated manner (Joëls and Baram, 2009; Harris et al., 2013). Over the past decades, accumulating evidence has especially implicated MR in emotional and cognitive control by appraisal of novel situations, learning strategies, and response selection (Vogel et al., 2016). For example, early studies using icv administration of a selective MR antagonist, albeit on a background of adrenalectomized animals, pointed to involvement of MR in search-escape strategies and behavioral reactivity to spatial novelty in rats (Oitzl and de Kloet, 1992; Oitzl et al., 1994). MR also plays a role in contextual and tone-cue formation and appraisal of situations, as this is negatively affected when mice are treated with spironolactone, an MR antagonist, prior to training (Zhou et al., 2011).

Another line of studies showed that corticosteroid hormones, through MR, promote stress- induced switching in spatial strategy formation (Schwabe et al., 2010; ter Horst et al., 2013b). Application of spironolactone was reported to block the switch from hippocampal to the cognitive less demanding striatal-based habit learning, resulting in poor performance in mice (Schwabe et al., 2010, 2013a,b; ter Horst et al., 2014; Arp et al., 2014).

In addition to these pharmacological studies, genetically modified animal models have also proven to be very useful in delineating the function of MR. Several rodent models have been described using either a genetically modified or viral modification strategy to specifically target MR in the brain. For instance, MR-deficient mice showed impaired perfor- mance in learning and memory tasks, behavioral flexibility, and switching between behav- ioral strategies in the radial and water maze and circular hole board (Berger et al., 2006; ter Horst et al., 2013a; Schwabe et al., 2010; Brinks et al., 2009). Conversely, in rats with HSV viral vectoremediated overexpression of MR or in transgenic MR overexpression micee enhanced memory performance, faster behavioral adaptation and reduced anxiety was found

48

4. The brain mineralocorticoid receptor: a resilience factor for psychopathology?

10 9 8 7 6 5 4 3 2 1 0

10 9 8 7 6 5 4 3 2 1 0

10 8 6 4 2 0

“very mild stress”

Frequency (Hz)

Frequency (Hz) Frequency (Hz)

FIGURE 4.1 Cellular responses of basolateral amygdala neurons to waves of stress hormones. Basolateral amygdala cells in vitro were exposed to waves of first isoproterenol (green) and next corticosterone (orange), mimicking the natural variations measured with microdialysis. The top panel shows a brief wave of 0.3 mM isoproterenol (mimicking very mild stress), the middle panel waves of 1 mM isoproterenol followed by 30 nM corticosterone (mimicking moderate stress), and the lower panel the application of 3 mM isoproterenol followed by 100 nM corticosterone (severe stress). The graphs show the averaged (þSEM) frequency of miniature excitatory postsynaptic currents in time. The intensity of the bar’s color corresponds to the significance of the effect; red bars indicate excitatory responses and blue bars indicate inhibitory responses. The difference between very mild and moderate stress is characterized by the appearance of a brief excitatory response, whereas the shift from moderate to severe stress is associated with the appearance of a delayed excitatory effect. Based on Karst, H. Joëls, M., 2016. Severe stress hormone conditions cause an extended window of excitability in the mouse basolateral amygdala. Neuropharmacology 110, 175e180. https://doi.org/10.1016/j.neuropharm.2016.07.027.

“moderate stress”

“severe stress”

 

Pharmacology, genetic variation, and vulnerability to psychopathology in humans 49

(Lai et al., 2007; Rozeboom et al., 2007; Ferguson and Sapolsky, 2008; Mitra et al., 2009). When a mouse line with overexpression of MR was combined with decreased GR, a similar behav- ioral phenotype was found including improved spatial memory and perseverance of a learned behavioral response (Harris et al., 2013).

All in all, the MR appears involved in increased attention and vigilance in anticipation of upcoming events, appraisal of novel information, and retrieval of previously acquired behav- ioral response patterns, to appropriately deal with the stressor. Moreover, activation of the MR facilitates encoding of the experience to facilitate learning processes. These initial phys- iological and behavioral reactions to novelty are crucial for the onset of the stress reaction.

The impact of MR (and GR) on cognitive performance depends on not only the genetic background but also its interaction with environmental influences, especially influences taking place early in life. Alterations in maternal care are thought to partly mediate the effects of early-life adversity on diminished functioning of MRs and GRs (Liu et al., 1995; Weaver et al., 2004; Champagne et al., 2008). Several studies suggest that high expression of MR may be beneficial in promoting resilience after chronic or early-life stress (ELS). For instance, ELS or chronic unpredictable stress in adulthood reduces hippocampal- dependent contextual learning while enhancing fear learning (Kanatsou et al., 2015, 2017). Forebrain-specific overexpression of MR in mice (partially) prevented this effect on contextual memory formation, most likely by impacting on neurogenesis and synaptic transmission in dentate granule cells in the hippocampus.

Pharmacological studies have the advantage that the window of application of (ant)agonists can be precisely timed. Treatment with the GR antagonist mifepristone (RU38486) is a relatively simple strategy, as it may reset or shift the MR:GR balance by (temporarily) inacti- vating GR while enhancing MR function. For instance, in mice, ELS enhances freezing behavior in-between conditioned cue exposure in fear learning, which is ameliorated by brief blockade of GR during the critical developmental window of adolescence (Arp et al., 2016). Similarly in rats, mifepristone (administered during early adolescence) was reported to normalize hippocampus striataledependent contextual memory and spatial learning deficits after maternal deprivation, possibly by impacting on the glutamatergic neurotransmission system (Loi et al., 2017b) (see Fig. 4.2). This effect was specifically found in males (Loi et al., 2017a). Yet, not all behavioral domains may be sensitive to mifepristone treatment during early adoles- cence, because ELS-induced deficits in behavioral inhibition and attention as measured by the five-choice serial reaction time task were not normalized (Kentrop et al., 2016).

Altogether, preclinical research has provided valuable knowledge on the in vivo functions of MR in the brain and generally suggests that this receptor may be protective for stress effects on brain function, especially prolonged or severe stress early in life.

Pharmacology, genetic variation, and vulnerability to psychopathology in humans

The mineralocorticoid and hypothalamus-pituitary-adrenal axis activity

As previously demonstrated in rodents by pharmacological and genetic approaches (Ratka et al., 1989; Harris et al., 2013), there is also evidence that MR affects basal and stress-induced

 

50

4. The brain mineralocorticoid receptor: a resilience factor for psychopathology?

(A)

PND 3

24h maternal depriva on

(B)

habitua on (d1)

learning trial II (d2)

PND 26-28

GR antagonist (mifepristone)

(C)

adult

behavioral tes ng

  

learning trial I (d2)

test trial (d3)

        

FIGURE 4.2

Effect of early-life stress on contextual memory and the possibility to intervene with mifepristone treatment during early puberty. (A) Timeline of the experiment. (B) Setup of the object-in-context experiment. Male rats were initially habituated in a context that had no object. Next, during training, rats were placed in the same context but with two identical objects (learning trial I) and then placed in a novel context with two identical novel objects (learning trial II). Finally the rats were placed in the latter context but with one object being replaced by an object from the first context (test trial). (C) The discrimination index as observed from the object in context experi- ment. Rats that earlier had been exposed to maternal deprivation showed impaired discrimination between the objects. This was fully restored in animals that had been treated with mifepristone between days 26 and 28. Data expressed as mean ` SEM. Posthoc testing: *P < .05; **P < .01. Based on Loi, M., Sarabdjitsingh, R.A., Tsouli, A., Trinh, S., Arp, M., Krugers, H.J., Karst, H., van den Bos, R., Joëls, M., November 2, 2017a. Transient prepubertal mifepristone treatment normalizes deficits in contextual memory and neuronal activity of adult male rats exposed to maternal deprivation. eNeuro 4 (5). pii: ENEURO.0253-17.2017. https://doi.org/10.1523/ENEURO.0253-17.2017. eCollection 2017 Sep-Oct; Loi, M., Mossink, J.C.L., Meerhoff, G.F., Den Blaauwen, J.L., Lucassen, P.J., Joëls, M., 2017b. Effects of early-life stress on cognitive function and hippocampal structure in female rodents. Neuroscience 342, 101e119. https://doi.org/10.1016/j.neuroscience.2015. 08.024.

HPA axis activity in humans. First, MR antagonists such as canrenoate (Arvat et al., 2001; Wellhoener et al., 2004) and spironolactone (Cornelisse et al., 2011; Deuschle et al., 1998; Otte et al., 2007; Young et al., 1998) increase basal cortisol levels. Vice versa, fludrocortisone, a potent MR agonist, inhibits the HPA axis and subsequently decreases basal cortisol levels (Otte et al., 2003). However, because fludrocortisone is also a quite potent GR agonist, these data are somewhat difficult to interpret.

These insights obtained with pharmacological approaches are supported when studying the effect of genetic variation in MR (de Kloet et al., 2016) (see Fig. 4.3). The MR SNP rs2070951 influences basal cortisol levels and the cortisol awakening response with higher basal cortisol levels in G-carriers but lower levels in C-carriers (van Leeuwen et al., 2010a; Muhtz et al., 2011; Klok et al., 2011a,b,c). In male twins, Val-carriers of I180V consistently displayed an increased cortisol stress response after repeated exposure to the Trier Social Stress Test (DeRijk et al., 2006), but not all studies have found significant stress effects for these individual MR SNPs (Bouma et al., 2011; Ising et al., 2008).

 

Pharmacology, genetic variation, and vulnerability to psychopathology in humans 51

FIGURE 4.3 The human MR gene and two major haplotype blocks. Introns are indicated in gray and the exons (1b, 1a, and 2e9) in color. P2 and P1 are promoter regions. UTR 1⁄4 untranslated region. In the 50 region, three common functional haplotypes have been described, based on two SNP, MR-2C/G (rs2070951) and MRI180V (rs5522). In the 30 region (exon 9), a second haplotype block is present based on rs5534 and rs2871 from which three (other) common haplotypes can be constructed. Frequencies of the haplotypes are indicated. Based on ter Heegde, F., De Rijk, R.H., Vinkers, C.H., February 2015. The brain mineralocorticoid receptor and stress resilience. Psychoneuroendocrinology 52, 92e110. https://doi.org/10.1016/j.psyneuen.2014.10.022. Epub 2014 Nov 7.

The MR variants rs5522 and rs2070951 are in low linkage disequilibrium and inherited as haplotypes. The CA combination (haplotype 2) resulted in vitro in much higher MR expres- sion and transactivation than GA (haplotype 1). Interestingly, in a group of school teachers, the CA MR haplotype 2 was associated with a higher cortisol, ACTH, and heart rate response following stress (van Leeuwen et al., 2011). The GA MR haplotype carriers showed the most pronounced sex difference in suppression of the CAR. Moreover, the male GA carriers with the highest CAR also showed the strongest resistance to dexamethasone suppression (van Leeuwen et al., 2010a).

Altogether, both pharmacological and genetic evidence support a role for MR in the regulation of the HPA axis, the exact nature of which may be related to (1) differences in sex, age, and contraceptive use; (2) unaccounted variation by trauma exposure and a history of psychiatric disorders; and (3) methodological differences (e.g., the use of single SNPs vs. haplotypes).

The mineralocorticoid, learning, and stress appraisal in humans

The MR is also important for stress-related memory processes in humans, because the MR antagonist spironolactone affects different aspects of stress-related memory formation. In healthy men, administration of spironolactone prior to stress exposure (but not prior to the control condition) resulted in short-term working memory impairments yet enhanced long- term memory (Cornelisse et al., 2011). Whether these effects result from MR blockade per se or a relative increase in GR activation cannot be delineated from these pharmacological studies. Spironolactone also prevented stress-induced increases in response inhibition (Schwabe et al., 2013a) as well as a switch from hippocampus-based learning to striatum- or amygdala-based learning approach (Schwabe et al., 2013b; Vogel et al., 2015, 2017). In support, Val-allele carriers of rs5522 showed an impaired stress-induced reward learning (Bogdan et al., 2010), suggesting that lower MR functionality may be detrimental for stress-related learning. Moreover, carriers of the MR haplotype 2 display an improved shift from cognitive to striatal habit learning (Wirz et al., 2017).

 

52 4. The brain mineralocorticoid receptor: a resilience factor for psychopathology?

The MR also impacts on learning strategies under nonstressful circumstances: the MR antagonist spironolactone impaired selective attention under nonstressful conditions (Otte et al., 2007), whereas the MR agonist fludrocortisone improved verbal memory in both healthy controls and depressed patients (Otte et al., 2015). The MR also facilitates stress appraisal by an appropriate evaluation of the context, with genetic variation in the MR exon SNPs rs5534/rs2871 (loss-of-function) being associated with negative memory bias, partic- ularly after exposure to early-life adversity (Vogel et al., 2014). This was interpreted as evidence that lower MR activity may enhance memory formation for sad and pessimistic stimuli, emphasizing that MR functionality is important for contextual recognition and subsequent appraisal of stress. Indeed, Val-carriers of rs5522 showed a greater threat- related amygdala reactivity (Bogdan et al., 2012; Kuningas et al., 2007).

The mineralocorticoid receptor and resilience and vulnerability for psychiatric disorders

With a role of the MR in HPA axis activity, memory, and appraisal, under both basal and stressful circumstances, it may be hypothesized that the MR is also involved in the onset and course of stress-related psychiatric disorders. Indeed, blunted or excessive HPA axis activity has been repeatedly linked to anxiety and mood disorders (Spijker and Van Rossum, 2012).

Postmortem studies investigating MR expression in the human brain have shown remarkably consistent results, with major depressive disorder (MDD) brains showing lower MR mRNA expression in the hippocampus (Klok et al., 2011a,b,c; Medina et al., 2013), inferior frontal gyrus, and cingulate gyrus (Klok et al., 2011a,b,c) and lower hippocampal MR expression in suicide victims (Young et al., 1998). Similarly, schizophrenia and bipolar disorder patients displayed lower MR mRNA levels in the dorsolateral prefrontal cortex (Qi et al., 2013; Xing et al., 2004). One study found higher MR expression in the hypo- thalamic paraventricular nucleus in MDD, which may be compensatory to reduced hippo- campal and cortical MR expression (Wang et al., 2008). Lower MR expression in limbic areas would reduce the tonic inhibition of the HPA axis and subsequently increase the risk for mood disorders. In support, data from preclinical studies show that various classes of antidepressants (among which MAO inhibitors, selective serotonin reuptake inhibitors (SSRI), and tricyclic antidepressants [TCA]) consistently increase hippocampal MR expres- sion in rodents (Bjartmar et al., 2000; Lopez et al., 1998; Reul et al., 1994; Seckl and Fink, 1992; Yau et al, 1995). This effect depends, in part, on the duration of antidepressant treat- ment (Yau et al., 2001).

There are several studies linking genetic MR variation to susceptibility for psychiatric disorders. MR haplotype 2 is associated with enhanced resilience to depression in females (Klok et al., 2011a,b,c) and a higher dispositional optimism with fewer thoughts of hopeless- ness (Klok et al., 2011a,b,c). In agreement, Val-allele carriers of rs5522 (with decreased MR activity) displayed increased vulnerability for depressive symptoms in elderly individuals (Kuningas et al., 2007). Moreover, MR haplotype 2 sex-dependently moderated the relation between childhood maltreatment and depressive symptoms both in a population-based sample and in a clinical sample (Vinkers et al., 2015). This is supported by a recent study

 

Concluding remarks 53

showing a pleiotropic interaction between childhood trauma and the MR on cortisol levels and stress-related phenotypes (Gerritsen et al., 2017).

These data suggest that increased MR activity could constitute a possible treatment for MDD. Indeed, the MR agonist fludrocortisone, as add-on treatment to the SSRI escitalo- pram in a double-blind placebo-controlled randomized clinical trial with 64 MDD patients, resulted in an accelerated escitalopram response in the responder group (Otte et al., 2010). This corresponds with earlier findings that the MR antagonist spironolactone decreased the antidepressant effects of the TCA amitriptyline (Holsboer, 1999). Furthermore, add-on treat- ment with metyrapone, a cortisol synthesis inhibitor, enhanced effectiveness of antidepres- sants, which could be partially due to metyrapone-induced MR upregulation (Jahn et al., 2004). Interestingly, impaired MR function may predict nonresponse to antidepressants, with SSRI responders showing an intact MR functionality following the prednisolone suppression test (Juruena et al., 2006, 2009). Preclinical studies, however, argued against beneficial effects of mineralocorticoid activation if aldosterone-selective MRs are excessively stimulated, because chronic aldosterone treatment in rats induced anxiety and depressive- like phenotypes (Hlavacova and Jezova, 2008; Hlavacova et al., 2012). This suggests that excessive aldosterone-selective MR stimulation leads to an increased vulnerability for anxiety and depression (Murck et al., 2012). Moreover, a complicating factor in using the MR as a drug target for depression is its potential cardiac proinflammatory effect (Rafatian et al., 2014) (see Concluding remarks section).

In summary, evidence for a role of the MR in psychiatric disorders stems from postmortem studies, pharmacological manipulations, genetic studies, and treatment studies. These findings suggest that in healthy individuals, high (but not supraphysiologically high) compared with low MR functionality may be related to resilience to MDD. Yet, large and methodologically sound studies investigating MR-related compounds are still lacking.

Concluding remarks Brain mineralocorticoids important for resilience?

As argued, MRs expressed in the limbic brain play a crucial role in mediating the action of naturally occurring glucocorticoids in coping with stress. This action exerted by corticoste- rone and cortisol involves the role of the receptor in the HPA axis itself: MR is important for the tone and threshold of the HPA axis responsiveness, which is revealed upon systemic, intracerebroventricular, or hippocampal application of MR antagonists (De Kloet et al., 1998; Joëls and de Kloet, 2017). MR also plays a role in several cognitive domains and is accompa- nied by emotional expressions of, for example, fear and aggression. Thus, MR activation results in increased attention and vigilance in anticipation of upcoming events, appraisal of novel information, and retrieval of previously acquired behavioral response patterns to deal appropriately with the stressor. Activation of the MR also promotes encoding of the experience to facilitate learning processes. Collectively, these initial physiological and behav- ioral reactions to novelty are important for the onset of the stress reaction (De Kloet et al., 2005; Joëls and de Kloet, 2017).

 

54 4. The brain mineralocorticoid receptor: a resilience factor for psychopathology?

The rise in cortisol and corticosterone that marks the onset of the stress reaction then proceeds to additionally occupy the lower-affinity GR, which in many limbic cells is colocalized with the MR. The GR mediates the action of corticosterone and cortisol, in a complementary manner to MR. Thus, MR activation initiates primary defense reactions, which are subsequently suppressed via GR with the goal to prevent these initial responses from overshooting and to become damaging themselves (Sapolsky et al., 2000; De Kloet et al., 2005). Increased excitability is suppressed by GR activation, and behavioral adaptation and fading of the concomitant stress-induced HPA axis activity are facilitated. Meanwhile, GR activation primes brain circuits to allow the individual to cope with similar challenges in future: this implies contextualization and memory consolidation of the selected coping strategy and its concordant emotional expressions.

To what extent can activation of MRs contribute to resilience? Resilience has been defined by the American Psychological Association as “the process of adapting well in the face of adversity, trauma, tragedy, threats or even significant sources of stress.” Resilience is the ability to learn from a stressful challenge and to grow in the face of adversity, a process that metaphorically has been labeled “to bounce back.” As pointed out by Southwick et al. (2014), resilience is not absent or present but represents a continuum, a complex construct that is variable in different contexts, shows a large individual variation, and can change over lifetime. Self-esteem, social support, and the socioeconomic status are some of the impor- tant determinants of resilience in coping with stress. When exposed to a stressor, a resilient individual is able to rapidly switch on its HPA axis and cortisol secretion, as long as it also efficiently terminates stress hormone release. This is precisely what does not happen during lack of control and uncertainty: rhythmicity is flattened and the neuroendocrine stress response develops slowly and persists (McEwen et al., 2015).

Stress mediators, such as noradrenaline or corticosterone/cortisol, are of obvious signifi- cance for understanding the mechanism of resilience. We propose that a proper balance in signaling cascades that regulate physiological responses and behavioral adaptation to a stressor is actually the key to resilience. Thus, for optimal resilience, the sympathetic and parasympathetic nervous system, the pro- and antiinflammatory cytokines, and the activating and inhibiting arms of the HPA axis need to be in balance. In the HPA axis, this balance is represented by the CRF/vasopressin/MR drive, which is balanced in time by a GR-mediated feedback. Supraphysiological activation of MR (relative to GR) is therefore expected to be as disadvantageous as conditions that lead to a strong reduction in MR func- tion (De Kloet, 2014). Interestingly, Selye (1950) distinguished glucocorticoids and mineralo- corticoids as opposing regulators in his pendulum hypothesis: the prophlogistic mineralocorticoids increase the risk for inflammation and the anti-phlogistic glucocorticoids cause risk for infection. As pointed out in The brain mineralocorticoid receptor section, in the brain the complementary MR- and GR-mediated actions are actually embodied by one single class of hormones: the naturally occurring glucocorticoids cortisol and corticosterone.

Current evidence suggests that low MR functionality may be a predisposing factor to develop psychopathology, especially in women. The sex dependency may be related to the promiscuity of the MR, as the receptor also responds to progesterone, acting as an antagonist. Hence, the rising progesterone levels during the cycle or during contraceptive use inhibit MR function and cause activation of the HPA axis as well as change the threshold for emotional expressions (Carey et al., 1995). Remarkably, rodent studies show stronger phenotypes in

 

Concluding remarks 55

male subjects, both of early-life adversity and interventions targeting the MR. It should be noted, however, that most studies in rodents are carried out in male subjects to start with, so that the amount of information on females is more restricted.

The role of brain MRs through modulation of cognitive processing cannot be regarded as independent from other physiological processes in which the receptor is involved. For instance, the aldosterone-selective MR neurons of the NTS innervate forebrain regions that express the nonselective MR, that is, the receptor that responds to glucocorticoids to regulate cognitive and emotional aspects and also the mesolimbic cortical dopaminergic pathways arising from the ventral tegmental A10 cell group (Geerling et al., 2006; de Kloet and Joëls, 2017). It is thought that this circuit mediates the high motivation of salt-depleted animals to search for salt and, in case of excess, rapidly can switch the taste of salt to disgust.

In recent experiments using the spontaneous hypertensive rats (SHRs), de Nicola’s group in Buenos Aires demonstrated a vicious chain of events that was initiated by the global overexpression of MR in this species in much the same way as shown by the classical DOCA-salt model. Hypertension causes vasculopathy, which leads to neuronal damage through hypoxia. At the same time, microglia proliferate, leading to the production of proinflammatory cytokines, which further aggravate a feedforward cascade of neurodegen- eration (Brocca et al., 2017). Virtually every step is promoted by overactivity of the MR, which has been demonstrated with the proinflammatory cytokines (Schöbitz et al., 1994). A similar chain of events is at the basis of congestive heart disease and obesity in adipose tissue, suggesting a common basis for the comorbidity of cardiovascular, metabolic, and brain disease.

Future directions

Many questions regarding the role of MRs in the brain are still open. First, the molecular mechanism of action most likely will resolve the enormous diversity in function displayed by the promiscuous MR. In their genomic mode of action, this includes the role of heterodime- rization of MR:GR, the function of the neuroD transcription factors to assure MR specificity and the context-dependent amplification in function via coregulators (Lachize et al., 2009; Van Weert et al., 2017). How these slow genomic actions are integrated with the rapid membrane-mediated MR actions is another mystery awaiting resolution.

Second, the gain in function MR haplotype 2 invariably predicts mental health in females (Klok et al., 2011a,b,c; Vinkers et al., 2015; Hamstra et al., 2017). Yet, genetic MR variants have been intensely studied so far only by a limited number of investigators, which calls for replication. How early-life experience modifies MR function by epigenetic pathways is another question that awaits an answer. Understanding when, where, and how such epigenetic programming occurs might help to predict a mechanism of resilience later in life; in other words, to better understand the mechanistic underpinning of the adaptive capacity by asking how early-life experience organizes the brain and body function for life to come and what role the MR:GR balance plays in programming (Daskalakis et al., 2013).

And finally: What is the mechanism causing the switch from a life-sustaining MR to a “proverbial” death receptor? (Brocca et al., 2017). It seems that boosting MR function under healthy conditions preserves health, but during persistent adversitydas demonstrated with

 

56 4. The brain mineralocorticoid receptor: a resilience factor for psychopathology?

proinflammatory feedforward cascade in the brain of hypertensivesdinappropriately high MR would demand treatment with MR antagonists as a lifesaver. These actions mediated by MR cannot be seen in isolation from its GR companion, because the functioning of both receptor types needs to be in balance to preserve homeostasis, resilience, and health.

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CHAPTER

5

GABAB receptors, depression, and stress resilience: a tale of two isoforms

Olivia F. O’Leary1, 2, John F. Cryan1, 2
1Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; 2APC Microbiome Institute, University College Cork, Cork, Ireland

Introduction

In the central nervous system, gamma-aminobutyric acid (GABA) acts on two types of receptors: ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors. GABAA receptors are ligand-gated ion channels while GABAB receptors are G-protein-coupled receptors. GABAB receptors are found presynaptically where they function as either autoreceptors limiting the release of GABA or as heteroreceptors inhibiting the release of glutamate. However, these receptors are also found postsynaptically where they induce slow inhibitory postsynaptic currents (Cryan and Kaupmann, 2005; Bettler et al., 2004). Functional GABAB receptors are heterodimers of GABAB1 and GABAB2 subunits, and the GABAB1 subunit is expressed as several isoforms (Lee et al., 2010; Fritschy et al., 1999). The GABAB1a and GABAB1b isoforms are the predominant subunit isoforms that are expressed in the brain, whereby the GABAB1b subunit isoform is predominantly localized postsynaptically, whereas the GABAB1a subunit isoform is mainly found presynaptically (Fritschy et al., 1999; Gassmann and Bettler, 2012; Vigot et al., 2006). In dendrites, GABAB1a localizes to glutamatergic terminals for heteroreceptor function, whereas GABAB1b localizes to spines opposing glutamate release sites, thus affecting presynaptic or postsynaptic inhibition (Gassmann and Bettler, 2012). Structurally, these two isoforms differ only by the presence of a sushi domain in the N-terminus of the GABAB1a receptor subunit isoform, which is thought to increase surface stability of GABAB(1a, 2) receptors and promote their axonal localization (Gassmann and Bettler, 2012; Hannan et al., 2012).

Interest in the role of the GABAB receptor in stress resilience began 30 years ago, when a potential role for the GABAB receptor in the pathophysiology and treatment of the

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00005-7 63 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

64 5. GABAB receptors, depression, and stress resilience: a tale of two isoforms

stress-related disorder, depression, was first reported (Pilc and Lloyd, 1984). Since then, many preclinical studies have reported a reciprocal but complex relationship between stress-related psychiatric disorders such as depression and anxiety with the GABAB receptor as outlined in the following sections.

The impact of stress-related psychiatric disorders and their treatments on GABAB receptor density, gene expression and function

Effects of antidepressants on GABAB receptor density in rodents

The first hint that the GABAB receptor may play a role in stress-related responses came from receptor binding studies in the early 1980s, which examined the effects of antidepres- sant treatments on GABAB receptor density (Pilc and Lloyd, 1984). Since then, many other studies have reported that this receptor is affected by several different antidepressant treat- ments although some conflicting and brain region-dependent results have also been reported (Felice et al., 2016; Ghose et al., 2011; Cryan and Slattery, 2010; Enna and Bowery, 2004). It was reported that chronic but not acute treatment with the antidepressants amitrip- tyline, desipramine, or citalopram increased GABAB receptor-binding sites (i.e., receptor density) in the rat frontal cortex (Pilc and Lloyd, 1984). These findings were reproduced in a later study, which also reported that other antidepressant treatments including fluoxetine, mianserin, trazodone, and repeated electroconvulsive shocks upregulated GABAB receptor binding in the rat frontal cortex (Lloyd et al., 1985). Such effects of antide- pressants on GABAB receptor binding seemed to be region dependent and were not apparent in the rat hippocampus (Lloyd et al., 1985). Chronic treatment with the antidepres- sant imipramine was also shown to increase GABAB receptor binding in the mouse cortex (Suzdak and Gianutsos, 1986). However, opposing data have also been reported. For instance, Pratt and Bowery (1993) reported that although desipramine increased GABAB receptor binding in the rat frontal cortex, neither paroxetine nor amitriptyline had any effect (Pratt and Bowery, 1993). Similarly, a lack of effect of desipramine, imipramine, and tranyl- cypromine on frontal cortex GABAB receptor binding has been reported by others (Cross and Horton, 1987, 1988; McManus and Greenshaw, 1991). On the other hand, the antidepressants desipramine and imipramine have been shown to reverse the reduction in frontal cortex GABAB receptor that is induced by learned helplessness, thus suggesting that antidepressants may affect GABAB receptor density not only under basal conditions but also in depression-like states (Martin et al., 1989).

Effects of antidepressants on GABAB receptor function in rodents

These findings of antidepressant-induced increases in GABAB receptor density in the cortex are consistent with findings that GABAB receptor function is increased following various antidepressant treatments. Indeed, it has been reported that imipramine-induced increases in GABAB receptor density were accompanied by enhanced receptor function as shown by the potentiation of baclofen (a GABAB receptor agonist)-induced adenylate cyclase activity in the mouse cerebral cortex (Suzdak and Gianutsos, 1986).

 

The impact of stress-related psychiatric disorders and their treatments on GABAB receptor density, gene expression and function 65

Repeated treatment with the antidepressant tranylcypromine has also been reported to enhance GABAB receptor function in the rat cerebral cortex as measured by baclofen- stimulated GTPgS binding (Sands et al., 2003). Similarly, chronic treatment with amitriptyline, desipramine, mianserin, or electroconvulsive shock increased GABAB receptoremediated modulation of serotonin release in the mouse frontal cortex (Gray and Green, 1987). In contrast to all of these findings, however, one study reported that antidepressants including desipramine and imipramine do not alter GABAB receptor function in the cerebral cortex (Szekely et al., 1987).

Interestingly, 7 days treatment with the antidepressants tranylcypromine, phenelzine, or desipramine (but not fluoxetine) increased GABAB receptor function in the rat hippocampus (Sands et al., 2004). This suggests that although antidepressants affect GABAB receptor density in the frontal cortex but not hippocampus (Lloyd et al., 1985), these drugs can affect receptor function in both the hippocampus and the frontal cortex (Lloyd et al., 1985; Sands et al., 2004). However, it should also be noted that the direction of change of antidepressant effects on GABAB receptor function may be region dependent, as it has been reported that chronic fluoxetine treatment reduced GABAB receptoreinduced GIRK responses in the rat dorsal raphe nucleus (DRN) (Cornelisse et al., 2007).

Clinical evidence of altered GABAB receptor density and function in depression and the antidepressant response

All of this preclinical evidence is supported by a growing body of clinical evidence of GABAB receptor dysfunction in depression (for review, see Felice et al., 2016; Ghose et al., 2011). Indeed, recent clinical neurophysiology studies suggest that deficits in GABAB receptors may play a role in major depression and the antidepressant response to fluoxetine (Levinson et al., 2010; Croarkin et al., 2014). In addition, the induction of growth hormone release by the GABAB receptor agonist baclofen is blunted in depressed patients (O’Flynn and Dinan, 1993; Marchesi et al., 1991). Moreover, it has been reported that the GABAB2 receptor subunit is upregulated in cortical and subcortical brain regions in depressed suicide victims compared with those without a history of depression (Klempan et al., 2009). Similarly, a 50% increase in GABAB2 subunit gene expression was reported in the dentate gyrus of the hippocampus in depressed individuals (Ghose et al., 2011). However, this upregulation is not reflected in earlier receptor binding studies in which similar GABAB receptorebinding profiles in the frontal or temporal cortices and the hippocampus had been reported in depressed suicide victims and controls (Cross et al., 1988) and in the frontal cortex of suicide victims and controls (Arranz et al., 1992).

Alterations in GABAB receptor density and function in animal models of stress and depression

Considering the relatively strong evidence for a potential role of the GABAB receptor in depression and the response to antidepressants, it is somewhat surprising that only a limited number of preclinical studies have measured GABAB receptor expression and

 

66 5. GABAB receptors, depression, and stress resilience: a tale of two isoforms

function in animal models of depression and stress. It has been reported that GABAB receptor binding in the frontal cortex is reduced in the rat learned helplessness model of depression (Martin et al., 1989). On the other hand, however, chronic restraint stress (7 days) had no effect on GABAB receptor activity in the cerebral cortex as measured by baclofen-stimulated GTPgS binding (Sands et al., 2003). Similarly, social stress did not affect GABAB receptoremediated GIRK currents in the rat DRN (Cornelisse et al., 2007).

In summary, most preclinical studies have reported that chronic treatment with several different antidepressants increases GABAB receptor density and activity particularly in the cortex. In support, clinical studies suggest that deficits in GABAB receptor function may play a role in major depression and the antidepressant response to fluoxetine; however, only a limited number of clinical studies have actually been conducted. Although no differ- ences in GABAB receptorebinding profiles have been reported in the frontal and temporal cortices of the suicide brain, increased expression of the GABAB2 receptor subunit has been reported in the hippocampus and cortex of depressed suicide victims. Taken together, these preclinical and clinical studies on GABAB receptor density and activity suggest a role for the GABAB receptor in antidepressant action and perhaps a more indirect or limited role in the pathophysiology of stress and depression. Nevertheless, as outlined in the following sections, it is clear that altering GABAB receptor activity regulates depression and anxiety- like behaviors and behavioral responses to stress.

Effects of GABAB receptor modulation on depression-like behaviors

There is a large body of convincing preclinical evidence that pharmacological or genetic manipulation of the GABAB receptor affects anxiety-, depression-, and antidepressant- related behaviors (Cryan and Kaupmann, 2005; Felice et al., 2016; Cryan and Slattery, 2010). Mice with null mutations of either the GABAB1 or GABAB2 receptor subunits demonstrate an antidepressant-like behavioral phenotype as indicated by reduced immobility in the forced swim test (FST; Mombereau et al., 2004, 2005). Moreover, GABAB receptor antagonists exert antidepressant-like effects in the FST, and in the learned helplessness, olfactory bulbectomy, and chronic mild stress paradigms (reviewed in Felice et al., (2016)). Specifically, the GABAB receptor antagonists CGP56433A, CGP51176, CGP5633A, CGP36742, and SCH50911 have all been shown to induce antidepressant-like behavior in the FST in rats or mice (Mombereau et al., 2004; Slattery et al., 2005; Nowak et al., 2006; Frankowska et al., 2007; Felice et al., 2012). GABAB receptor antagonists are also effective in other rodent models of depression and antidepressant activity including the olfactory bulbectomy model (CGP36742 and CGP51176) (Nowak et al., 2006), chronic mild stress (CGP51176) (Nowak et al., 2006), and learned helplessness model (CGP36742) (Nakagawa et al., 1999). On the other hand, it is positive allosteric modulators (PAMs) of GABAB receptors that exert anxiolytic effects in tests of innate anxiety although PAMs do not exert any effects in conditioned fear paradigms (Frankowska et al., 2007; Sweeney et al., 2013; Li et al., 2015; Cryan et al., 2004). Taken together, it is clear that reducing GABAB receptor function has antidepressant-like effects, whereas positive allosteric modu- lation of the receptor has anxiolytic effects.

 

The role of GABAB1 receptor subunit isoforms in stress resilience 67 The role of GABAB1 receptor subunit isoforms in stress resilience

Although it is clear that pharmacological modulation of GABAB receptors can influence depression and anxiety-like behaviors, relatively few studies have examined their effects in the behavioral responses to chronic stress. Nevertheless, it has been reported that the GABAB receptor antagonist, CGP51176, prevented anhedonia in the chronic mild stress para- digm (Nowak et al., 2006). More recently, we have used GABABð1aÞ-=- and GABABð1bÞ-=- mice as tools to delineate the roles of specific GABAB1 receptor subunit isoforms in depression and anxiety-related behaviors as well as in resilience and susceptibility to stress-induced changes in these behaviors. Indeed, we recently reported that GABAB1a and GABAB1b receptor subunit isoforms differentially regulate stress resilience in both male and female mice (O’Leary et al., 2014) (Fig. 5.1). Specifically, male GABABð1aÞ-=- mice were more susceptible, whereas male GABABð1bÞ-=- mice were more resilient to chronic social defeat stress (O’Leary et al., 2014). In the social interaction test, social defeat stress decreased social interaction to a greater extent in GABABð1aÞ-=- mice when compared with wild-type mice. On the other hand, mice lacking the GABABð1bÞ-=- isoform were resilient to this stress-induced social avoidance. Moreover,

FIGURE 5.1 Summary of the main differences between GABABð1aÞ-=- mice in their response to stress and potential underlying mechanisms of stress resilience in GABABð1bÞ-=- mice. CORT, corticosterone; DRN, dorsal raphe nucleus; FST, forced swim test; MS, maternal separation; NAcc, nucleus accumbens; SDS, social defeat stress; TST, tail suspension test.

 

 

68 5. GABAB receptors, depression, and stress resilience: a tale of two isoforms

social defeat stress induced anhedonia in GABABð1aÞ-=- mice as measured by reduced prefer- ence to drink a sweet solution of saccharin over water, whereas GABABð1bÞ-=- mice were resil- ient to this measure of stress-induced anhedonia. In an independent cohort of mice, we also examined the impact of early-life stress on depression and anxiety-related behaviors in adult- hood and using a model amenable to both male and female mice (O’Leary et al., 2014). To this end, we used unpredictable maternal separation combined with unpredictable maternal stress, whereby pups were separated from their mother at an unpredictable time during the light or dark cycle and during which time the mother was also exposed to a brief unpredictable stressor at an unpredictable time during the 3 h separation period. In agreement with our findings in socially defeated male GABABð1aÞ-=- mice, we found that maternally separated female GABABð1bÞ-=- mice also exhibited an anhedonic-like response in the saccharin preference test when compared with both GABABð1bÞ-=- and wild-type mice. We also assessed the ef- fects of maternal separation on anhedonia in male mice using the female urine sniffing test (Malkesman et al., 2010). In this test, a cotton bud dipped in water or the urine of female mice that are in estrus is presented to the male mouse in its home cage. Male mice tend to spend more time sniffing the urine over water, and this is taken as a measure of sexual in- terest. It has been previously shown that rodents that exhibit learned helplessness spend less time sniffing the urine, an effect prevented by chronic antidepressant treatment (Malkesman et al., 2010). Maternal separation decreased the preference for urine in wild-type mice and completely abolished this preference in GABABð1aÞ-=- mice while having no effect in GABABð1bÞ-=- mice (O’Leary et al., 2014). Together with the findings from the social defeat experiment, this suggests that GABABð1aÞ-=- mice are more susceptible, whereas GABABð1bÞ-=- mice are more resilient to stress-induced anhedonia.

The impact of chronic stress on antidepressant-like behavior was also assessed in these mice using the FST and tail suspension test, but the findings from these tests were more complex than those assessing anhedonia readouts. This was due in part to genotype differ- ences under control conditions. Under baseline conditions, both GABABð1aÞ-=- and GABABð1bÞ-=- mice exhibited decreased immobility in the FST (O’Leary et al., 2014). Although these findings might be interpreted as both GABABð1aÞ-=- and GABABð1bÞ-=- mice having an antidepressant-like phenotype in the FST, a different picture emerges when they were exposed to maternal separation stress. In the FST we found that female (but not male) maternally separated GABABð1bÞ-=- mice retained their antidepressant-like behav- ioral phenotype suggesting they were more stress resilient, whereas maternally separated GABABð1aÞ-=- mice did not retain this phenotype. In addition, in the tail suspension test, both nonstressed and stressed male and female GABABð1aÞ-=- mice exhibited increased immobility, thus suggesting that GABABð1aÞ-=- mice have a depression-like behavioral phenotype in this test. On the other hand, both nonstressed and stressed male GABABð1bÞ-=- mice exhibited reduced immobility, thus suggesting an antidepressant-like phenotype. However, caution is required when interpreting these reductions in immobility in GABABð1bÞ-=- mice, as another study did not observe this decreased immo- bility in the FST (Jacobson et al., 2017), and these mice also show increased locomotor activity (O’Leary et al., 2014). Nevertheless, we also observed the female maternally separated GABABð1bÞ-=- mice do not exhibit hyperactivity and yet exhibit reduced immobility in the FST; thus a role in antidepressant-like behavior cannot be completely discounted.

 

Potential mechanisms underlying the differential roles of GABAB1a and GABAB1b receptor subunit isoforms in stress resilience 69

Although the data gathered from GABABð1aÞ-=- and GABABð1bÞ-=- mice suggest that deletion of either subunit isoform can differentially modulate stress resilience, surprisingly little work has been done on investigating whether the expression of these subunits is altered by stress or models of stress-related psychiatric disorders. Nevertheless, we have reported that the help- less H/Rouen genetic mouse model of depression exhibits increased GABAB(1b) mRNA expression in the hippocampus when compared with their nonhelpless controls (O’Leary et al., 2014) and that a probiotic that promotes antidepressant-like effects increased the expression of this subunit in the mouse hippocampus (Bravo et al., 2011). In contrast, we did not observe any changes in hippocampal GABAB1a mRNA expression in the helpless H/Rouen mouse strain (O’Leary et al., 2014). On the other hand, a previous small postmor- tem human brain study reported that GABAB1a mRNA expression was decreased in the den- tate gyrus of depressed individuals (Ghose et al., 2011), and others have reported antidepressant-induced increases in GABAB1a mRNA expression in the rat hippocampus (Sands et al., 2004). Given these somewhat opposing findings, a more systematic investiga- tion of brain-wide impact of depression, stress, and antidepressant treatments on the expres- sion of these subunit isoforms is required.

Taken together, these studies support a role for the GABAB1a receptor in depression, in antidepressant action, and in determining stress susceptibility, whereby reduced GABAB1a expression in the hippocampus is associated with depression in humans and increased stress susceptibility in mice, whereas increased hippocampal expression seems to occur following antidepressant treatment. On the other hand, increased GABAB1b expression in the hippo- campus is a phenotype of a genetic mouse model of depression, and deletion of this subunit increases stress resilience in mice.

Potential mechanisms underlying the differential roles of GABAB1a and GABAB1b receptor subunit isoforms in stress resilience

The neurobiological mechanisms underlying the differential roles of the GABAB1a and GABAB1b receptor subunit isoforms in stress resilience are not yet fully understood, but as outlined in the following sections, several studies suggest that the serotonin neurotransmitter system, the hypothalamic-pituitary-adrenal (HPA) axis, selected brain regions, and adult hippocampal neurogenesis may play a role.

The serotonin neurotransmitter system

The serotonin (5-HT) neurotransmitter system has long been implicated in the patho- physiology and treatment of the stress-related psychiatric disorder depression (O’Leary and Cryan, 2010; Lucki, 1998). Indeed, the selective serotonin reuptake inhibitor (SSRI) antidepressants were developed to increase synaptic availability of this neurotransmitter in the brain. There is growing evidence of a functional link between the serotonin system and GABAB receptors. Indeed, most 5-HT cell bodies in the dorsal and medial raphe nuclei express the GABAB receptor (Abellan et al., 2000a; Varga et al., 2002). In addition, it has been demonstrated that activation of GABAB receptors by the agonist, baclofen, modulates the release of 5-HT in the DRN, the nucleus accumbens, and the striatum (Abellan et al.,

 

70 5. GABAB receptors, depression, and stress resilience: a tale of two isoforms

2000a,b; Tao et al., 1996; Takahashi et al., 2010). Moreover, we have previously shown that the antidepressant-like effects of GABAB receptor antagonists in the rat-FST are dependent on an intact serotonergic system (Slattery et al., 2005). Reciprocally, mice lacking the serotonin transporter exhibit desensitized GABAB receptors in the raphe nuclei (la Cour et al., 2004), and rats chronically treated with the SSRI, fluoxetine, exhibit reduced GABAB receptoremediated GIRK responses in the DRN (Cornelisse et al., 2007). Importantly in the context of stress, it has been shown that social defeat stress increases GABA-mediated inhibition of 5-HT in the DRN of stress-susceptible mice, whereas GABA silencing disinhibited serotonergic cells and promoted a stress-resilient phenotype in mice exposed to social defeat (Challis et al., 2013). This suggests that GABA-serotonin in- teractions in the DRN play a role in stress resilience. Indeed, we have found that GABABð1bÞ-=- mice (which are more stress resilient) exhibit enhanced stress-induced expres- sion of the immediate early gene, c-Fos, in the DRN, when compared with the stress- susceptible GABABð1aÞ-=- or the normo-stress-sensitive wild-type mice, thus suggesting that the DRN is a key brain region involved in GABAB1 receptor subunit regulation of stress resilience (O’Leary et al., 2014).

The 5-HT1A receptor is thought to play a pivotal role in the stress-related psychiatric disorders, depression, and anxiety (O’Leary and Cryan, 2010; Blier and Ward, 2003; Cryan and Leonard, 2000). These receptors are localized in the raphe nuclei where they act as soma- todendritic autoreceptors that inhibit 5-HT cell firing but are also found postsynaptically in a number of limbic brain regions important in the regulation of emotion, such as the hippocam- pus (Hoyer et al., 2002). Desensitization of this receptor has been long implicated in the mech- anism of antidepressant action (Blier and Ward, 2003; Albert et al., 2014; Hensler, 2003; De Vry, 1995) and in enhancing the onset of antidepressant action perhaps through increased 5-HT availability in the forebrain (Artigas et al., 1996; Blier et al., 1997; Ferres-Coy et al., 2013). Thus, we recently examined 5-HT1a receptoremediated responses in both GABABð1aÞ-=- and GABABð1bÞ-=- mice (Jacobson et al., 2017). In this study, both male and fe- male GABABð1aÞ-=- mice exhibited a blunted hypothermic response to the 5-HT1A receptor agonist 8-OH-DPAT, thus suggesting that these mice have impaired presynaptic 5-HT1A autoreceptor function (Jacobson et al., 2017). In agreement with these findings, previous in situ hybridization studies suggest that it is the GABAB1a isoform that is predominantly expressed on serotonergic cell bodies in the DRN (Bischoff et al., 1999). GABABð1aÞ-=- mice also exhibited attenuated 8-OH-DPAT-induced stimulation of the HPA axis and body posture flattening, thus suggesting that postsynaptic 5-HT1A receptors are also densensitized, although this desensitization seems to be weaker than that occurring at presynaptic 5-HT1A receptors (Jacobson et al., 2017). These effects were generally not associated with alterations in 5-HT1A receptor expression nor with alterations in 5-HT1a receptor G-protein coupling. In addition, no alterations in 8-OH-DPAT-induced responses were observed in the GABABð1bÞ-=- mice (Jacobson et al., 2017).

Taken together, these data suggest that the DRN may be an important brain region involved in the stress-resilient phenotype of GABABð1bÞ-=- mice and that the sensitivity of presynaptic and postsynaptic 5-HT1A receptors is reduced in the stress-susceptible GABABð1aÞ-=- mice. Given the role of 5-HT1A receptor desensitization in the response to SSRI antidepressants, it will be of interest to determine whether GABABð1aÞ-=- mice exhibit altered sensitivity to these drugs.

 

Potential mechanisms underlying the differential roles of GABAB1a and GABAB1b receptor subunit isoforms in stress resilience 71 The hypothalamic-pituitary-adrenal axis

Because the HPA axis is strongly implicated in stress resilience and vulnerability (Franklin et al., 2012; Reul et al., 2015; Henckens et al., 2016), it comes as no surprise that its function has been somewhat interrogated in GABAB1 subunit isoform knockout mice (O’Leary et al., 2014; Jacobson et al., 2017). Under baseline conditions, plasma corticosterone concentrations do not seem to differ between wild-type, GABABð1aÞ-=-, and GABABð1bÞ-=- male mice (Jacobson et al., 2017). However, GABABð1aÞ-=- mice exhibit blunted corticosterone and adrenocorticotropic hormone (ACTH) release in response to the 5-HT1A receptor agonist 8-OH-DPAT, whereas GABABð1bÞ-=- mice did not differ from wild-type mice (Jacobson et al., 2017). This suggests that serotonergic regulation of the HPA axis is impaired in GABABð1aÞ-=- mice. We have also examined the impact of stress on plasma corti- costerone in GABABð1bÞ-=- and GABABð1bÞ-=- mice. In male mice, stress-induced increases in plasma corticosterone were decreased in GABABð1aÞ-=- mice and increased in GABABð1bÞ-=- mice (O’Leary et al., 2014). However, these differences in stress-induced corticosterone con- centrations cannot fully explain the differential susceptibility of GABABð1aÞ-=- and GABABð1bÞ-=- mice to stress-induced changes in behavior. This is because female GABABð1aÞ-=- and GABABð1bÞ-=- mice did not differ in their corticosterone response to stress but yet exhibited differential susceptibility to stress-induced changes in depression-like behavior (O’Leary et al., 2014). However, it must also be kept in mind that there is sexual dimorphism in HPA axis regulation, and thus, it is unlikely that stress-induced changes in this system and its contribution to stress resilience would be similar in both males and females (Goel et al., 2014; Bangasser and Valentino, 2012).

Location, location, location.

Toward identifying the neural circuitry underlying the differential stress susceptibility between GABABð1aÞ-=- and GABABð1bÞ-=- mice, we measured the effects of acute restraint stress on the expression of c-Fos (an immediate early gene) in several stress-related brain areas in adult wild-type, GABABð1aÞ-=-, and GABABð1bÞ-=- mice, with and without prior maternal separation stress.

The nucleus accumbens was the only area where stress-induced c-Fos expression was differentially regulated in the stress-resilient GABABð1bÞ-=- mice by prior exposure to maternal separation stress. Specifically, maternal separation significantly increased stress- induced c-Fos expression in the nucleus accumbens of GABABð1bÞ-=- mice but not in wild- type or GABABð1aÞ-=- mice, and these effects of acute stress were not apparent in GABABð1bÞ-=- mice that had not undergone prior maternal separation. This suggests that the nucleus accumbens may be a key node in the neural circuitry of stress resilience in GABABð1bÞ-=- mice. Interestingly, GABABð1aÞ-=- mice exhibited decreased stress-induced c- Fos activation in the ventral tegmental area (VTA), and this effect was not apparent in GABABð1aÞ-=- mice that had undergone maternal separation, thus suggesting that the VTA might play a role in the stress-susceptible phenotype of these mice. Indeed, dysfunction of the nucleus accumbens and its associated reward circuitry including the VTA has already been implicated in susceptibility to stress-induced anhedonia (Russo and Nestler, 2013). Moreover, it is well established that GABAB receptors modulate VTA and nucleus

 

72 5. GABAB receptors, depression, and stress resilience: a tale of two isoforms

accumbensemediated hedonic processing as systemic, intra-VTA, or intranucleus accumbens (shell) administration of GABAB receptor agonists attenuates the rewarding effects of several drugs of abuse (Vlachou and Markou, 2010). Although there is clear role for GABAB receptor modulation of the hedonic effects of drugs of abuse, relatively little is known about GABAB receptor modulation of stress-induced anhedonia. Nevertheless, one study reported that reductions in sucrose preference induced by chronic mild stress in rats were prevented by chronic treatment with a GABAB receptor antagonist (Nowak et al., 2006), and we have shown that GABABð1aÞ-=- mice are more susceptible, whereas GABABð1bÞ-=- mice are more resilient to stress-induced anhedonia (O’Leary et al., 2014). Taken together, stress-induced differential neuronal activity patterns in the VTA- nucleus accumbens reward system of the brain in GABABð1bÞ-=- and GABABð1aÞ-=- mice may at least partially contribute their differential susceptibility to stress-induced anhedonia although this has yet to be directly tested by inhibiting these isoforms specifically in the nu- cleus accumbens or VTA.

One of the most robust genotype-dependent effects of acute stress on c-Fos expression was observed in the hippocampus (O’Leary et al., 2014), a key brain area involved in regulation of the stress response (Jacobson and Sapolsky, 1991; Brown et al., 1999) whereby the number of c- Fos-positive cells in response to acute stress was significantly increased in GABABð1bÞ-=- mice

compared with wild-type and GABABð1aÞ-=- mice. This enhanced stress-induced c-Fos activa-

tion was most apparent in the dentate gyrus and ventral CA3 regions of the hippocampus and occurred to the same extent in both nonseparated and maternally separated GABABð1bÞ-=- mice. Interestingly, GABABð1aÞ-=- mice exhibited decreased stress-induced c-Fos

in the ventral CA3, and this effect was not apparent when they had undergone prior maternal separation. Together, this suggests that GABAB receptors in the hippocampus might be impor- tant in the differential response to stress, and this observation is further supported by our find- ings (described in the next section) that maternal separation stress differentially affects adult hippocampal neurogenesis in GABABð1bÞ-=- versus GABABð1aÞ-=- mice.

Finally, we also observed that GABABð1bÞ-=- mice exhibited enhanced stress-induced neural activation in the DRN irrespective of whether they had undergone prior maternal separation or not, but unlike the hippocampus, these increases were largely restricted to comparisons with GABABð1aÞ-=- and not wild-type mice (O’Leary et al., 2014). As described earlier in this chapter,

there is accumulating evidence of a GABAB-serotonin interactions in the DRN (Cornelisse et al., 2007; Slattery et al., 2005; Takahashi et al., 2010), and the DRN plays a role in stress resilience (Challis et al., 2013). Taken together, this supports the hypothesis that GABAB receptors in the DRN may play a role in stress resilience. Within this context, however, it is noteworthy that it is the GABAB1a isoform rather than the GABAB1b isoform that is mainly expressed on seroto- nergic cells bodies DRN (Bischoff et al., 1999) and yet we did not observe any differences in stress-induced c-FOS expression in GABABð1aÞ-=- mice when compared with wild-type mice.

Adult hippocampal neurogenesis: a mechanism for resilience?

Neurogenesis, the birth of new neurons, occurs in just a few areas of the adult brain including the dentate gyrus of the hippocampus, and several extrinsic factors can alter the

 

Potential mechanisms underlying the differential roles of GABAB1a and GABAB1b receptor subunit isoforms in stress resilience 73

proliferation and survival of these adult-born neurons including stress and chronic antide- pressant treatments (Kempermann et al., 2015; Bergmann et al., 2015; Christian et al., 2014; Malberg et al., 2000; O’Leary et al., 2013). Moreover, there is emerging evidence that these adult-born hippocampal neurons may play a role in buffering the stress response as well as antidepressant regulation of the HPA axis (Levone et al., 2015; Snyder et al., 2011; Surget et al., 2011).

Accumulating evidence suggests that the GABAB receptor also modulates adult hippocampal neurogenesis (Felice et al., 2012; O’Leary et al., 2014; Giachino et al., 2014). GABAB1-=- mice exhibit increased adult hippocampal progenitor cell proliferation as well as accelerated neuronal differentiation when compared with their wild-type counterparts (Giachino et al., 2014). In addition, we have shown that a GABAB receptor antagonist, CGP52432, which has antidepressant-like behavioral effects in the FST increased hippocam- pal cell proliferation in mice (Felice et al., 2012). Interestingly, we observed that the effect of CGP52432 on hippocampal cell proliferation occurred in the ventral rather than the dorsal hippocampus. This finding is intriguing in light of a growing body of evidence that suggests the hippocampus is functionally segregated along its longitudinal axis into dorsal and ventral regions, whereby the dorsal hippocampus (dHi) plays a predominant role in the spatial learning and memory, whereas the ventral hippocampus (vHi) plays a predominant role in the regulation of emotion-related processes (Bannerman et al., 2004; Fanselow and Dong, 2010). Moreover, there is emerging evidence that adult neurogenesis may also be differentially regulated along this axis with the effects of stress on neurogenesis occurring predominantly in the vHi (Tanti and Belzung, 2013; O’Leary and Cryan, 2014; O’Leary et al., 2012).

Given the impact of stress and the GABAB receptor on adult hippocampal neurogenesis, and the identification of the hippocampus as a key brain area expressing altered neuronal responses to stress (as measured by c-Fos expression) in GABABð1bÞ-=- versus GABABð1aÞ-=- mice, we examined whether increased adult hippocampal neurogenesis may contribute to the stress-resilient phenotype of the GABABð1bÞ-=- mice (O’Leary et al., 2014). We found that male GABABð1bÞ-=- mice exhibit increased proliferation of newly born cells in the vHi but not dHi. We also found that these stress-resilient GABABð1bÞ-=- mice exhibited increased survival of new adult-born cells in the hippocampus. Interestingly, we found that under base- line conditions, this increase in the survival of new adult-born cells occurred in the dHi but not the vHi, but in GABABð1bÞ-=- mice that had undergone early-life stress (maternal separa- tion), this increased survival of new adult-born cells shifted from the dorsal to the ventral hip- pocampus. Thus, further supporting the emerging view that adult neurogenesis in the vHi rather than the dHi plays a predominant role in the response to stress. GABABð1bÞ-=- mice were also resistant to the early-life stress-induced decrease in the survival of adult-born cells in the vHi, thus suggesting a possible mechanism underlying their stress-resilient behavioral phenotype. Using female mice, we confirmed that increased adult hippocampal neurogenesis occurs in GABABð1bÞ-=- mice, whereas no differences were observed between GABABð1aÞ-=- mice and wild-type mice. This finding also suggests that the increases in adult hippocampal neurogenesis observed in GABABð1bÞ-=- mice is not sex dependent and thus parallels the sex-independent stress-resilient behavioral phenotype observed in these mice (O’Leary et al., 2014).

 

74 5. GABAB receptors, depression, and stress resilience: a tale of two isoforms

The mechanisms underlying GABAB receptor modulation of adult hippocampal neurogenesis are not yet known but may involve regulation of brain-derived neurotrophic factor (BDNF). BDNF is a neurotrophin involved in adult hippocampal neurogenesis. Moreover, it is required for antidepressant-induced increases in adult hippocampal neurogenesis and antidepressant-like behavior, and it also plays a role in stress resilience (O’Leary and Castren, 2010; Sairanen et al., 2005; Saarelainen et al., 2003; Berton et al., 2006; Krishnan et al., 2007; Bjorkholm and Monteggia, 2016). GABAB receptor antagonists have been shown to elevate BDNF protein and mRNA levels in various brain regions including the hippocampus (Heese et al., 2000; Enna et al., 2006). Thus, it will be of interest to determine whether the stress-resilient phenotypes of GABABð1bÞ-=- are due to enhanced BDNF signaling.

Conclusions

In summary, GABAB1 receptor subunit isoforms differentially regulate stress resilience (Fig. 5.1). Reductions or deletions of GABAB1b are associated with an antidepressant-like behavioral phenotype and resilience to psychostress-induced anhedonia and psychosocial stress-induced social avoidance, whereas increased hippocampal GABAB1b expression in the hippocampus has been found in a genetic mouse model of depression. On the other hand, mice lacking the GABAB1a receptor subunit isoform are more susceptible to stress- induced anhedonia and social avoidance. Experiments using c-Fos immunohistochemistry to delineate the neural circuitry underlying the differential stress sensitivity of GABABð1bÞ-=- and GABABð1aÞ-=- mice suggest that the VTA-nucleus accumbens reward pathway, the DRN, and the hippocampus are likely key brain areas involved in this neural circuitry. More- over, adult hippocampal neurogenesis and the serotonin neurotransmitter system have been shown to be differentially affected in GABABð1aÞ-=- and GABABð1bÞ-=- mice. Taken together, the GABAB1a and GABAB1b subunit isoforms represent potential novel therapeutic targets for the treatment of stress-related psychiatric disorders.

Acknowledgements

We thank Dr. Daniela Felice for assistance in creating Fig. 5.1. References

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CHAPTER

6

Sex differences in the programming of stress resilience

Kathleen E. Morrison1, 2, C. Neill Epperson3,

Tracy L. Bale1, 2
1Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD,

United States; 2Center for Epigenetic Research in Child Health and Brain Development, University of Maryland School of Medicine, Baltimore, MD, United States; 3Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, United States

Introduction

Sex is a critical factor in determining when an individual is vulnerable to stress, what type of stress is likely to produce long-term negative consequences, and in which behavioral domains the stress-induced dysfunction will manifest. Understanding how sex interacts with stress to impair psychological well-being is an important avenue of research. Exposure to chronic or extreme stressors is a major risk factor for neuropsychiatric disorders such as affective disorders, schizophrenia, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD), many of which are sex biased in their symptomology and prevalence (Tolin and Foa, 2006; Newschaffer et al., 2007; Erskine et al., 2013; Cover et al., 2014; Gore et al., 2014). Although stress researchers have long examined the negative conse- quences of stress, recent years have seen an increase in the study of resilience to stress. This is likely due to two factors: (1) epidemiological data demonstrate that whereas most humans will undergo some sort of traumatic or stressful life event, approximately an average of 10%e20% will develop long-term mental health disorders, although prevalence is dependent on age of insult, sex, and genetic factors, and (2) basic scientists are taking note of tremendous individual variation in how animals respond to stress and have begun to study these sub- groups that would have potentially been overlooked in the past (Galea et al., 2005; Cohen et al., 2007; Thomas et al., 2010).

Resilience is the capability to cope with adverse experiences such that an individual is not subject to the negative psychological and biological consequences that would otherwise lead

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00006-9 81 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

82 6. Sex differences in the programming of stress resilience

to biological dysfunction and increased disease risk (Russo et al., 2012; Cooper et al., 2015). Resilience may be demonstrated by resistance to the negative effects of stress or by recovery to a normal state of functioning more quickly than expected following a stressful event. It is important to distinguish between resistance to, and recovery from, stressful events, as these outcomes may involve distinct brain regions, neurochemical processes, and unique bio- markers. In this chapter, we use the term resilience to be inclusive of all levels of response. Throughout this chapter, it will become clear that resilience is not the same, psychologically or physiologically, as having not gone through the stressful life event (i.e., it is not the same as being unexposed or as being returned to “normal”). Indeed, resilience represents a third type of response that involves a discrete set of neural substrates and cellular mechanisms that enable individuals to avoid at least some of the negative consequences of extreme stress (Russo et al., 2012).

The term resilience carries with it many assumptions mainly that the resilient group is in a more advantageous state than the vulnerable group. Although this may seem like the easiest explanation, it is important to remember that the utility of a biological response is context dependent. Therefore, an additional nuance of resilience is how it is contextualized. Take, for example, the outcome of an altered hypothalamic-pituitary-adrenal (HPA) axis response to stress, a common affective disorder endophenotype that is observed in preclin- ical animal models including that of prenatal or pubertal stress and in models of transge- nerational transmission of stress dysregulation (Mueller and Bale, 2008; Rodgers et al., 2013; Morrison et al., 2017). Stress pathway dysregulation, as manifested in either increased or decreased reactivity, may reflect an organism’s inability to respond appropriately to a changing environment. Therefore, we might deem any individual who has a dysregulated HPA axis response following a stressful life event to be vulnerable, while those individuals who show no dysregulation are resilient. This interpretation makes sense considering the association between HPA axis dysfunction and disease state (Heim et al., 2008). However, an alternative interpretation may be that a change in the HPA axis response to stressors is adaptive. In the case of a reduced HPA axis response seen in the offspring of stressed males, a dampened HPA axis response to stress may reflect greater offspring fitness, particularly if the offspring’s environment is also stressful (Rodgers et al., 2013). In contrast, in the instance of pubertal adversity, both humans and mice show HPA axis dysregulation and alterations to maternal mood and behavior. Women are more likely to score at risk for post- natal depression, and mice show altered maternal behavior (Morrison et al., 2017). The find- ings in this instance indicate that the altered HPA axis is linked to the disease risk and reproductive status during which the stressor occurred, making relevant when the organ- ism/individual is being tested. Therefore, it is important to contextualize why stress- induced changes might manifest as resilience or risk, and to fully characterize the other end- points, such as depressive-like and anxiety-like behaviors, that pair with these physiological outcomes.

It is also important to describe what is meant by sex differences in resilience. The mere presence of a sex difference in the behavioral or physiological response to a stimulus does not necessarily qualify one sex as “resilient” and the other as “vulnerable.” Instead, sex differences in resilience arise when some aspect of their biology places males and fe- males on separate trajectories for the consequences of stress (Fig. 6.1). Take, for example, an arbitrary behavior where there is a known baseline sex difference in output of that

 

Introduction 83

FIGURE 6.1 Arbitrary behavioral responses are represented to demonstrate theoretical distinctions between a behavioral sex difference versus a sex difference in resilience to the effects of a stressful life event. Importantly, a sex difference in a behavioral response does not necessarily predict which sex will be resilient. (A) In this hypothetical example, stress-naïve females display double the amount of a behavior as stress-naïve males. When exposed to a stressful life event, there are several possibilities for resilience or risk outcomes. (B and C) On the one hand, it is possible that there will be no sex difference in how individuals respond to the stressful life event. (B) It is possible that neither males nor females will demonstrate any long-term behavioral change or that (C) both females and males will display the same magnitude of behavioral change in response to a stressful life event. (D and E) Alternatively, there may be a sex difference in how individuals respond. (D) Some stressful life events produce a behavioral effect only in males, and in this instance, females would be considered resilient. (E) The reverse can also be true, wherein females display a behavioral change and males are considered resilient.

behavior, such as rumination and self-blame in humans or risk-taking behavior in rodents (Fig. 6.1A) (Spindler et al., 2010; Johnson and Whisman, 2013; Jolles et al., 2015). Untested by the addition of a stressful life event, one is not able to determine whether males or fe- males might be categorized as resilient. It is possible that there will be no sex difference in behavioral responding following a stressful life event, suggesting that males and females are equivalent in either their resilience (Fig. 6.1B) or risk (Fig. 6.1C). Alternatively, it is possible that males and females will differ in the consequences of a stressful life event, rendering either females (Fig. 6.1D) or males (Fig. 6.1E) as resilient. This example is pre- sented in arbitrary units to illustrate many theoretical outcomes in stress-induced risk and resilience. Within this chapter, we will discuss specific examples of each of these possible outcomes. Furthermore, even though this is a nascent field, it is becoming very clear that the sex difference in programming resilience is highly nuanced. Labeling one sex with an outcome of “resilient” must be followed by qualifiers such as, to which type of stress, during which period of development, and evidenced in which behavioral or phys- iological outcome.

In general, two areas under discussion in this chapter, sex differences and resilience, are relatively new as major focuses in the field of stress research. The negative consequences of stress on males have long been studied, and although there has been a small group of expert sex difference researchers, recent changes in expectations by major funding bodies and scientific journals have fueled research on sex as a biological variable for most re- searchers. We aim here to address the current state of the field and to propose new ideas and challenges to be met in the coming decades of research. It should be noted that we will be focusing on areas where sex differences are known and some understanding of the sex-specific programming has been pursued.

 

84 6. Sex differences in the programming of stress resilience
Sex x life span interaction in producing resilience

Sex differences in the consequences of stress shift dramatically throughout the lifetime. In the prenatal period, females are likely to be resilient to the effects of a variety of stressors, including maternal trauma, maternal psychosocial stress, and maternal depression (Van Os and Selten, 1998; Khashan et al., 2008; Gerardin et al., 2011). Sex differences in resilience have been the most thoroughly studied during the prenatal window of development. One impetus for the wealth of studies that have been conducted during this time is the link be- tween the risk for neuropsychiatric disorders and adverse exposures in utero and, during childhood, sensitive periods of early brain development. During the prenatal period, the brain is forming and is undergoing substantial and rapid development. Prenatal stress is a risk factor for neurodevelopmental disorders, including ASD, ADHD, and schizophrenia, which show a marked sex bias toward presentation in males, with the overall sex ratio at 4:1 for boys:girls in ASD and 3.2:1 for ADHD (Newschaffer et al., 2007; Erskine et al., 2013; Davis and Pfaff, 2014; Gore et al., 2014). Animal studies that utilize prenatal stress confirm that female offspring are resilient to negative outcomes such as stress axis dysregu- lation, cognitive deficits, behavioral reactivity, and metabolic issues, which are endopheno- types of neurodevelopmental disorder symptoms (Lemaire et al., 2000; Schneider et al., 2002; Kapoor and Matthews, 2005; Mueller and Bale, 2007, 2008).

From birth to puberty, there are limited sex differences in the physiological stress response and presentation rate of affective disorders; however as discussed above, males are at greater risk for what is being referred to as neurodevelopmental disorders such as autism and ADHD (Kessler, 2003; Romeo and McEwen, 2006; Romeo, 2010). The directionality of sex differences in resilience to stress-induced affective dysfunction shifts in puberty and adolescence, when males are protected. Women are twice as likely as men to suffer from posttraumatic stress disorder (PTSD), and recent analyses suggest that this difference arises during puberty (Garza and Jovanovic, 2017). The same is true for depression and several anxiety disorders that emerge in adolescence, which is twice as high in females as in males (Wade et al., 2002; Hantsoo and Epperson, 2017). Importantly, there are sex differences in symptom severity in major depressive disorder (MDD) when adolescent onset is compared with adult onset. Individuals with adolescent-onset MDD are more likely to be women than those with adult-onset MDD, supporting the hypothesis that puberty and adolescent periods represent a time of increased risk in women. In all individuals with adolescent onset MDD, there was increased incidence of symptom severity including more suicide attempts compared with adult-onset MDD patients (Zisook et al., 2007). Despite these known relationships, puberty has been relatively understudied compared with early life in terms of stress reprogramming, especially in the area of sex differences. Animal models have produced somewhat conflicting results in the sex specificity of the effects of stress either during the onset of puberty or during the adolescent period, with some studies showing sex differences, some finding no difference in males and females, and some finding effects that are sex specific depending on the outcome (Toledo-Rodriguez and Sandi, 2011; Weathington et al., 2012; Harrell et al., 2013). These studies all utilize different stressors, applied for different lengths of time, and starting at slightly different ages. A significant issue for studying this period is the inconsistency across rodent models as to what constitutes puberty and adolescence. This is problematic for inter- pretation of findings, as well as for rigor and reproducibility. Development of the brain and

 

Sex x life span interaction in producing resilience 85

hormone axes during this period is rapid and dynamic, which may also account for dispar- ities in animal research. In humans, adolescence is more protracted and associated with a peak and subsequent decline in cortical gray matter and a continual and sexually dimorphic increase in cortical white matter volume in both the frontal and parietal lobes by early adult- hood (Pfefferbaum et al., 1994; Giedd et al., 1999; Perrin et al., 2008; Gennatas et al., 2017). Furthermore, the development of important limbic brain areas, including the prefrontal cortex, hippocampus, and amygdala, which are known to be disrupted in neuropsychiatric disorders, has been demonstrated across adolescence in animal models (Lee et al., 2003; Isgor et al., 2004; Matsuoka et al., 2010; Scherf et al., 2013).

When the stressful life event occurs in adulthood, the sex difference in resilience is less pro- nounced, perhaps because adults are generally more resilient to the same stressors that will produce long-term consequences in younger individuals. Furthermore, although adults are still susceptible to acute consequences of stress, lasting 24e48 h following stress, they are less likely to be subject to the long-term reprogramming observed in younger and aged pop- ulations. In animal studies, stressors that produce dysfunction when experienced earlier in life are less likely to have any major or lasting effects on behavior in adults (Belda et al., 2004; Lupien et al., 2009). This may be because nervous system development plateaus in adulthood. Although the brain is still sensitive to input, and will therefore respond to stress as it is happening, it is more likely to return to baseline following the end of stress (Lupien et al., 2009). Even stressors that can produce more long-lasting effects, such as ethological stressors like social defeat stress, will not produce a permanent change in behavior among adults. In hamsters, it has been demonstrated that the effect of social defeat stress can last up to 33 days, and although this is relatively long-lasting, it is not a lifetime effect (Huhman et al., 2003). Alternatively, there are models such as learned helplessness, where exposure to uncontrollable or inescapable shock in adults produces a robust change to a suite of behav- iors. In this instance, the effects are found to dissipate by 72 h following stressor exposure (Hammack et al., 2012). There are exceptions to these findings, most notably in the case of PTSD. PTSD is triggered by exposure to a severe traumatic event, and a single event can pro- duce a lifetime of negative consequences. However, PTSD only presents in a subset of indi- viduals that are exposed to trauma, and individual differences in biological responses such as the HPA axis are being examined as an underlying component of disease risk (Rodgers and Bale, 2015). Adulthood can then be a prime example of when the “two-hit” hypothesis of stress susceptibility or the concept of allostatic load, wherein an individual needs two risk factors, such as genetic risk, prior stressful experience, vulnerable period of brain devel- opment, or some physiological risk factor (see pregnancy below), to manifest as disease (Nederhof and Schmidt, 2012; Kuhn et al., 2016). Indeed, studies have shown that some amount of stress, whether in a controllable situation or at a subthreshold level for leading to disease, can produce better coping and resilience in the future (Karatsoreos et al., 2013).

One example of the vulnerable window for risk and resilience of adults is during preg- nancy and the postpartum period, when risk for affective disturbance is revealed in up to 20% of women (Dorn and Chrousos, 1997; Babb et al., 2015). Peripartum depression and anx- iety are associated with significant adverse and long-term effects for both mother and baby (Gavin et al., 2005; Borri et al., 2008; Vesga-López et al., 2008). In consideration of the “two-hit” hypothesis, pregnancy can be thought of as an additional hit of stress that can interact with factors such as early-life stress or stress during pregnancy and postpartum to

 

86 6. Sex differences in the programming of stress resilience

produce vulnerability to long-term negative outcomes. Although there are limited animal studies that focus on pregnancy and the maternal outcome, as opposed to how stress during pregnancy impacts the offspring, their results do support clinical findings. During pregnancy, females experience another period of nervous system vulnerability, where stressful experi- ences can produce long-term negative outcomes (Brummelte et al., 2006). The mechanisms of brain vulnerability during pregnancy are understudied, although it has been hypothesized that increased levels of hormones and alterations in the immune system are key factors (Sherer et al., 2017). Chronic stress or glucocorticoid exposure during pregnancy and post- partum produces disruptions in maternal behavior and lasting alterations in hippocampal plasticity of the dam (Brummelte et al., 2006; Nephew and Bridges, 2011). There are also data in rodents showing that a negative experience during one pregnancy can influence the behavior of females during subsequence pregnancies. For example, elevated stress hor- mones during one pregnancy can alter postpartum behavior during a second pregnancy, even in the absence of any kind of negative stimulus in the index pregnancy or postnatal period (Wong et al., 2011). These preclinical data suggest that pregnancy and postpartum are windows of vulnerability for stressful life experiences to precipitate lasting dysfunction in brain and behavior. Therefore, entering into pregnancy and postpartum can transiently decrease the typical resilience observed in adult animals, rendering females vulnerable to stressful life experiences.

In aged populations, we see again that males are more likely to be resilient to the effects of stress on cognitive decline and affective disturbance. However, risk for disturbance increases in women. Women are two to three times more likely to experience first onset depression dur- ing perimenopause, and late-onset schizophrenia is two times higher in women than in men (Nemeroff, 2007; Freeman et al., 2014). In the aging brain, reproductive senescence, particu- larly the perimenopausal period, leads to another vulnerable period for sensitivity to the effects of a stressful life event, especially in women. Biological functions such as the HPA axis are altered in a sex-specific way in aging. Older women show increased cortisol in response to a variety of stressors, including a cognitive challenge, pharmacological challenge, or psychological challenge, compared with age-matched men as well as younger men and women (Seeman et al., 2001; Kudielka et al., 2004; Kudielka and Kirschbaum, 2005; Otte et al., 2005). As the HPA axis is disrupted in many affective disorders, this shift in responsive- ness might represent an increased vulnerability in perimenopausal women. There have been similar findings in animal studies of the HPA axis during aging, where aged female rats have higher basal corticosterone compared with age-matched males (Bowman et al., 2006). The decrease in estrogen during aging has been associated with issues of cognitive function, potentially through alterations to synaptic plasticity. For example, neural plasticity, as evi- denced by hippocampal and hypothalamic synaptogenesis, is sensitive to estrogen (Woolley, 2007). Animal studies have shown that middle-aged female mice are more susceptible to stress effects on neurogenesis in the hippocampus than males (Tzeng et al., 2016).

How is it that the sex of an individual produces such a dynamic change in resilience throughout the life span? The ability to conduct mechanistic studies that examine the drivers of sex-specific nervous system development have pointed to the role of gonadal hormones and sex chromosome complement as key factors in nervous system development and resil- ience to stress.

 

Sex hormone x life span interaction in producing resilience 87 Sex hormone x life span interaction in producing resilience

Sex differences in nervous system development seem to arise from several sources. The role of gonadal hormones in producing sex differences in brain development and behavior is well established (MacLusky and Naftolin, 1981; McCarthy et al., 2012). The classic view of this is known as the “activational and organizational” hypothesis, whereby exposure to different gonadal hormones, androgens in males and estrogens in females, programs perma- nent sex-specific development and behavior. During the prenatal and perinatal window, males experience a testicular testosterone surge that is responsible for organizing the brain to respond to future activational effects of hormones, such as that occurs at puberty and throughout adulthood, to produce male-specific brain development and behaviors (Phoenix et al., 1959). For many decades following the establishment of the “organizational and activa- tional” hypothesis, it was accepted dogma that the hormone surge that occurs during puberty merely “turns on” the sex differences that were programmed perinatally. However, more recent studies have shed light on the discovery that the onset of hormones in puberty also organizes brain and behavior (Romeo, 2003; Schulz et al., 2009). When gonadal hormone exposure in puberty is delayed, there are irreversible effects on brain maturation. Castrated males show deficits in masculine behavior that cannot be recovered by later testosterone treatment or sexual experience. This extends to other behaviors such as flank-marking, which is dependent on testosterone exposure. Castration prior to puberty results in disruption in flank-marking and the neural circuits that underlie the behavior. If males were castrated prior to the start of puberty, adult exposure to testosterone could not recover the deficits in flank- marking behavior. Similar studies have been done in females, demonstrating that ovariec- tomy prior to puberty disrupts lordosis behavior in adults (Schulz et al., 2004, 2006; Schulz and Sisk, 2006). Therefore, aging represents another period where there is a sex difference in resilience to stress. Males may be categorized as resilient, although this is only relative to females who are really demonstrating increased vulnerability.

Gonadal testosterone contributes to prenatal and perinatal sex-specific brain development. Animal studies have shown that aromatization of gonadal testosterone to estradiol in the brain drives masculinization, which affects cell differentiation and brain connectivity (McCarthy and Arnold, 2011; McCarthy and Nugent, 2013). This estradiol is critical in direct- ing cell death and cell birth in the developing nervous system, especially in sexually dimor- phic brain regions (Morgan and Bale, 2012; McCarthy and Nugent, 2013). In females, other processes are important for feminizing sex-specific regions of the brain, including DNA methylation to repress masculinization (Nugent et al., 2015).

Although the role for gonad-derived sex hormones in brain development is clear, recent work has uncovered critical new sources of these hormones during gestation. Even prior to the presence of testicular testosterone during the perinatal period, the placenta provides the developing fetus with steroid hormones. The placenta is a particularly interesting candi- date for determining sex differences in resilience. The placenta is the barrier between the maternal and fetal compartments, determining what signals pass through to the fetal compartment (Nugent and Bale, 2015). The placenta has robust steroidogenic activity, and the male placenta produces high levels of testosterone during gestation. This testosterone exposure has been implicated in the vulnerability of males to prenatal stress. Clinical studies

 

88 6. Sex differences in the programming of stress resilience

show a correlation between fetal testosterone and alterations in steroidogenic activity in the placenta that are characteristic of neurodevelopmental disorders (Ruta et al., 2011; Lombardo et al., 2012; Gore et al., 2014; Baron-Cohen et al., 2015). Therefore, female resilience to prenatal stress may be in part derived from the fact that female placentas are not sensitive to disrup- tions in steroidogenic activity.

The surge of sex hormones in puberty also influences physiological processes that deter- mine how males and females respond to stress. The responsiveness of the HPA axis in pre- pubescent animals is different from that of the fully matured adult response. In response to a variety of stimuli, male and female prepubescent rodents have an HPA axis characterized by a protracted hormonal response compared with neonatal and adult animals, and an insensi- tivity to factors, such as gonadal hormones, that normally modulate the adult response (Romeo et al., 2004a,b, 2013). Following the rise in hormones that is triggered by the reemer- gence of gonadotropin-releasing hormone, the HPA axis, as well as other important processes including sex-specific cell proliferation in several brain regions, begins to mature into the adult, sex-dependent phenotype. Although it is known that gonadal hormones are critical in organizing the pubertal brain, more work needs to be done to directly address the role that these hormones play in stress resilience.

Still another relative mystery is the mechanism by which extraordinarily high hormone levels during pregnancy could produce a stress vulnerability that is not normally seen in adult females. Neuroactive steroids such as estradiol, progesterone, and allopregnanolone are dramatically increased in the periphery and in the brain, where they can modulate the function of multiple neurotransmitter systems. Within 3 days of childbirth, these same neuro- active steroids drop to postmenopausal levels. These dynamic changes in steroid levels require the female brain to be flexible and resilient. The complex questions of the mechanisms of risk for affective dysfunction during pregnancy represent an important area for future research, as maternal mental health is being recognized as an increasingly significant concern in the lifetime of women.

The sex difference in resilience in aging, when females are more vulnerable to stress than males, is explained in part by the onset of reproductive senescence in females when gonadal steroids shift dramatically and somewhat erratically for years and then decline to hypogonadal levels during the postmenopause. In contrast, males experience less dramatic or no change in gonadal hormone levels until much later in life. These hormonal fluctuations and resultant hypogonadism are likely contributors to the reduced resilience in aging females, as estradiol and progesterone are key molecules in maintaining brain structure and function, including executive function, learning and memory, and stress regulation (Shanmugan and Epperson, 2014). As with puberty and pregnancy, the exact nature of the mechanism linking reduced gonadal hormone levels to vulnerability in aged females has yet to be examined.

Sex chromosome x life span interaction in producing resilience

As gonadal hormones are critical to determining sex differences in the brain, it is important to understand what drives sex differences in gonadal hormone secretion. Sex chromosome complement, XX in females and XY in males, is the determining genetic factor for sex of an individual and the underlying contributor in many sex-specific biological processes,

 

Conclusion 89

including gonadal hormone secretion. As described above, a long-held view of brain devel- opment is that exposure to gonadal hormones is the main driver of sexual differentiation. In recent years, it has also been shown that sex chromosome complement produces organiza- tional sex differences in the brain that are independent of gonadal hormone levels. This work has been achieved with the use of the “four-core” genotype mice, a line of mice where the testes determining factor gene, Sry, has been transposed onto an autosome, producing gonadal females (XX or XY , with ovaries) and males (XY, XY Sry, or XXSry, with testes) (De Vries et al., 2002). Studies utilizing these mice have demonstrated a role for sex chromo- somes that is dissociable from the action of gonadal hormones in brain maturation. For example, sex differences in the vasopressin system are more masculinized XY Sry males than XXSry males, indicating an effect of sex chromosome complement beyond the fact that both of these types of males have testes (De Vries et al., 2002). Although the specific role for sex chromosomes in stress resilience has not been examined, the work with the four-core model suggests that sex chromosome complement is critical in guiding sex- specific development of brain and behavior.

Developmentally, sex chromosomes play a critical role very early in gestation, including an important role in the function of the placenta. The placenta is a tissue of fetal origin, and therefore the fetal aspect of the placenta carries the sex chromosome complement of the fetus. Sex chromosome complement is a critical determinant in the response of the placenta to maternal insults, where the female placenta seems to provide a protective effect (Nugent and Bale, 2015). Genes on the sex chromosomes are expressed early in placental dif- ferentiation in rodents and humans, providing sex-specific transplacental signals. Impor- tantly, genes linked to sex chromosomes play a role in female resilience to maternal stress (Bale, 2016). In an established mouse model of early prenatal stress (EPS), male, but not fe- male, offspring demonstrate increased stress sensitivity as adults (Mueller and Bale, 2008). Through genome-wide screening for EPS-induced changes in the placenta, the X-linked gene O-linked N-acetylglucosamine transferase (OGT) was identified as a top candidate for regu- lating the cellular response to changes in the maternal milieu. Subsequent mechanistic studies confirmed that lower levels of OGT in males promote an increased risk for stress-induced changes in neurodevelopmental programming and metabolic regulation (Howerton et al., 2013; Howerton and Bale, 2014). Therefore, the increased level of OGT within the female placenta appears to provide a resiliency factor to the effects of maternal insults. This provides one very early developmental mechanism whereby sex chromosomes are a critical factor in prenatal female resilience.

Conclusion

As stress is an inevitable and seemingly increasing part of daily life, the opportunity to study what programs resilience, as well as risk, is an important direction of scientific research. By studying resilient populations, we can learn (1) what types of experiences counteract the effects of stress and (2) the genetic, biochemical, and molecular signature of resilience (Lyons et al., 2010; Drury et al., 2016). The nascent field of studying sex differences in resilience has already provided evidence that it is important to understand how males and females respond differently to stress, as has been discussed in this chapter.

 

90 6. Sex differences in the programming of stress resilience Acknowledgments

This work was supported by the National Institutes of Health grants HD091376 (KEM), MH099910 (TLB and CNE), ES028202 (TLB), MH104184 (TLB), and MH108286 (TLB).

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CHAPTER

7

Active resilience in response to traumatic stress

Gal Richter-Levin1, 2, 3, Iris Müller4, 5, Kuldeep Tripathi2,

Oliver Stork4, 6
1Department of Psychology, University of Haifa, Haifa, Israel; 2Sagol Department of

Neurobiology, University of Haifa, Haifa, Israel; 3The Integrated Brain and Behavior Research Center (IBBR), University of Haifa, Haifa, Israel; 4Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany; 5Department of Psychological Sciences, Purdue University, Indianapolis, IN, United States; 6Center for Behavioral Brain Sciences, Magdeburg, Germany

Resilienceda passive lack of effect or an active response?

The response to stress is variable. Some individuals are able to overcome and manage exposure to even severe stress, whereas others will be severely affected by the same experience. It is common to say “he/she was not affected by the experience,” but in fact, two different possible scenarios could explain such lack of effect at the level of behavioral symptoms: either indeed the stress experience had no effect or the stress experience did affect the neural stress response, but it was activated in such a way that enabled coping. When considering severe stressful experiences, it is in fact unlikely that the experience had no effect. It is much more likely that there was an impact, but that the response was effective in coping with the challenge. This is what we refer to here as “active resilience.”

Employing a model of posttraumatic stress disorder (PTSD) we developed, we recently found that, like in humans, some animals are significantly affected by exposure to trauma, whereas others did not exhibit any significant symptoms. Interestingly, the map of activation of brain areas in the nonaffected animals was different not only from that of the affected in- dividuals but also from that of the control, not exposed group. These results indicate that indeed, resilience is not a passive lack of response but rather an active response that enabled coping (Ritov et al., 2016). Furthermore, the selective map of activity of resilient individuals indicated a significant contribution to activation of GABAergic interneurons, suggesting that

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00007-0 95 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

96 7. Active resilience in response to traumatic stress

these interneurons may play an important role in active resilience (Ritov et al., 2016). Thus, although we are certain that various neural systems in several brain areas contribute to active resilience, in this chapter we will focus on one such target molecule, glutamic acid decarbox- ylase (GAD).

Two isozymes of glutamic acid decarboxylase

g-Aminobutyric acid (GABA) is synthesized through the decarboxylation of glutamate by two isozymes of GAD, named GAD65 and GAD67, after their respective molecular weights. These two enzymes are encoded by separate genes and underlie differential modes of regu- lation (Erlander et al., 1991; Kaufman et al., 1991). Although these enzymes are typically coex- pressed in GABAergic neurons, total levels and ratios differ greatly between brain regions and individual cells (Sheikh et al., 1999; Heldt and Ressler, 2007). Moreover, the isozymes appear to produce GABA for different cellular purposes. Several findings suggest that GAD65 produces GABA for rapid release in an activity-dependent manner: (1) it is primarily found at the synapse (Kaufman et al., 1991), (2) saturation with the cofactor pyridoxal phos- phate is low (Kaufman et al., 1991; Martin et al., 1991), and (3) membrane association to GABA vesicles is reversible (Christgau et al., 1991, 1992; Reetz et al., 1991). In contrast, GAD67 is localized in the cytoplasm and synthesizes GABA for metabolic needs of the cell (Erlander et al., 1991; Kaufman et al., 1991). However, this functional distinction is by no means strict, as the isozymes can form heteromers (Sheikh and Martin, 1996). Knockout of GAD65 indicates that GAD67 can, to some extent, produce GABA for vesicular release (Wu et al., 2007). The two isozymes display specific developmental functions, as GAD67 is critical in prenatal development (Asada et al., 1997), whereas GAD65 determines GABA levels in postnatal maturation (Stork et al., 2000; Iwai et al., 2003; Ji and Obata, 1999).

GAD genes are regulated in response to fear and stress

The comparison of effects of acute and chronic stress on GAD expression (Bowers et al., 1998) suggests a highly specific and differential expression regulation of both isozymes in the amygdala, bed nucleus of the stria terminalis, dentate gyrus (DG), and CA3, as well as various hypothalamic subregions, including peri-paraventricular region, medial preoptic area, anterior hypothalamic area, and the dorsomedial hypothalamic nucleus. Widespread regulation of GAD67 has recently been reported after chronic social subordination stress (Makinson et al., 2015). It should be considered that GAD expression is highly dependent on the nature of the stressor experienced and the species-specific stress response. It was shown that expression of GAD67 is reduced in the mouse amygdala after chronic restraint stress (Gilabert-Juan et al., 2011) and in the str. lacunosum-moleculare of area CA1 as well as str. lucidum and str. radiatum of area CA3 following chronic mild stress (Gilabert-Juan et al., 2016). However, another study, in rats, found no effect of restraint but reduced GAD65 in the hippocampus and reduced GAD67 in the amygdala after chronic daily corticosterone injection (Lussier et al., 2013). GAD67 is increased in the rat amygdala after

 

 

GAD is required for resilience 97

isolation rearing, with no apparent effect on GAD65 levels (Gilabert-Juan et al., 2012), but GAD65/67 immunoreactivity is lastingly decreased throughout the rat amygdala as well as in the dorsal lateral septum following a 7-day unpredictable peripubertal stress protocol (Tzanoulinou et al., 2014; Cordero et al., 2016). Moreover, GAD65 and GAD67 were found to be differentially regulated in the dorsal hippocampus and the amygdala following condi- tioned fear stress (Bergado-Acosta et al., 2008; Heldt and Ressler, 2007). Following Pavlovian fear conditioning, GAD65 is transiently decreased in both regions, although with different time course (6 h after training in the hippocampus, 24 h after training in the amygdala; Bergado-Acosta et al., 2008). Moreover, GAD65 in the hippocampal subregion cornu amonis (CA)1 increases in the surrounding of brain-derived neurotrophic factor (BDNF)eenriched neurons after contextual fear conditioning (Chen et al., 2007). We could further show that GAD65 expression in the dorsal DG decreases only after controllable but not after uncontrol- lable stress in a two-way active avoidance paradigm, whereas its expression in the basolateral amygdala (BLA) is reduced regardless of stressor controllability (Hadad-Ophir et al., 2017). In line with this, expression of GAD67, but not of GAD65, in the hippocampus and medial prefrontal cortex (PFC) was decreased in a model of chronic unpredictable stress exposure (Banasr et al., 2017). Another study showed no change of GAD65 in the BLA following unpredictable restraint stress but a positive correlation of individual expression levels in area CA1 with performance in a spatial learning task (Ortiz et al., 2015) Thus, controlling levels of GAD65 and GAD67 expression appear to provide a mechanism for fine-tuning of inhibitory function in response to different stressful experiences and stress qualities and may explain the differential effects of mutation of these genes in different forms of stress-induced psychopathology. However, these results also portray a complex relationship between GAD65 and GAD67 expression and the impact of stress exposure.

GAD is required for resilience

Work from animal experiments strongly suggests that deficiency in either GAD65 or GAD67 is detrimental to the animal’s ability to resist stress-induced pathology.

Homozygous GAD67( / ) mice die shortly after birth due to the development of cleft pal- ate (Asada et al., 1997). In contrast, GAD65( / ) mice are viable and display no discernible morphological alterations but have around a 50% deficit in GABA content in the adult amyg- dala, hippocampus, and parietal cortex (Asada et al., 1996; Kash et al., 1997; Stork et al., 2000). This results in a reduction of phasic inhibition as observed in the amygdala (Lange et al., 2014) without apparent changes in the expression of GABAA receptors or response to the GABAA receptor agonist muscimol (Kash et al., 1999). Moreover, tonic inhibition may be diminished as indicated by the analysis of cortical wedges of GAD65( / ) mice (Walls et al., 2010).

Behaviorally, GAD65( / ) mice show increased levels of anxiety, and reduced anxiolytic effects of the benzodiazepine diazepam are observed which likely result from a deficit in GABAergic function in the BLA (Kash et al., 1999; Stork et al., 2000). Recently, we demon- strated an effect of a GAD65 promoter polymorphism on harm avoidance as an endophe- notype related to anxiety behavior in women, mediated by the anterior cingulate cortex (Colic et al., 2019).

 

98 7. Active resilience in response to traumatic stress

Furthermore, in mice we could demonstrate the generalization of auditory fear memory to a neutral acoustic stimulus in GAD65( / ) mice (Bergado-Acosta et al., 2008). Shaban et al. (2006) reported auditory generalization upon intensive training as well as reduced presynaptic inhi- bition of thalamic fibers terminating in the amygdala of mice deficient for the presynaptic GABAB(1a) receptor. And indeed, GAD65 deficiency leads to a reduced spillover of GABA to presynaptic GABAB receptors (Lange et al., 2014). Of note, the observed fear generalization of GAD65( / ) mice and associated network activity changes occurred only during long-term memory but not during short-term memory retrieval, suggesting that GAD65 serves to prevent generalization during the consolidation process of fear memory (Bergado-Acosta et al., 2008).

Moreover, it appears that both GAD65 and GAD67 support fear extinction. Other than in acquisition and retrieval, GAD67 in the amygdala is of significant importance, as a regional knockdown results in profound extinction deficit (Heldt et al., 2012). Differences in GAD67 expression level in the central amygdala and its induction in both prelimbic cortex and central amygdala are associated with enhanced contextual freezing levels and responsiveness to a corticotropin-releasing factor (CRF) receptor 1 antagonist in high-anxiety rats (Skorzewska et al., 2017). Extinction of 1-day-old fear memory results in high GAD67 levels in the PFC and low GAD65 levels in hippocampal DG and CA1, whereas increased GAD65 levels are observed in the amygdala after extinction of a 14-day-old fear memory (Sangha et al., 2012). These data demonstrate the differential recruitment of GAD65 and GAD67 with respect to memory duration as, for example, the dorsal hippocampus is involved in recently acquired memories but not in older ones (Frankland et al., 2006). Accordingly, GAD65( / ) mice 1 day after fear learning display impaired cue-specific extinction accompanied by sus- tained amygdalo-hippocampal synchronization (Sangha et al., 2009).

GAD65 is required for preventing behavioral overreaction to a threat situation, as GAD65( / ) mice show an altered expression of conditioned fear, that is, increased escape attempts compared with wild types. This behavioral change occurs in the presence of apparently normal autonomous or hormonal activation and is particularly evident when high-intensity unconditioned stimulus (US) are used (Stork et al., 2003) or when training and retrieval take place in the first half of their active phase (Bergado-Acosta et al., 2014). Moreover, GAD65( / ) mice spend less time being immobile in the forced swim test (Stork et al., 2000), underlining their generally increased psychomotor activity upon stress experi- ence. Mapping of conditioned fear-induced neural activity patterns in GAD65( / ) mice with c-Fos immunohistochemistry revealed an increased activation of the hippocampus, amygdala, and anterior and ventromedial hypothalamus, when compared with high freezing mutants and wild types (Bergado-Acosta et al., 2014). This is in agreement with the observa- tion that stimulation of the ventromedial hypothalamus (Wilent et al., 2010) and the amyg- dala (Sajdyk and Shekhar, 2000) can trigger escape behaviors and that reducing the GABAergic tone in the ventromedial hypothalamus increases anxiety- and panic-related behavior (Bueno et al., 2007) as well as fear-potentiated startle (Santos et al., 2008). Undi- rected activity outbreaks are characteristic for panic disorders (Blanchard et al., 1997), and application of yohimbine, a panicogenic drug, triggers fear responses similar to those of GAD65 mutants (Blanchard et al., 1993). Thus, it is not surprising that genetic studies have found an association of the GAD1 gene, encoding GAD67, with panic disorder in human pa- tients (Hettema et al., 2006; Weber et al., 2012). A hyperexcitable hippocampus with reduced GAD65/67 expression was also reported in a genetic mouse model of panic disorder, the

 

GAD65 haplodeficiency conveys stress resilience 99

TrkC transgenic mouse, which could be rescued by intrahippocampal application of tiaga- bine, an inhibitor of GABA reuptake (Santos et al., 2013).

Strikingly, in GAD65( / ) mice, mild stress experience elicits epileptic seizures and induces c-Fos expression particularly in the DG and CA3 region of the hippocampus (Kash et al., 1997). In accordance, we observed increased probability of recurrent epileptiform discharges in area CA3 of hippocampal slices after application of moderate concentrations of kainate (Müller et al., 2015). As suggested by others, a possible mechanism behind this un- controlled excitability could be an impairment in GABA release under elevated network excitability (such as during stress; Choi et al., 2002; Hensch, 1998; Kash et al., 1997; Tian et al., 1999). Comparably, stress is reported to be one of the leading factors responsible for triggering seizures in epilepsy patients (Frucht et al., 2000; Haut et al., 2007; Nakken et al., 2005; Spector et al., 2000; Sperling et al., 2008).

Stress is also considered an important trigger for schizophrenia (Walker and Diforio, 1997). Although the majority of genetic and postmortem findings implicate GAD67 rather than GAD65 in this disease (Curley et al., 2011; Glausier et al., 2015; Guidotti et al., 2000; Impagnatiello et al., 1998; Liu et al., 2001; Volk et al., 2000), diminished GAD65 in PFC has recently been reported in a mouse model of schizophrenia (Richetto et al., 2014). Heldt et al. (2004) reported impaired prepulse inhibition (PPI) in GAD65( / ) mice, indicating deficits in sensorimotor gating (Ludewig et al., 2002). Likewise, a mouse strain with diminished multisen- sory integration also displays reduced GAD65 expression (Gogolla et al., 2014). GAD65( / ) mice further display moderate deficits in social behavior, specifically reduced aggressive behavior in the male intruder test (Stork et al., 2000). In contrast, GAD67(þ/ ) mice, in spite of only minor reduction of total brain GABA content (16% in the young adult), display pro- nounced disturbances in social behavior, including reduced social affiliation and aggressive behavior as well as a reduced sensitivity for both social and nonsocial odors. They also present reduced baseline levels of adrenocorticotropic hormone and corticosterone levels due to a dys- regulation of CRF expression in the paraventricular nucleus (Kakizawa et al., 2016) However, in contrast to GAD65( / ) mice, they show no evidence for alterations of anxiety-like behavior (Sandhu et al., 2014), emphasizing again the isoform specificity of GAD functions.

In summary, the highly dynamic and region-specific regulation of GAD65 and GAD67 expression is required to cope with stressful situations, develop appropriate behavioral responses, and prevent the development of pathologies. The upcoming task will be to deter- mine how the stress-induced regulation of these isozymes in defined brain regions contributes to each of these protective functions and what are the precise neuronal circuits involved.

GAD65 haplodeficiency conveys stress resilience

In humans, susceptibility to develop PTSD or other stress-induced psychopathologies is largely increased by the experience of childhood adversity (Chou, 2012; Ehlert, 2013), but of all trauma-exposed individuals, only about 20%e30% will go on to develop a clinical pheno- type (Zohar et al., 2008). Genetic disposition, childhood abuse, and lack of social support have been identified as critical determinants for pathology development (Yehuda and LeDoux, 2007), and animal models of juvenile stress have been developed to study some of these processes (Avital and Richter-Levin, 2005; Horovitz et al., 2012; Tsoory et al., 2008).

 

100 7. Active resilience in response to traumatic stress

We investigated the potential interaction of juvenile stress with GAD65 mutation in GAD65(þ/ ) mice, which display a delayed maturation of the GABAergic system during adolescence but normal levels in adulthood (Müller et al., 2014; Stork et al., 2000). To this end, we applied either brief variable stress (Tsoory et al., 2008) or prolonged social isolation (Pibiri et al., 2008) to juvenile GAD65 haplodeficient mice and their wild-type littermates. Both stressors varied in intensity and duration. Given the importance of proper GABAergic functioning in response to stress (Vaiva et al., 2006, 2004) and the delayed GABAergic matu- ration in these mice (Stork et al., 2000), we expected increased vulnerability in GAD65(þ/ ) mice to adulthood challenges such as fear conditioning. In contrast, resilience to the variable juvenile stress regimen could be observed, as haplodeficient mice displayed significantly reduced contextual generalization of fear memory following juvenile variable stress (Müller et al., 2014). No comparable genotype difference was observed concerning social affiliation and depression-like behavior in a tail suspension test, indicating that the protective effect of GAD65 haplodeficiency was specific for the behavioral fear domain (Müller et al., 2014). More- over, we could rule out an effect on fear expression, as hyperactivity bouts were not increased in GAD65(þ/ ) mice (Müller et al., 2015).

This indicates that, in GAD65(þ/ ) mice, adaptive processes can be triggered by brief stressful events in youth, before GABA production reaches its normal level in adulthood (Müller et al., 2015), and that this delayed maturation of the GABAergic system can somehow enable later resilience toward challenges in adulthood.

GAD65 and stress resilienceda complex picture

Results obtained so far clearly indicate that GAD65 functioning is relevant to stress vulner- ability and stress resilience. However, the variable results regarding stress-related alterations in the expression of GAD65 reported above, together with the differences between effects of homozygous GAD65( / ) knockout and GAD65 haplodeficiency (GAD65(þ/ ) mice), suggest that the role of GAD65 in stress vulnerability and stress resilience may differ in different brain regions and between different developmental stages. More temporal- and spatial-specific ma- nipulations of expression are required to more accurately describe the role played by this enzyme in coping with stress.

Recently, we initiated a study in which the expression of GAD65 is modulated by means of viral vectors in a temporal- and spatial-specific manner. This approach enables deciphering the role of local alterations in GAD expression at specific developmental time periods. Although the results are still accumulating, we found that reducing the expression of GAD65 in the ventral hippocampus of adult rats has a very different impact compared with a similar manipulation in the dorsal hippocampus. Reducing the expression of GAD65 in the ventral hippocampus is associated with increased anxiety, as measured in the open field test and the elevated plus maze. In contrast, reducing the expression of GAD65 in the dorsal hippocampus resulted in a significant reduction in anxiety behavior. Potentially, such local manipulation could be expected to reduce the impact of exposure to trauma and increase resilience. We have started examining this possibility by first exposing animals to juvenile trauma, then employing such viral vector manipulation in the dorsal hip- pocampus, and testing the impact of the trauma in adulthood, comparing between animals

 

References 101

that did or did not receive that manipulation. Preliminary data seem very promising, and although more experiments are required to finalize these findings, the results obtained so far strongly support the concept that GAD65 levels of expression may affect both stress vulnerability and stress resilience, depending on the brain region and the developmental stage under investigation.

Summary

GABAergic malfunctions are present in various mental disorders, but further research will have to consider that GABAergic interneurons in the brain appear with an almost bewildering variety of anatomical, physiological, and neurochemical features. Different subpopulations of such interneurons are perfectly equipped for patterning the information input (dendrite target- ing interneurons), controlling cellular excitability and output generation (basket cells and chandelier cells), and controlling various forms of complex network activities (Winkelmann et al., 2014). These interneurons use a variety of neuropeptide cotransmitters that themselves exert profound effects on fear, anxiety, and stress response (e.g., neuropeptide Y, cholecysto- kinin, Lach and de Lima, 2013; Serova et al., 2014; Sherrin et al., 2009; Hadad-Ophir et al., 2017; Banasr et al., 2017; Raza et al., 2017). The interaction of neuropeptide function with GAD65-mediated GABA synthesis still needs to be explored. Future studies with conditional mutants and acute genetic intervention tools will be able to address the observed differential GAD65 and GAD67 regulation in such selected interneuron populations and their roles in stress-induced pathogenesis and stress resilience.

Acknowledgments

This work was supported by the German Research Foundation (Project STO488/6 to OS and GRL).

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CHAPTER

8

Rhythms of stress resilience

Francesca Spiga, Stafford L. Lightman

Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, United Kingdom

Hypothalamic-pituitary-adrenal axis rhythms

Glucocorticoids (cortisol in humans and corticosterone in rodents; GCs) are vital hormones that regulate many physiological functions, including glucose, fat, and protein metabolism (Cherrington, 1999; Macfarlane et al., 2008; Munck et al., 1984). In addition, GCs exert anti- inflammatory and immunosuppressive actions and can affect mood and cognitive function (Chrousos, 1995; de Kloet, 2000; McEwen, 2007). Circulating levels of GC are regulated by the activity of the hypothalamic-pituitary-adrenal (HPA) axis (Fig. 8.1A). The activity of the HPA axis increases when the organism is exposed to stress.

The HPA axis is also active under basal (i.e., unstressed) conditions, and the release of GCs hormones is characterized by a circadian rhythm (Fig. 8.1B), with higher levels of hormone during the active phase (night in rodents, day in human). The circadian variation in GC levels over the 24-h cycle is not made up of a smooth change in hormone levels but is in fact char- acterized by a rapid ultradian, pulsatile pattern of hormone secretion, with a periodicity of approximately 1 h in the rat (Fig. 8.1B). Ultradian GC rhythm has been reported in numerous species, including rat (Jasper and Engeland, 1991; Windle et al., 1998b), rhesus monkey (Holaday et al., 1977; Tapp et al., 1984), sheep (Fulkerson, 1978), and human (Henley et al., 2009; Lewis et al., 2005; Weitzman et al., 1971).

Circadian and ultradian rhythms of GCs are important factors in determining the behav- ioral, neuroendocrine, and genomic response to stressors. A number of studies have shown that disruption of these rhythms occurs in a number of physiological and pathological con- ditions, including aging and chronic inflammatory disease (reviewed in Spiga et al., 2014). Importantly, changes in GC rhythms are also associated with changes in the GCs response to stressors.

In this chapter, we will address the importance of GC circadian and ultradian rhythms for stress resilience; for the sake of clarity, we will describe findings from studies in rodent, unless differently specified.

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00008-2 107 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

108 8. Rhythms of stress resilience

FIGURE 8.1 (A) The hypothalamic-pituitary-adrenal (HPA) axis and (B) circadian and ultradian rhythm of glucocorticoid secretion in the rat.Reproduced with permission from Spiga et al., 2014.

Circadian rhythm and stress response

The circadian rhythm of the HPA axis is regulated by light inputs via the oscillatory activ- ity of the biological master clock, the suprachiasmatic nucleus (Spiga et al., 2014). Cells within the SCN possess a circadian activity regulated by an oscillating transcriptional network of clock genes. This is composed by transcriptional, translational, and posttranslational feed- back loops in which heterodimers of the activator proteins CLOCK and BMAL (encoded by the Clock and Bmal1 genes, respectively) regulate the expression of the repressors proteins CRYs (encoded by the Cry1 and Cry2 genes) and PERs (encoded by the Per1, Per2, Per3 genes). CRYs and PERs in turn translocate back into the nucleus and repress the activities of the BMAL-CLOCK complex, thus establishing circadian rhythmicity in gene expression (Lowrey and Takahashi, 2011; Panda et al., 2002).

It has been known for long time that the responsiveness of the HPA axis to stress depends on the time of day of exposure to the stress (Atkinson et al., 2006; Dunn et al., 1972; Gallant and Brownie, 1979; Gibbs, 1970; Kant et al., 1986; Torrellas et al., 1981; Zimmermann and Critchlow, 1967). However, the mechanisms underlying this time-dependent responsiveness are still not clear. Several studies have shown that disruptions of the circadian clock result in altered basal HPA axis activity and GC concentration; however, only few have investigated changes in HPA axis responsiveness to stress in clock gene mutant mice.

Basal GC concentration is elevated in Cry mutant mice (Barclay et al., 2013; Lamia et al., 2011; Leliavski et al., 2014; Turek et al., 2005; Yang et al., 2009), whereas mutations of Bmal1, Clock, and Per are associated with decreased hormone concentration (Barclay et al., 2013; Lamia et al., 2011; Leliavski et al., 2014; Turek et al., 2005; Yang et al., 2009). However, mutation of Cry and Bmal1 is associated with reduced responsiveness to stress (Barclay et al., 2013; Lamia et al., 2011; Zhang et al., 2011), whereas mutation of Per is associated with enhanced response to stress (Barclay et al., 2013; Lamia et al., 2011; Zhang et al., 2011).

 

The importance of pulsatility for hormonal and behavioral response to stress 109

The effects of clock gene mutations on GC concentrations can occur at different levels of the HPA axis. For example, deletion of Bmal1 leads to decreased adrenal sensitivity to ACTH during the active phase (Bartlang et al., 2012; Engeland et al., 1977; Leliavski et al., 2014; Oster et al., 2006), resulting in decreased GC response to stress. Furthermore, CRY pro- tein can bind to the GC receptor, inhibiting its activity and, therefore, the effects of GCs. Thus, hypersecretion of GC in Cry mutant mice is due to impaired GR-mediated negative feedback inhibition in the brain and pituitary (Lamia et al., 2011).

GC responsiveness to stress not only depends on the time of day but also on the nature of the stressor. For example, exposure to physical stressors such as hemorrhage (Lilly et al., 2000) or hypoglycemia (Kalsbeek et al., 2003) during the active phase results in an increase in circulating GCs that is greater than when exposure to the stressors occurs during the inactive phase. In contrast, exposure to psychological stressors such as novelty (Buijs et al., 1997), restraint (Bradbury et al., 1991), inflammation (Mathias et al., 2000), foot shock and immobilization (Retana-Marquez et al., 2003), shaking stress (Bernatova et al., 2002), as well as procedures that are routine in animal house maintenance (i.e., handling, cage changing, grouping) (Gattermann and Weinandy, 1996) during the inactive phase results in a stronger increase in GC release than during the active phase.

The importance of pulsatility for hormonal and behavioral response to stress

A number of studies have investigated the functional interaction between GC pulsatility and the response to stress. In these studies, when rats were exposed to noise stress during different phases of their ultradian corticosterone secretory profile (Sarabdjitsingh et al., 2010; Windle et al., 1998a). The timing of exposure to the stressor, relative to the phase of the ultradian rhythm, was crucial in determining the magnitude of the corticosterone response. Indeed, in this study, it was found that the corticosterone response is considerably greater when the stressor is applied during the rising phase of a corticosterone pulse than during the falling phase (Fig. 8.2). These findings suggest a facilitated stress response during the rising phase and/or an inhibitory effect during the falling phase and indicate the exis- tence of a dynamic interaction between basal GC pulsatility and the ability of an animal to mount an optimal hormonal stress response.

To understand in more detail the interaction between pulsatility and stress responsiveness, a mathematical modeling approach has also been used (Rankin et al., 2012). In addition to explaining earlier observations that the magnitude of the stress response depends on the timing of the stress, this model has also shown that an external stress can act as a resetting mechanism to the phase of the endogenous ultradian rhythm; that is, depending on the timing of the stress, the phase of the ultradian rhythm can either be advanced or delayed.

The mechanism underlying the differential HPA axis response to stress in relationship to the ultradian corticosterone rhythm has been further investigated in adrenalectomized rats in which the endogenous hormone was replaced with an intravenous infusion of hourly pulses of corticosterone (Sarabdjitsingh et al., 2010). Consistent with previous studies (Windle et al., 1998b), exposure of these rats to noise stress results in an increase in ACTH that is more

 

110

8. Rhythms of stress resilience

(A)

                      

(B)

                      

FIGURE 8.2 The phase of the ultradian corticosterone rhythm is important for the amplitude of the stress response. Rats were exposed to noise stress (10 min, 114 dB). Rats were stressed during the rising phase (A) or the falling phase (B) of an endogenous corticosterone pulse. rats exposed to stress during the rising phase show much greater corticosterone responses than animals stressed during the falling phase. Reproduced with permission from Spiga et al., 2014.

pronounced when the stressor is applied during the rising phase than during the falling phase of the corticosterone pulse. The same study also shows that the differential ACTH response to noise stress, relative to the phase of corticosterone pulse, was also associated with a different behavioral response to the stressor. Indeed, the behavioral response to the noise stress was higher in rats stressed during the rising phase than the falling phase of the corticosterone pulse. These findings are consistent with earlier behavioral studies showing that the corticosterone response of rats exposed to a male intruder is higher during the rising phase of an endogenous corticosterone pulse, and these rats are also more aggressive than rats exposed to the intruder during the falling phase of the pulse (Haller et al., 2000a,b).

Glucocorticoid rhythms and the response to stress in physiological and pathological conditions

In the previous section, it was discussed how both experimental and mathematical studies provided evidence suggesting that corticosterone ultradian rhythm is important for

 

Glucocorticoid rhythms and the response to stress in physiological and pathological conditions 111

maintaining optimal hormonal responsiveness to stress (Rankin et al., 2012; Windle et al., 1998b); however, the relationship between the phase of the corticosterone pulse and the response to stress is not always respected. In this section, we will review some experimental models in which circadian and ultradian corticosterone rhythms are different from the “normal” male adult rat, and we will describe how the stress response changes in each of these conditions.

Gender. A marked difference in the levels of basal corticosterone secretion between male and female rodents is well recognized (Atkinson and Waddell, 1997), with higher levels in female rats characterized by both an increase in the number of pulses and an increase in pulse magnitude (Seale et al., 2004a). In the rat, gonadal steroids have major effects on the pulsatile pattern of corticosterone. Indeed, following gonadectomy, male rats have increased overall corticosterone secretion similar to that observed in female rats, whereas ovariectomized females have reduced corticosterone with levels similar to those observed in male rats (Seale et al., 2004a). Androgen replacement reverses the increase in corticosterone secretion induced by castration in male rats, and estradiol replacement, in turn, reverses the effects of ovariec- tomy on corticosterone secretory activity in female rats (Seale et al., 2004b).

The differences in the ultradian and circadian corticosterone rhythm observed between male and female rats are also associated with a differential response to both psychological noise stress and LPS-induced immune challenge. These are higher in females than intact male, whereas corticosterone response to stress is similar between female and castrated males but lower in ovariectomized females (Seale et al., 2004a). As seen for basal corticosterone pul- satility, the effects in the stress response are induced by gonadectomy and reversed by androgen and estradiol replacement in males and females, respectively (Seale et al., 2004b).

Neonatal masculinization or feminization also affects basal and stress-induced corticoste- rone secretion patterns in adult life in female and male rats, respectively (Seale et al., 2005a,b). For example, neonatal masculinization results in reduced corticosterone pulsatility in adult female rats, and this effect is associated with reduced corticosterone responses to both noise and LPS stress, as observed in normal adult males (Seale et al., 2005a). In contrast, neonatal deprivation of testosterone in male rats results in increased corticosterone pulsatility and is associated with increased corticosterone response to noise stress or LPS administration (Seale et al., 2005a).

Aging. Marked differences in the pattern of corticosterone pulsatility occur across the rat life cycle (Lightman et al., 2000). For example, although corticosterone secretion in juvenile and adults rats is characterized by changes in pulse amplitude over the 24-h cycle resulting in the well-defined circadian rhythm of corticosterone, in elderly (>12 month old) rats, circa- dian rhythmicity is lost, as a result of decreased pulse amplitude during the peak phase. With respect to the stress, one study reports that aging is associated with increased variability in corticosterone response to stress (Segar et al., 2009); however, another study showed a decreased corticosterone response to restraint in aging rats (Buechel et al., 2014).

Reproductive cycle. Over the course of their reproductive cycle, female rats show differences in corticosterone rhythms (Windle et al., 2013). During lactation the circadian rhythm of corti- costerone is maintained; however, compared with virgin rats, this is associated with a flat- tening of the rhythm that is due to a decrease in the evening peak levels, and an increase in the number of corticosterone pulses throughout the 24 h. However, 2 days after experi- mental weaning, corticosterone levels are significantly suppressed throughout the 24-h

 

112 8. Rhythms of stress resilience

period, and these effects are reversible, as no differences in either circadian or ultradian rhythms of corticosterone are observed between 13 days postlactating dams and virgin rats. With regard to the stress response during the reproductive cycle, although, as expected, in virgin rats, noise stress causes a rapid increase in plasma corticosterone concentration, in the lactating group, which has an increased number of pulses across the 24-h cycle, no effects on plasma corticosterone levels are seen following noise stress. Furthermore, in the experimen- tally weaned group, which show lower basal corticosterone levels and a lower number of pulses, the response to noise is of similar amplitude but more prolonged compared with

the virgin group (Windle et al., 2013).
Genetic background. Differences in ultradian corticosterone rhythms have been investigated

across rats with different genetic backgrounds. Studies have shown that Wistar, Sprague Dawley, Lewis, and Fisher 344 all exhibit a pulsatile pattern of corticosterone release. However, significant differences between strains have been observed (Windle et al., 1998a). Similar to male and female Sprague Dawley and Wistar rats, female Lewis rats have a clear circadian rhythm, with greater pulse amplitude in the evening than in the early morning. In contrast, circulating corticosterone concentration is higher in female Fischer rats and lacks circadian variation, with no difference in pulse amplitude between the morning and the evening.

In addition to the observed differences in the pattern of ultradian rhythmicity, Fisher and Lewis rats also differ in their corticosterone response to stressors. It is well known that Lewis rats are susceptible to a range of inflammatory conditions, including streptococcal cell walleinduced arthritis (Sternberg et al., 1989a,b), whereas the Fisher rat does not develop these conditions. Because of the antiinflammatory effect of endogenous GCs, these differences in disease susceptibility may be linked to differences in the dynamics of corticosterone secre- tion. In contrast to inflammatory stress, Fisher rats exhibit a response to noise stress that is greater and more prolonged than in the Lewis female rat. Furthermore, although Fisher rats respond equally to a noise stress, regardless of when it occurs in relation to the phase of the endogenous corticosterone rhythm, Lewis rats lack a corticosterone response when the noise is applied during the falling phase of the ultradian pulse (Windle et al., 1998a).

Chronic inflammatory stress. Chronic inflammation is a model of chronic stress that has high clinical relevance. In particular, a model of chronic inflammatory disease that has been exten- sively studied in the rat is Mycobacterium adjuvanteinduced arthritis. Increased circulating corticosterone and ACTH concentrations, and loss of the normal circadian rhythm of HPA activity, have been observed in Piebald-Viral-Glaxo (PVG) rats infected with the Mycobacte- rium adjuvant (Windle et al., 2001). During the symptomatic period, infected rats show dramatic changes in pulsatility, with an almost doubled number of pulses throughout the 24-h cycle related to continued pulsatility during the normally quiescent lights-on period. Interestingly, neither the amplitude nor the duration of the pulses is different from control rats, indicating that the increase in circulating hormone is solely due to this increased number of pulses. A different response to stress has been observed in rats exposed to chronic inflam- mation (adjuvant-induced rheumatoid arthritis). In these rats, the relationship between the pulse phase and the timing of the stress is maintained throughout the development of the inflammation (Windle et al., 2001). However, the overall corticosterone response to noise stress is significantly lower in arthritic rats than in controls. Thus, it is possible that as the number of pulses increases and the interpulse periods reduce in symptomatic rats, there is a greater

 

Cortisol rhythms and stress resilience in humans 113

proportion of time when the rats are unable to respond to stress. These data provide evidence for a direct relationship between increased basal HPA axis activity, associated with chronic dis- ease, and a decreased response to acute stress, and this is indeed consistent with previous data showing a decreased corticosterone response to acute stress in rats with adjuvant-induced arthritis (Aguilera et al., 1997; Harbuz et al., 1993) and also in humans with rheumatoid arthritis (Chikanza et al., 1992). Interestingly, there is no difference in the corticosterone response to LPS between rats with adjuvant-induced arthritis and control rats.

Exposure to constant light. Another model of chronic stress that has been found to effect corticosterone pulsatility in the rat is exposure to constant light. Experimental animals are normally kept under a 12-h light-dark cycle, with light input acting as a zeitgeber processed through the SCN. Disruption of the SCN signal, either by physical lesioning of the SCN or by disruption of the light input, induces a loss of circadian rhythmicity, and this is associated with changes in corticosterone pulsatility (Waite et al., 2012). Rats maintained under condi- tions of constant light for a prolonged period of time (5 weeks) lose their circadian corticoste- rone rhythm, which is due to increased pulsatility during the nadir phase of the circadian cycle, with no difference between the nadir and the peak phase pulse amplitude. These same rats have increased levels of CRH mRNA in the morning, which probably accounts for the increased corticosterone secretion during the nadir phase. This suggests that removal of the inhibitory SCN input to the hypothalamic PVN results in sufficient CRH secretion throughout the 24 h to maintain ultradian pituitary-adrenal activity. Consistent with the disinhibitory effect on basal corticosterone, rats exposed to constant light also exhibit a higher corticosterone response to restraint stress.

Neonatal programming. Exposure to stress during the neonatal period has profound effects on physiological functions that can be observed in adult life. This phenomenon is known as neonatal programming. Early-life stress can also program the development of the HPA axis with changes that persist for the rest of the life of the organism. The effect of neonatal programming on corticosterone pulsatility in the rat has been investigated using a model of early-life infection (Shanks et al., 2000). In rats exposed to endotoxin (Salmonella enteritidis) in neonatal age (days 3 and 5 postpartum), basal levels of corticosterone are higher both during the nadir and peak phase of the circadian cycle in adult life. This is due to an increase in both the number and amplitude of corticosterone pulses throughout the 24-h cycle. Changes in basal corticosterone pulsatility in rats neonatally exposed to an inflammatory stress are also associated with a differential corticosterone response to stress (Shanks et al., 2000). Rats that receive endotoxin in early life show an increase in both the amplitude and number of corticosterone pulses during basal conditions in adult life and are also hyper responsive to noise and inflammatory stress.

Cortisol rhythms and stress resilience in humans

The studies we have described reflect GC circadian and ultradian rhythms and their rele- vance for stress resilience in rodents, with an emphasis on the effects of physiological (e.g., estrus cycle and aging) and pathological (e.g., chronic stress and inflammation) conditions. These data, however, also have strong clinical implications. Indeed, cortisol secretion in humans is also characterized by both circadian and ultradian rhythmicity, and as observed

 

114 8. Rhythms of stress resilience

in a number of animal studies, changes in these rhythms can occur in human in pathological states, including depression and other stress-related disorders (Oster et al., 2017). Although responsiveness to stress in humans is highly subjective and social contextedependent (Cohen et al., 2007), a number of human studies have investigated whether there is a daily variation in the cortisol response to acute stress exposure. In these studies, experimental or pharmaco- logical stressors, such as CRH administration, physical exercise, and psychosocial stressors, were used. Cortisol response to CRH is higher in the afternoon or evening, an observation that is consistent with a circadian responsiveness of the adrenal gland to ACTH (Ulrich-Lai et al., 2006). However, as observed in animal studies, circadian responsiveness to stress is also dependent on the type and intensity of the stressor. For example, cortisol secretion following exposure to low to moderate intensity physical exercise was higher in the morning, whereas it was higher in the evening in subject performing high-intensity exer- cise (Scheen et al., 1998). In contrast, clinical studies have shown no differences between morning and evening in cortisol responses to the Trier Social Stress Test (Kudielka et al., 2004).

GCs regulate synaptic plasticity and neurotransmitter activity and are able to modify emotional and cognitive behavior. The maintenance of physiological GC rhythms is therefore extremely important, especially under acute stressful conditions or during poststress cogni- tive adaptations (Kalafatakis et al., 2016b). To clarify the clinical importance of ultradian rhythmicity in man, ongoing studies are using a model of steroid replacement in which GCs are infused in either a physiological circadian rhythm with its underlying ultradian rhythm or as a constant infusion, which abolishes the ultradian component of the circadian rhythm (Kalafatakis et al., 2016a). By using these methods, researchers are currently testing the hypothesis that the pattern of systemic GC oscillations leads to differential neurobehavio- ral phenotypes and activation of brain areas related to mood and emotional processing. Specifically, this study will shed light on the impact of GC rhythms on neural processing, emotional reactivity and perception, mood, and self-perceived well-being.

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CHAPTER

9

Mitochondrial function and stress

resilience

Laia Morató, Carmen Sandi

Laboratory of Behavioral Genetics, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

Introduction

Stress is a major risk factor for the development of psychopathologies, such as depression or posttraumatic stress disorder (PTSD). However, extensive data from both animal and hu- man studies highlight the existence of major differences in individuals’ susceptibility to stress (Duclot and Kabbaj, 2013; McEwen et al., 2015; Russo et al., 2012). This has been particularly well documented for depression, with broad evidence showing that while some individuals show high vulnerability to develop depressive symptoms following stress exposure, others remain resilient (Russo et al., 2012; Sandi and Richter-Levin, 2009). Similarly, PTSD studies are starting to place increasing emphasis on identifying factors that explain individual differ- ences in response to traumatic stress exposure and promotion of resilience (Yehuda et al., 2015).

The identification of mechanisms underlying stress-resilient phenotypes has proved difficult most probably due to the complexity of the gene-by-environment (G E) interac- tions inherent to stress-related disorders (Sharma et al., 2016). Recently, genetic studies have started to identify a set of genes whose differential expression can affect stress respon- siveness (Klok et al., 2011; Wong et al., 2017) and interindividual differences in resilience to stress-induced psychopathology (Klok et al., 2011; Nievergelt et al., 2015; Wong et al., 2017). Importantly, some of the identified genetic variants correspond to genes that regulate different aspects of mitochondrial function and energy metabolism (Cai et al., 2015a; Czarny et al., 2018; Flaquer et al., 2015; Kishi et al., 2010; Kovanen et al., 2015; Libert et al., 2011).

These genetic insights, along with cumulative evidence underscoring alterations in mito- chondrial function following stress exposure and in the context of stress-related psychopa- thologies (Gong et al., 2011; Manji et al., 2012; Morava and Kozicz, 2013; Picard et al., 2014, 2015), suggest that optimal mitochondrial functioning could be at the core of stress

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00009-4 119 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

120 9. Mitochondrial function and stress resilience

resilience. This view has been principally supported by recent rodent studies highlighting dif- ferences in the functioning of mitochondria in the nucleus accumbensda brain region involved in stress adaptationdin association with individual differences in trait anxiety (Hol- lis et al., 2015; Larrieu et al., 2017; van der Kooij et al., 2018). This link is especially relevant because high trait anxiety is a phenotype particularly vulnerable to stress and stress-related psychopathologies.

In this chapter, we will present key findings in this emerging research field to illustrate how various aspects related to mitochondrial function can contribute to differential stress re- sponses and susceptibility. We will start by briefly describing the essentials of mitochondria structure and function and their contributions to synaptic processes and interactions with glucocorticoids. Subsequently, we will summarize evidence from human and animal studies that support the hypothesis that mitochondrial function and stress resilience are closely con- nected. Finally, we will discuss the therapeutic potential of boosting mitochondrial function to combat stress-related disorders.

The mitochondrion

Mitochondria are complex and highly dynamic organelles that divide, fuse, and move throughout the cell. They have double membrane (i.e., inner and outer mitochondrial mem- brane) and their own genomic material, known as mitochondrial DNA (mtDNA). Mitochon- dria are considered the powerhouses of the cell because of their efficient capacity to produce energy in form of adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS) system. In a nutshell, the oxidation of nutritional substrates through a variety of catabolic reactions (i.e., glycolysis, fatty acid beta-oxidation or tricarboxylic acid [TCA] cy- cle) gives rise to reducing equivalents, named nicotinamide adenine dinucleotide (NADH) and flavoadenine dinucleotide (FADH2). Electrons from these reducing equivalents are trans- ferred through the complexes I to IV of the electron transfer chain (ETC) generating a proton gradient across the inner mitochondrial membrane. Subsequently, ATP synthase (or complex V) uses the energy stored in this electrochemical gradient to convert ADP into ATP (Reeve et al., 2011).

In addition to their bioenergetic function, mitochondria play a very prominent role in several other processes, including calcium (Ca2þ) homeostasis and production of reactive ox- ygen species (ROS). Through the expression of the mitochondrial calcium uniporter, located in the inner mitochondrial membrane, mitochondria can rapidly uptake free Ca2þ from the cytoplasm arising from internal stores or extracellular influx (Kamer and Mootha, 2015). Conversely, mitochondria can release Ca2þ to the cytosol through a Naþ/Ca2þ exchanger expressed in the inner mitochondrial membrane (Palty et al., 2012). On the other hand, mito- chondria produce ROS, which are partially reduced intermediates of oxygen (e.g., superoxide anion O2 0, hydrogen peroxide [H2O2], or hydroxyl radical [OH ]), generated as by- products of the electron transfer at the complexes I and III of the ETC. Oxidative stress and its damaging effects on proteins, lipids, and DNA occur when the equilibrium between ROS production and antioxidant capacity is disrupted. Neurons are especially vulnerable to oxidative damage because of their high rate of oxidative metabolic activity, their low antiox- idant capacity, and the high abundance of peroxidizable polyunsaturated fatty acids in

 

Mitochondria and glucocorticoids 121

neuronal membranes in addition to their nonreplicative nature (Murphy, 2009). However, it is important to note that ROS are not only deleterious to cell function, but they also serve important regulatory functions notably acting as signaling molecules capable of modulating gene transcription and epigenetic changes (Schieber and Chandel, 2014). Finally, mitochon- dria are also required for other biological processes, which will be less discussed in this chap- ter, such as the activation of apoptotic cell death and the biosynthesis of several macromolecules, including steroid hormones (Reeve et al., 2011).

Mitochondria in neurotransmission and synaptic plasticity

The brain has high energy requirements. Despite representing only 2% of the total body mass, it makes use of around 20% of the total oxygen and 25% of the total glucose consumed by the organism (Mink et al., 1981). To meet activity-related high metabolic demands, mitochondria are recruited to activated synapses where ATP is essential for suc- cessful neurotransmission and neuroplasticity (Harris et al., 2012). Specifically, mitochon- drial functions contribute to basic processes in both the pre- and the postsynaptic compartments.

Presynaptically, ATP is fundamental for the transport of synaptic vesicles, the release and recycle of neurotransmitters, and the regulation of ATP-powered ionic pumps critically impli- cated in the propagation of action potentials (Lord et al., 2013; Marland et al., 2016; Pathak et al., 2015; Rangaraju et al., 2014; Sun et al., 2013; Verstreken et al., 2005). In addition, TCA cycle intermediates generated in the mitochondria serve as the building blocks for the synthesis of GABA and glutamate (Sibson et al., 1998; Waagepetersen et al., 2001).

Postsynaptically, both ATP production and mitochondrial Ca2þ buffering are required for the reversal of ionic gradients produced following neuronal excitation (Harris et al., 2012). Importantly, synaptic mitochondria are more susceptible to Ca2þ overload and alteration in the ETC compared with nonsynaptic mitochondria (Yarana et al., 2012). Mitochondrial Ca2þ buffering has also been implicated in the production of long-term potentiation (Billups and Forsythe, 2002; Delaney and Tank, 1994; Kang et al., 2008; Levy et al., 2003; Stanton and Schanne, 1986; Tang and Zucker, 1997; Yang et al., 2003; Yarana et al., 2012), a learning- related plasticity phenomenon highly susceptible of modulation by stress (Luksys and Sandi, 2011). Extension or migration of mitochondria into dendritic protrusions correlates with the development and maintenance of dendrites as well as synapse and spine formation (Li et al., 2004), two neurobiological processes extremely sensitive to regulation by experience and stress (McEwen and Chattarji, 2004).

Mitochondria and glucocorticoids

Classically, the mode of action of the activated glucocorticoid receptor (GR) involves the translocation from the cytoplasm to the nucleus where it can modulate transcription of a large number of genes. Noteworthy, some of the GR-regulated genes include nuclear-encoded mitochondrial genes. Recent studies have demonstrated that activated, ligand-bound GRs can also translocate to the mitochondria, where they can regulate expression of genes

 

 

122 9. Mitochondrial function and stress resilience

encoded in the mitochondrial genome. Indeed, mtDNA contains sequences with strong homology to glucocorticoid response elements (Psarra and Sekeris, 2011).

Pioneering studies in cortical cultured neurons showed that physiological doses of gluco- corticoids promote mitochondrial function, as indicated by increased mitochondrial mem- brane potential and Ca2þ buffering capacity along with neuroprotective effects against kainic acideinduced apoptosis. However, supraphysiological doses of glucocorticoids exert the opposite effects in the abovementioned mitochondrial functions and enhance the kainic acid apoptotic effects (Du et al., 2009). These studies further showed that whereas acute treat- ment with both physiological and supraphysiological doses of glucocorticoids promotes GR translocation into the mitochondria, the extent of GR translocation to the mitochondrial was reduced under long-term glucocorticoid treatments involving supraphysiological doses (Du et al., 2009). This finding was validated in in vivo experiments that showed that chronic treat- ment with supraphysiological glucocorticoid doses downregulates mitochondrial GR levels in the prefrontal cortex (Du et al., 2009).

Recently, chronic treatment with either corticosterone or stress was shown to increase GR binding to mtDNA in the rat hippocampus along with an upregulation of several mtDNA- encoded genes (e.g., Nd-3, Nd-4, Cox-2, Nd-4l, Atp-6, Atp-8, Nd-5, Cox-3, Cox-1, and Cytb). On the contrary, acute stress was shown to downregulate the expression of mtDNA- encoded complex I subunit genes (Hunter et al., 2016). Collectively, these results indicate that glucocorticoids can increase the capacity of mitochondria to meet the rise in energy demands required for a successful adaptation of the brain to stress. However, sustained glucocorticoid actions on mitochondria might eventually lead to maladaptive effects.

Mitochondrial dysfunction in stress-related disorders: human studies

A first line of evidence linking mitochondrial dysfunction with stress-related disorders is provided by clinical observations from patients with mitochondriopathies. Mitochondrial disorders are typically caused by mutations of genes encoded either in the mtDNA or in the nuclear DNA that affect the OXPHOS system. Although mitochondrial diseases are multi- systemic disorders, the brain is the most commonly affected organ (DiMauro et al., 2013). Of note in the context of this chapter, patients with mitochondrial disorders present a high inci- dence of psychopathologies, including anxiety and depression. Moreover, the onset of anxi- ety and depression symptoms in these patients typically precedes the appearance of primary mitochondrial disorder symptoms (Fattal et al., 2007; Inczedy-Farkas et al., 2012; Koene et al., 2009; Morava et al., 2010; Morava and Kozicz, 2013). Remarkably, brain metabolic dysfunc- tion might contribute to anxiety and mood changes in these patients, as suggested by data from 1H-magnetic resonance spectroscopy (1H-MRS) revealing correlations between several metabolites (e.g., N-acetyl aspartate, creatine, glycerophosphocholine, myoinositol, and glu- tamate þ glutamine [Glx]) in the hippocampus and anxiety levels (Anglin et al., 2012).

In addition, converging data from neuroimaging, proteomic, genomic, and genetic ap- proaches are pointing to alterations in mitochondrial function in stress-related disorders, such as depression and PTSD. For example, several positron emission tomography (PET) studies have highlighted a downregulation of cerebral metabolism in depressed patients, particularly affecting brain regions critically involved in the regulation of mood, such as

 

Mitochondrial dysfunction in stress-related disorders: human studies 123

the prefrontal cortex, basal ganglia, and anterior cingulate gyrus (Su et al., 2014; Videbech, 2000). Evidence supporting that this hypofunctionality is potentially related to alterations in energy metabolism is provided by a number of magnetic resonance spectroscopy (MRS) studies in depressed patients. Using 31P-MRS, low concentration of ATP was detected in the basal ganglia of depressed subjects (Moore et al., 1997). Importantly, combination of spec- troscopy (i.e., 1H-MRS and 13C-MRS) with infusion of [1-13C] glucose revealed that mitochon- drial energy production is 26% lower in occipital glutamatergic neurons in these patients (Abdallah et al., 2014). The existence of dysfunctional mitochondria in these patients is further supported by postmortem proteomic and genomic studies focusing on specific brain regions. To illustrate, proteomic studies focusing on the prefrontal cortex and anterior cingu- late cortex of patients with depression showed alterations in the expression of proteins coded by mtDNA, predominantly of the OXPHOS system (Beasley et al., 2006; Gottschalk et al., 2014; Johnston-Wilson et al., 2000; Martins-de-Souza et al., 2012; Zuccoli et al., 2017). Notably, these changes in the metabolism of the brain might be region specific. This possibility is supported by a study in which alterations in the expression of three complex I subunits (i.e., NDUFV1, NDUFV2, and NDUFS1) in depressive patients were observed in the cere- bellum, but not in the prefrontal cortex, striatum, or parietooccipital cortex (Ben-Shachar and Karry, 2008).

Similarly, neuroimaging studies in PTSD patients, including PET and MRS, have also high- lighted alterations in cerebral metabolism and perfusion, receptor binding, and metabolite profiles in limbic regions, medial prefrontal cortex, and temporal cortex (Im et al., 2016). The potential link between these findings and mitochondrial dysfunction is supported by a growing body of data. For example, PTSD-specific expression fingerprints of 800 informative mitochondria genes were reported using human mitochondria-focused cDNA microarrays in postmortem samples from the dorsolateral prefrontal cortex (Su et al., 2008). The largest group of dysregulated genes corresponded to genes involved in mitochondrial dysfunction, oxidative phosphorylation, and cell survival and apoptosis (Su et al., 2008). Analysis of peripheral blood cells from depressive and PTSD patients revealed that mitochondrial abnor- malities are not restricted to the brain. A reduction of mtDNA copy number in these cells has been reported in patients diagnosed with depression or PTSD (Bersani et al., 2016). In addi- tion, mitochondrial respiration was found to be lower in depressive patients than in controls and correlated negatively with the severity of depressive symptoms (Karabatsiakis et al., 2014). Dysregulation of several ETC subunits was also found in blood samples of PTSD patients, which also exhibited altered glycolysis and TCA metabolism (Zhang et al., 2015). However, it should be noted that some studies have reported opposite evidence to the one indicated above. To illustrate, a study reported increased mtDNA in depressive patients and a correlation between the amount of mtDNA and the total number of stressful life events (Cai et al., 2015b). Clearly, this emerging field is still in development, and further studies are needed to obtain a clear picture of the contribution of different aspects of mitochondrial func- tion to these disorders.

Moreover, several studies suggest that oxidative stress and inefficient repair mechanisms of DNA damage may contribute to the development of stress-related psychopathologies. Ev- idence includes increased levels of reactive oxygen and nitrogen species (Czarny et al., 2018) as well as increased mtDNA oxidative damage in depressed patients. Although direct mea- surements of oxidative stress in traumatized humans are still missing, its potential relevance

 

124 9. Mitochondrial function and stress resilience

for PTSD is bolstered by a mounting body of data showing high levels of oxidative damage markers in blood from stressed individuals (Miller and Sadeh, 2014). In agreement with the hypothesis that oxidative stress plays a role in PTSD-associated neurodegeneration, single- nucleotide polymorphisms (SNPs) in oxidative stress-related genes moderate the association between PTSD and reduced thickness of the right prefrontal cortex in PTSD patients (Miller et al., 2015). Similarly, genetic variants in oxidative stress-related genes have also been asso- ciated with vulnerability to develop depression (Czarny et al., 2018) and PTSD (Flaquer et al., 2015). Interestingly, evidence for PTSD includes the identification of mitochondrial single- nucleotide polymorphisms (mtSNPs) in the ATP synthase subunit 8 (MT-ATP8) and the NADH dehydrogenase subunit 5 (MT-ND5) genes, both linked to the regulation of mitochon- drial ROS (Flaquer et al., 2015).

The idea that genetic variation may alter the effectiveness of mitochondrial function to respond to stress and, hence, influence stress resilience, goes well beyond genes related to oxidative stress. Notably, polymorphisms in the SIRT1 gene were first associated with anxiety (Libert et al., 2011) and depression (Kishi et al., 2010). Sirtuin 1 (SIRT1) is a NADþ- dependent deacetylase that regulates mitochondrial function and biogenesis through the deacetylation and activation of transcriptional regulators such as FOXO and PGC-1a (Houtkooper et al., 2012). Importantly, a recent study showed that a SNP in the locus 50 in the SIRT1 gene exceeds genome-wide significance in association with recurrent major depres- sive disorder in two different cohorts of Chinese patients. However, comparison with results from the Psychiatric Genomics Consortium (PGC), a megaanalysis of European studies, failed to provide robust replication for this SNP, which might be explained by differences in sample ascertainment or ethnicity (Cai et al., 2015b). Future studies are warranted to clarify the relevance of this gene in the context of anxiety and depression.

Stress effects in mitochondrial function: animal studies

Alterations in brain mitochondrial function have been described in animals subjected to stress, frequently consisting of body restraint. Early studies showed that severe acute immo- bilization stress in rats induces oxidative damage, not only in plasma and liver, but also in lipid, protein, and DNA of several brain areas (Liu et al., 1996). Recently, a milder acute stress version consisting of 30 min of restraint stress in rats was found to inhibit complex I activity in the brain (Batandier et al., 2014). Other studies showed that exposure of rats to a combi- nation of restraint stress and tail shock protocoldwhich induces PTSD-like behaviorsd upregulates TCA cycle genes and a subunit of the ATP synthase (complex V) (Li et al., 2014; Zhang et al., 2015).

Given the considerable impact of acute stress in mitochondrial function, it is not surprising that chronic stress leads also to substantial effects in a broad variety of parameters. Specif- ically, several studies involving chronic mild stress in rats were found to lead to inhibition of complexes I, III, and IV in the cortex and cerebellum (Rezin et al., 2008), as well as increased generation of ROS in the hippocampus and prefrontal cortex (Lucca et al., 2009). They also showed alterations in mitochondrial ultrastructure, inhibition of mitochondrial respiration, and dissipation of the inner mitochondrial membrane potential in hippocampus,

 

Stress effects in mitochondrial function: animal studies 125

cortex, and hypothalamus (Gong et al., 2011). Using metabolomics and proteomics ap- proaches, a study focusing on the cerebellum confirmed that chronic mild stress alters glycol- ysis, the TCA cycle, and ATP synthesis (Shao et al., 2015).

The studies discussed above clearly show that stress can affect different components of mitochondrial function. However, they do not provide enough information to establish a link between mitochondria and stress resilience. Evidence for such a link has started to be provided by studies involving different living conditions and a focus on social structures. Us- ing a proteomic approach, environmental enrichment was found to affect both basal and acute restraint stress-induced levels of mitochondria-related proteins in the nucleus accum- bens, a brain region that mediates neural adaptations involved in certain stress-induced depressive-like behaviors. Specifically, whereas the levels of proteins involved in the TCA cy- cle and ETC were lower in environmentally enriched than in socially isolated rats under basal conditions, the two groups showed opposite modulation in the expression of these proteins in response to acute stress, that is, increased in enriched rats, whereas decreased in socially iso- lated rats (Fan et al., 2013). Moreover, a recent 1H-NMR study in mice reported a differential metabolic profile in the nucleus accumbens in relation to both social status and vulnerability to chronic social defeat. Thus, subordinate mice showed lower levels of several energy-related metabolites (i.e., creatine and phosphocreatine, glutamate, glutamine, aspartate, myoinositol, N-acetyl-aspartate, and taurine) than dominant mice under basal conditions. However, the levels of these metabolites following chronic social defeat stress increased only in subordinate mice (Larrieu et al., 2017).

Importantly, recent studies using genetically modified mice presenting either deletions or mutations in specific mitochondrial genes have causally implicated mitochondrial function in stress responsiveness. Mice deficient for Nd6 and Co1 (subunits of complex I and complex IV of the ETC, respectively) or Ant (mitochondrial ATP-ADP translocator) presented an altered response to acute restraint stress (Picard et al., 2015). Two mouse studies that focused on SIRT1 reported increased vulnerability to chronic social defeat following viral-mediated overexpression of SIRT1 in the nucleus accumbens (Kim et al., 2016), suggesting a region- specific contribution of this protein to stress resilience. However, and surprisingly, the same viral-mediated overexpression of SIRT1 in the hippocampus led to opposite results (Abe-Higuchi et al., 2016).

Other studies have investigated whether manipulation of mtDNA influences mice behavior, although not yet on stress responsiveness. These studies have shown, for example, that mice harboring a mutant form of Polg (the mtDNA polymerase) exclusively in neurons exhibit depressive-like behaviors concomitant with mtDNA deletions and mitochondrial dysfunction (Kasahara et al., 2016). The presence of more than one mtDNA variantda state known as heteroplasmydcan also impact behavior. Mice carrying a mixture of mtDNA from the NZB and the 129 mouse strains displayed less depressive- and anxiety-related behaviors than control homoplasmic mice (i.e., mice with only one type of mtDNA, either from NZB or the 129 background) (Sharpley et al., 2012).

Another line of evidence linking mitochondrial function with vulnerability to stress is provided by studies that take into account individual differences in anxiety trait. High- anxiety trait is a vulnerability factor to develop stress-induced depression (Castro et al., 2012; Sandi et al., 2008; Sandi and Richter-Levin, 2009). Notably, mice selectively bred for

 

126 9. Mitochondrial function and stress resilience

more than 40 generations for high or low anxiety-like behaviors revealed perturbations in cellular metabolism and antioxidant responses, when studied in the cingulate cortex. Partic- ularly, highly anxious animals showed decreased glycolysis, pentose phosphate pathway, and antioxidant defense together with increased OXPHOS, TCA cycle, and mitochondrial transport (Filiou et al., 2011). Strikingly, oral administration of a mitochondria-targeted antioxidant (MitoQ) was effective to exert anxiolytic effects in the high anxious line (Nuss- baumer et al., 2016). Furthermore, decreased mitochondrial respiration, ATP production, and complex I and II expression together with increased ROS production were also observed in the nucleus accumbens of high-anxious outbred rats compared with low- anxious rats. Remarkably, microinfusion of specific mitochondrial complex I or II inhibitors (malonic acid or 3NP) into the nucleus accumbens significantly reduced social rank, mimicking the low probability to become dominant observed in high-anxious animals. Conversely, infusion of the mitochondria booster nicotinamide was able to prevent the sub- ordinate status of high-anxious individuals (Hollis et al., 2015; van der Kooij et al., 2018).

Altogether, the studies summarized in this chapter present converging evidence in support of the view that optimal mitochondrial function might be a critical mechanism in stress coping and facilitation of stress resilience. Accordingly, facilitating mitochondrial function might be a plausible way to improve individuals’ capacity to cope with stress and, hence, to promote resilience.

Promoting stress resilience through activation of mitochondrial function

Interestingly, classical antidepressants (e.g., desipramine, fluoxetine, or imipramine) have been shown to modulate mitochondrial function (Adzic et al., 2016; Villa et al., 2017) and reduce oxidative stress (Liu et al., 2015). Moreover, antidepressant effects of ketamine have been ascribed to the activation of energy metabolism and the antioxidant defense system (Weckmann et al., 2017).

Other work has shown that compounds that promote mitochondrial function and/or redox homeostasis when given either alone or in combination with existing therapies amelio- rate symptoms of stress-related disorders. For instance, the use of antioxidants such as N-acetyl cysteine alone or as supplements has provided promising effects in clinical trials for depression (Berk et al., 2008) and PTSD (Back et al., 2016). In the same line, dietary poly- phenol or antioxidant intakes were positively associated with psychological resilience in healthy subjects (Bonaccio et al., 2018). A further example includes evidence from clinical trials indicating that the efficacy of the antidepressant medication was accelerated by the sup- plementation of patients with creatine monohydrate, a metabolite that facilitates the recycling of ATP (Kondo et al., 2011; Lyoo et al., 2012; Nemets and Levine, 2013).

Furthermore, mitochondrial function can be pharmacologically boosted with resveratrol, a natural activator of SIRT1. This polyphenol was found to exert antidepressive effects in mice subjected to early-social isolation (Lo Iacono et al., 2015) and in rats subjected to chronic unpredictable mild stress (Ge et al., 2013; Liu et al., 2014). In addition, dietary intake of glucoraphanin, a compound that promotes the expression of antioxidant enzymes, confers stress resilience in mice subjected to social defeat (Yao et al., 2016).

 

References 127 Conclusions and future perspectives

Mitochondria are primarily responsible for meeting the high-energy demand of the brain. This dependence on energy makes neurons particularly vulnerable to mitochondrial dysfunc- tion. Indeed, mitochondrial dysfunction is a hallmark of neurodegenerative diseases (Reeve et al., 2011). Therefore, it is not surprising that optimal mitochondrial function is also essential to cover the energy requirements associated to stress adaptation within the brain.

In this chapter, we have compiled results from multiple studies that demonstrate that mitochondrial function is altered in stress-related disorders, such as depression and PTSD, and in mice subjected to a variety of stress protocols. We highlight mitochondria as an impor- tant cellular resilience mechanism and hypothesize that enhancing mitochondrial function may represent a novel therapeutic strategy to treat stress-induced disorders. Future studies should try to elucidate which brain regions and neuronal types are more vulnerable to mito- chondrial dysfunction upon stress. They should also address whether mitochondrial dysfunc- tion in animals subjected to stress is permanent or reversible.

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CHAPTER

10

Understanding resilience: biological approaches in at-risk populations A.V. Seligowski, S.B. Hill, C.D. King, A.P. Wingo,

K.J. Ressler

Division of Depression and Anxiety, McLean Hospital; Department of Psychiatry, Harvard Medical School, Belmont, MA, United States

Introduction

Most of the world’s population experiences a traumatic event at some point in their lives. Although approximately 8% develop posttraumatic stress disorder (PTSD; Kessler et al., 2012), the large majority of individuals do not. Rather, many individuals who experience trauma have some initial symptoms, such as intrusive memories or avoidance of reminders (e.g., places that resemble where the trauma occurred), which dissipate within weeks. A large body of research is dedicated to understanding what places individuals at greater risk for developing PTSD and related functional impairment. An additional, important area of research focuses on the individuals who do not develop significant psychopathology. These individuals are typically referred to as being “resilient.”

There are different ways to define resilience; however, the field has not solidified the proper way to understand it. Some define resilience as the lack of PTSD or other pathology, despite the presence of risk/trauma exposure. This may be captured by self-report and inter- view measures as a below-threshold score (i.e., below a clinical cutoff of PTSD). More nuanced conceptualizations of resilience suggest that it reflects more active and adaptive pro- cesses that help individuals recover from stressful and traumatic events (Charney, 2004). Such perspectives suggest that resilience could even be considered a preexisting personality trait, independent of risk exposure. Thus, in addition to a lack of significant psychological symptoms, we can also define resilience by the specific mechanisms that help to reduce one’s risk of developing such symptoms. Although there is no single predictor of PTSD devel- opment following trauma, there do appear to be biological markers, mechanisms, and pro- cesses that contribute to the buffering of trauma’s effects.

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00010-0 133 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

134 10. Understanding resilience: biological approaches in at-risk populations

This chapter will discuss approaches for studying these biological facets of resilience as a trait in at-risk populations. Specifically, we will cover genetic, physiological, and neuroimaging approaches to the study of psychological resilience and discuss how resilience itself may be seen as an individual trait with its own biomarkers and intermediate pheno- types. A further understanding of resilience will also help inform therapeutic approaches aimed at enhancing, building, or training resilience in at-risk populations.

Definitions and measurement of resilience

Resilience is a multidimensional construct, and its conceptualization has included a variety of elements ranging from personal characteristics to environmental factors. Some salient individual resilience attributes include ego strength, hardiness, positive emotions, optimism, spirituality/faith, adaptive coping styles, and cognitive flexibility (Feder et al., 2009; Southwick et al., 2005). Environmental factors contributing to resilience comprise role models, close and nurturing family bonds, and access to quality or supportive relationships (Feder et al., 2009; Southwick et al., 2005). Given its complexity, resilience has been operation- ally defined in various ways, and its measurement has been challenging. In a recent review by Windle et al. (2011), 15 measures of resilience were evaluated based on their psychometric properties. Although they did not identify a measure that could be considered a “gold standard” for assessing resilience, three scales stood out as having the highest overall ratings: The Connor-Davidson Resilience Scale (CDRISC), the Resilience Scale for Adults (RSA), and the Brief Resilience Scale (BRS).

The CDRISC (Fig. 10.1) captures the core personality characteristics of resilience including hardiness, tenacity, strong self-efficacy, emotional and cognitive control under pressure,

FIGURE 10.1 Dimensions of resilience captured by the Connor-Davidson Resilience Scale (CDRISC).

 

 

Definitions and measurement of resilience 135

adaptability, ability to bounce back, spiritual coping, tolerance of negative affect, and goal orientation (Campbell-Sills and Stein, 2007; Connor and Davidson, 2003). It is a 25-item mea- sure in which each item is rated on a scale of 0e4, with higher scores reflecting greater levels of resilience. The CDRISC is one of the most widely used and best validated measures of resil- ience (e.g., Campbell-Sills and Stein, 2007; Fincham et al., 2009; Green et al., 2010; Pietrzak et al., 2010; Stein et al., 2009; Wingo et al., 2010). It has been tested in the US general popu- lation, community samples, primary care patients, psychiatric patients, members of different ethnic groups and cultures (China, Korea, Japan, Pakistan, Iran, Portugal, Spain, Russia, the Netherlands, Australia, Italy, Norway, South Africa, Uganda, Gaza), survivors of various traumas, Alzheimer’s caregivers, adolescents, college students, adults, elders, selected profes- sional or athletic groups, patients in treatment for PTSD, and Iraq combat veterans (see bibliography at http://www.cd-risc.com). It has excellent psychometric properties with an internal consistency Cronbach’s a of 0.85 and test-retest reliability correlation of 0.87 (Campbell-Sills and Stein, 2007; Connor and Davidson, 2003).

The RSA is a 45-item measure of resilience covering five different dimensions: personal competence, social competence, family coherence, social support, and personal structure (Friborg et al., 2003). It has been used with both psychiatric outpatients and healthy control participants. The BRS is a six-item measure in which participants are asked to rate items on a scale of 1e5, with higher scores indicating greater resilience (Smith et al., 2008). The BRS has been tested among samples of undergraduate students, cardiac rehabilitation patients, patients with fibromyalgia, and healthy controls.

Although not a direct measure of resilience, the Positive and Negative Affect Schedule (PANAS) may also lend itself to studies of resilience in the aftermath of trauma (Watson et al., 1988). The PANAS is a 20-item measure consisting of two mood scales for measuring positive and negative affect. The positive affect subscale assesses enthusiasm, determina- tion, excitement, and interest, among other affective states. Positive affect has been theo- rized to promote flexible thinking, facilitate adaptive coping strategies, and counteract the physiological effects of negative emotions (Ong et al., 2009). Under stressful conditions, positive emotions are thought to sustain continued coping efforts and restore the vital re- sources that are depleted by stress (Feder et al., 2009; Ong et al., 2009). In a study of widows, positive emotions contributed to faster psychological recovery from the death of a spouse or life partner (Ong et al., 2009). Not surprisingly, individuals with high CDRISC scores tend to bias toward positive emotions when faced with uncertain emotional expressions (Arce et al., 2009). In short, daily experience of positive emotions helps individ- uals bounce back from major life stressors and increase resilience and life satisfaction (Cohn et al., 2009).

Another measure relevant to the study of resilience is the Short Grit Scale (Grit-S; Duckworth and Quinn, 2009). Grit has been defined by Duckworth et al. (2007) as “persever- ance and passion for long-term goals.” This involves continuously working toward goals and maintaining interest despite challenges. The Grit-S is an eight-item measure of grit consisting of two factors: Consistency of Interest (e.g., “I often set a goal but later choose to pursue a different one”; reverse scored) and Perseverance of Effort (e.g., “Setbacks don’t discourage me”; Duckworth and Quinn, 2009). Across multiple samples, the Grit-S has demonstrated strong psychometric properties, as well as associations with achievement, conscientiousness, and career and marriage stability (Duckworth and Quinn, 2009; Eskreis-Winkler et al., 2014).

 

136 10. Understanding resilience: biological approaches in at-risk populations

These associations remained significant despite the inclusion of variables such as intelligence and demographic factors. Among low-income adolescents, higher levels of grit may be protective against engaging in maladaptive behaviors such as substance use and fighting (Guerrero et al., 2016). Given that trait-level grit is relevant to several functional outcomes, it may be worthy of consideration in the context of resilience to trauma.

Biological facets of resilience

Genetics

Recent studies in the field of genetics have identified several candidate genes that appear to be implicated in resilience. The literature on specific candidate genes should be interpreted with caution because of the potential presence of bias and low statistical power. The primary focus of current genetics research in PTSD and resilience is on large, unbiased genome-wide association studies (GWASs). We will review some of the more robust candidate gene studies and recent GWASs that relate to resilience.

Candidate studies

One particular gene that has received attention is the gene encoding the serotonin (5HT) transporter, 5HTT. Specifically, a polymorphism in the promoter region of this gene (5HTTLPR) has been implicated as a genetic risk factor for poor stress resilience, such that the short allele variant (S) is less efficient at the cellular level of serotonin transport than the long allele variant (Lesch et al., 1996). With the occurrence of stressful life events (including trauma), this polymorphism has been shown to confer greater risk for depression (e.g., Caspi et al., 2003; Kaufman et al., 2004; Zalsman et al., 2006), anxiety sensitivity (Stein et al., 2008), and trait anxiety/neuroticism (Schinka et al., 2004). Expanding upon this research, Stein et al. (2009) examined 5HTTLPR in direct relation to emotional resilience, which was measured with the CDRISC (Connor and Davidson, 2003). Consistent with prior research, the authors found that individuals with one to two copies of the S allele variant demonstrated lower resilience scores than those without the S allele, and they also showed that this relationship was linear, such that increase in S allele copies was associated with lower resilience. Odds ratio analyses suggested that for each S allele copy, an individual’s chance of being in a “low-resilient” category increased by 63%. It is note- worthy that this was the first study to demonstrate that resilience itself, measured as a trait, was significantly associated with its own genetic risk factor. This provides further support for examining psychopathology and risk by their underlying intermediate phenotypes rather than symptom presentation alone, consistent with NIMH’s research domain criteria (RDoC) initiative.

Pituitary adenylate cyclaseeactivating polypeptide (PACAP) has been implicated in the stress response, and in particular, it has been found to regulate corticotropin-releasing factor (CRF) function. Building on prior PACAP research in rodents, Ressler et al. (2011) examined its relations with PTSD among humans with trauma exposure. Lower levels of PACAP38 (a PACAP peptide) were associated with lower PTSD symptoms among females, but not males. This effect was also observed when the individual symptom clusters of PTSD were tested,

 

Biological facets of resilience 137

and both analyses were replicated in an additional female sample. Further analyses sug- gested that a single-nucleotide polymorphism (SNP) in the estrogen receptor response element within the PAC1 receptor ADCYAP1R1, rs2267735, was significantly predictive of PTSD diagnosis among females, but not males. The rs2267735 CG and GG genotypes in particular were associated with less severe PTSD symptoms, whereas the CC genotype was associated with more severe symptoms (Ressler et al., 2011). Thus the G-allele carriers in these studies could be seen as resilient to the effects of severe trauma exposure.

The dopamine receptor gene, DRD4, has previously demonstrated a moderating effect on the relationship between childhood stress and both internalizing and externalizing behaviors among children. To explore its role in resilience, DRD4 was recently studied as a potential candidate gene among individuals with varying levels of child adversity. Das et al. (2011) tested the potential moderating effect of a specific polymorphism, DRD4-exIII-VNTR, on the relationship between child adversity and adult self-reported resilience. A gene x environment interaction was observed such that the 7rþ allele of DRD4-exIII-VNTR pre- dicted greater resilience despite the presence of child adversity (as child adversity increased, resilience decreased among those with the 7r allele).

Another dopaminergic gene that has received attention is the catechol-O-methy- ltransferase (COMT) gene. Specifically, the Met allele of the COMT gene has been associated with greater risk for PTSD and depression following stressful and/or traumatic events (Boscarino et al., 2011; Kolassa et al., 2010). Given that COMT is responsible for dopamine regulation in the brain (which has a role in inhibition), one of the proposed mechanisms for the effect of the Met allele on PTSD is fear inhibition/safety learning (Norrholm et al., 2013). To further examine this, van Rooij et al. (2016) tested the interaction of childhood trauma and COMT on inhibition and resilience among adults. Inhibition was assessed via hippocampal activation during a Go/NoGo task, and resilience was assessed via self- report. The Met allele of COMT was associated with decreased inhibition, whereas the Val allele was predictive of improved inhibitiondpotentially an intermediate phenotype of resil- ience. Furthermore, hippocampal activity was positively correlated with trait resilience, and it mediated the effect of childhood abuse on resilience among those with the Val allele. These findings suggest that increased hippocampal activation (i.e., inhibition) may be a mechanism through which the Val allele of COMT confers greater resilience among individuals with childhood trauma.

Given the known impact of trauma and PTSD on the hypothalamic-pituitary-adrenal (HPA) axis, another candidate gene implicated in risk/resilience is FKBP5 due to its regula- tion of glucocorticoid receptor activity. Specifically, SNPs in the FKBP5 gene have been shown to predict PTSD symptoms among trauma-exposed individuals. In a study of adults with child abuse and adult-onset trauma, Binder et al. (2008) found that four FKBP5 SNPs interacted with child abuse to predict adult PTSD symptoms. Thus, differences in genes asso- ciated with HPA axis regulation may confer risk or resilience for PTSD through their role in glucocorticoid receptor activation (i.e., the presence of certain SNPs may alter the effects of childhood trauma on stress hormone regulation, and subsequently PTSD). A similar finding was reported by Sarapas et al. (2011), such that FKBP5 expression mediated the relationship between FKBP5 genotype and PTSD symptoms among adults exposed to the 9/11 attacks.

The CRF receptor 1 gene (CRHR1) has also been studied in relation to resilience. Like FKBP5, CRHR1 is a gene involved in HPA axis regulation. Specifically, CRHR1 modulates

 

138 10. Understanding resilience: biological approaches in at-risk populations

the effect of CRF and the subsequent release of cortisol throughout the adrenal cortex. CRF is known to influence arousal, executive functioning, and memory consolidation. Several SNPs of CRHR1 have been shown to interact with childhood abuse to predict resilience, such that a TAT haplotype of three SNPs exerted a protective effect by reducing vulnerability to depression symptoms (Bradley et al., 2008). This finding was replicated by Polanczyk et al. (2009) in a sample of women who enduredchildhood maltreatment, such that the TAT haplotype was associated with reduced depression risk.

The HPA axis is linked to the nitrous oxide network within the hippocampus (a brain region known to be involved in PTSD resilience due its role in memory consolidation). Given this link, two genes within the nitrous oxide pathway have been implicated in PTSD resilience: NOS1AP and NOS1 (Bruenig et al., 2017; Lawford et al., 2013). The proposed link between these systems involves N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) activity. Specifically, changes in NMDA receptor activ- ity (regulated by NOS1AP and NOS1) influence nitrous oxide production, and increased nitrous oxide contributes to lower GABA levels, which then leads to HPA axis dysfunction. In a study by Bruenig et al. (2017), a SNP of NOS1AP, rs4657178, was associated with self- reported resilience among trauma-exposed veterans without PTSD, whereas another SNP, rs17460657, was associated with resilience among those with PTSD. A SNP of NOS1, rs10744891, was also associated with resilience among the PTSD group. The SNP within the trauma-exposed control group may be of particular interest because it could highlight the role of NOS1AP SNP rs4657178 in promoting resilience from PTSD despite significant trauma exposure. In contrast, the findings within the PTSD group suggest that although rs17460657 and rs10744891 may foster greater resilience, they may not be protective against PTSD symptoms.

Given its role in the stress response and fostering relationships, oxytocin is another candi- date gene of interest. A recent study examined the rs53576 polymorphism of the oxytocin re- ceptor gene (OXTR) in relation to resilient coping and positive affect among adults with varying degrees of trauma exposure (Bradley et al., 2013). For individuals with the GG and AG genotypes of OXTR rs53576, positive childhood environment was predictive of more resilient coping and positive affect in adulthood.

In summary, a number of biological pathway-focused, candidate gene studies have demonstrated interesting potential genetic associations with resilience-related phenotypes. However, these studies have typically been underpowered, and the findings from these studies have not generally been replicated in larger-scale and unbiased studies. Thus, inter- pretations from these studies must be made with caution, with the need for replication and integration with larger-scale unbiased genome-wide studies and other biological complemen- tary approaches, as outlined below.

Genome-wide unbiased studies

As part of a prospective longitudinal study of risk and resilience, Nievergelt et al. (2015) conducted a GWAS on US service members scheduled for overseas deployment. Across ge- netic ancestry groups, the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) demonstrated genome-wide significance differentiating risk versus resilience responses to trauma exposure. This study was novel in its examination of effects across genetic ancestry, which also increased statistical power.

 

Biological facets of resilience 139

Other studies have approached resilience through the examination of transcriptome-wide analyses to identify which peripheral blood RNA expression may differentiate risk versus resilience. DICER1 is an enzyme that creates mature microRNAs (miRNAs) from pre- microRNA. miRNAs are involved in the regulation of many genes and in synaptic develop- ment and plasticity. Recently, a series of studies implicated DICER1 and miRNAs in PTSD risk/resilience among adults with trauma exposure. In a transcriptome-wide association study, persons with comorbid PTSD and depression had significantly lower expression of DICER1 relative to controls after adjusting for the relevant confounding factors (genome- wide false discovery rate at P < .05; Wingo et al., 2015). This association was replicated in two independent samples (Wingo et al., 2015). Lower DICER1 expression was also associated with greater amygdala activation in response to threat stimuli (an intermediate phenotype of PTSD). This finding provides a neurobiological parallel to that of the PTSD and depression diagnosis and provides further support for the potential role of DICER1 as a contributor to risk or resilience following trauma. Additionally, expression level of miR-3130-5p was signif- icantly lower in persons with PTSD with comorbid depression compared with controls (Wingo et al., 2015). This association with risk versus resilience was replicated in an indepen- dent sample (Wingo et al., 2015).

Since frequent experience of positive emotion despite high level of stress or trauma is a marker of resilience, Wingo et al. (2016) next conducted a GWAS of tendency to experience positive emotion among a high-risk sample of inner-city adults with high stress and trauma exposure. Two SNPs reached genome-wide significance, such that the minor alleles of rs322931 and rs7550394 were associated with more frequent experience of positive emotion. The minor allele of rs322931 was also significantly associated with better fear inhibition dur- ing a fear conditioning task. Wingo et al. (2016) suggested that this effect may be mediated by miR-181a and miR-181b given that rs322931 influences the expression of brain miR-181a. Prior studies have implicated miR-181a in reward neurocircuitry as well as synaptic plas- ticity, which are relevant to learning and resilience.

Physiology

Distinctions in physiological responses between those with and without PTSD point to resilience factors that may be important following trauma exposure. In fear conditioning par- adigms, individuals with PTSD have demonstrated decreased ability to distinguish between safety stimuli and danger stimuli compared with those without PTSD (i.e., decreased fear discrimination; Glover et al., 2011; Norrholm et al., 2011; Schumacher et al., 2013). Addition- ally, those with PTSD demonstrate higher startle to a safety cue (i.e., decreased fear inhibi- tion; Jovanovic et al., 2009; Norrholm et al., 2011; Sijbrandij et al., 2013). Overall, this suggests that better fear discrimination and fear inhibition may contribute to psychological resilience following trauma. In a prospective longitudinal study of soldiers who were about to be deployed, similar results were found during the extinction phase of the conditioning paradigm. Specifically, better extinction learning prior to deployment was predictive of fewer PTSD symptoms (resilience) after soldiers returned from deployment (Lommen et al., 2013). Similarly, a study of police academy cadets found that those who reported less subjective fear under low threat had less severe symptoms of PTSD when assessed 1 year later (Pole et al., 2009).

 

140 10. Understanding resilience: biological approaches in at-risk populations

Skin conductance is another physiological measure that has been implicated in resilience following trauma exposure. In general, individuals with trauma exposure and no PTSD tend to demonstrate lower skin conductance than those with PTSD, suggesting that they experience less sympathetic arousal both at rest and in response to challenge (Pole, 2007). Heart rate variability (HRV), or variability in the time period between heart beats, is an auto- nomic nervous system indicator typically associated with emotion regulation. Higher HRV is associated with better emotion regulation (Beauchaine, 2001; Demaree et al., 2004; Volokhov and Demaree, 2010) and with fewer symptoms of PTSD among trauma-exposed individuals (e.g., Hauschildt et al., 2011; Sack et al., 2004; Shah et al., 2013). Thus, skin conductance and HRV may be considered additional resilience factors following trauma exposure, although no studies to date have examined these measures in relation to self-reported resilience. Although not exhaustive, Table 10.1 includes a summary of the studies implicating startle response, skin conductance, and HRV in recovery from trauma.

Neuroimaging

Other predictors of resilience following trauma may be gleaned from structural and func- tional brain differences among individuals with and without PTSD. Given its role in learning and memory, the hippocampus has long been a region of interest related to PTSD develop- ment and maintenance. In general, individuals with PTSD tend to have smaller hippocampal volume (see Karl et al., 2006 and O’Doherty et al., 2015 for reviews). However, few studies have examined hippocampal volume in direct relation to resilience measured as a trait. Rather, most studies have compared hippocampal volume among trauma-exposed individ- uals with and without PTSD, where those without PTSD are considered “resilient.” Addition- ally, studies have been limited in their retrospective nature, such that it is often unclear whether volumetric differences were present before or after trauma exposure.

In an effort to address these issues, Gilbertson et al. (2002) examined hippocampal volume among monozygotic twin pairs, where one twin was a veteran with combat exposure and the other was a nonveteran. Smaller right hippocampal volume was predictive of PTSD in trauma-exposed individuals. Notably, healthy identical twins of low-severity PTSD veterans showed significantly greater hippocampal volume than those with PTSD or their nonexposed siblings. Overall, this indicates that greater hippocampal volume may serve as a preexisting resilience factor for individuals exposed to trauma (Gilbertson et al., 2002). Building on this research, a recent study examined baseline hippocampal volume in relation to treatment response. In a study of individuals with PTSD who underwent prolonged exposure (PE), those who responded well to treatment (suggesting more resilience) had greater hippocampal volume at baseline than those who did not respond (Rubin et al., 2016).

Two other brain regions of interest are the amygdala and the anterior cingulate cortex (ACC). Although the amygdala is involved in emotional memory and fear conditioning, the ACC plays a role in emotion regulation. Overall, individuals with PTSD tend to have smaller amygdala and ACC volumes compared with those without PTSD (see Karl et al., 2006 and O’Doherty et al., 2015 for reviews). Similar to studies of the hippocampus, amyg- dala and ACC research has primarily focused on comparisons between trauma-exposed

 

TABLE 10.1

Examples of biological facets of resilience.

Physiology
Heart rate variability

Green et al. (2016), Hauschildt et al. (2011), Keary et al. (2009), Liddell et al. (2016), Minassian et al. (2014), Park et al. (2017),

Sack et al. (2004), Sahar et al. (2001), Shah et al. (2013)

Skin conductance

Bryant et al. (1995), Carson et al. (2000), Casada et al. (1998), Cuthbert et al. (2003), Goldfinger et al. (1998), Hinrichs et al. (2017), Liberzon et al. (1999),
Orr et al. (1995/2000), Pitman et al. (1990/2001), Pole et al. (2009), Rothbaum et al. (2001), Shalev et al. (1997)

Startle response

Glover et al. (2011), Grillon et al. (1998), Jovanovic et al. (2009/2010/2012),

Morgan et al. (1995/1996/1997),
Orr et al. (1995), Norrholm et al. (2011), Schumacher et al. (2013), Shalev et al. (1998), Sijbrandij et al. (2013)

Biological facets of resilience

141

Genes

5HTTLPR

Stein et al. (2009)

ADCYAP1R1

Ressler et al. (2011)

COMT

van Rooij et al. (2016)

Neuroanatomy

Anterior cingulate cortex

Chen et al. (2006, 2012), Kitayama et al. (2006), Felmingham et al. (2009) Reynaud et al. (2013), Rocha-Rego et al. (2012), Woodward et al. (2006)

Amygdala

Morey et al. (2012), Rogers et al. (2009), Weniger et al. (2008), Wignall et al. (2004)

Hippocampus

Apfel et al. (2011),
Bonne et al. (2008),
Bossini et al. (2008), Bremner et al. (1995), Bremner et al. (1997, 2003), Chen et al. (2006),

Emdad et al. (2006), Felmingham et al. (2009), Gilbertson et al. (2002), Lindauer et al. (2004, 2005), Pavic et al. (2007), Villarreal et al. (2002), Wang et al. (2010), Weniger et al. (2008), Wignall et al. (2004), Yehuda et al. (2007),

Zhang et al. (2011)

  

CRHR1

Polanczyk et al. (2009)

DICER1

Wingo et al. (2015)

DRD4

Das et al. (2011)

FKBP5

Binder et al. (2008), Sarapas et al. (2011)

miR-181a, miR-181b

Wingo et al. (2016)

NOS1, NOS1AP

Bruenig et al. (2017)

OXTR

Bradley et al. (2013)

PRTFDC1

Nievergelt et al. (2015)

 

142 10. Understanding resilience: biological approaches in at-risk populations

individuals with and without PTSD rather than resilience as a trait, per se. As an example, one study explored resilience as a trait and found that increased amygdala activity was asso- ciated with greater self-reported resilience among fire-fighters (Reynaud et al., 2013). Given the known role of poor emotion regulation in PTSD, it follows that larger volumes/activation of brain regions implicated in emotion and its regulation may promote resilience following stressful life events. However, like research on the hippocampus, it is difficult to know whether increased amygdala and ACC volume/activation are protective factors or whether PTSD results in decreased amygdala/ACC volume/activation. Furthermore, it is unclear what differential gross measures of size or activation levels mean for neural circuit function. To further elucidate these findings, future neuroimaging studies would benefit from taking a prospective approach where possible (e.g., military and first-responder samples, monozy- gotic twin studies), as well as from examining resilience as a trait in addition to the lack of PTSD following trauma.

Resilience as a multidimensional trait

Research on the aforementioned biological mechanisms of resilience provides support for the notion that resilience should be conceptualized as a trait with its own intermediate phenotypes rather than simply the lack of psychopathology. As a multidimensional trait, resilience encompasses differential heritability interacting with the environment, which leads to improved function and well-being via intermediate phenotypes such as improved regula- tion of emotion and physiology (Fig. 10.2).

Future resilience research should also examine biological markers in association with specific resilience measures, such as the CDRISC. This approach would also allow for the probing of resilience in the context of PTSD. For example, some individuals may have a diag- nosis of PTSD and yet many aspects of functioning could be intact. Examining resilience as a trait would allow researchers to better understand how some individuals cope with PTSD and are resilient despite significant symptoms. Taken together, the research reviewed here suggests that several candidate genes and SNPs, along with physiological mechanisms and neuroimaging characteristics, provide a biological model of resilience pathways.

FIGURE 10.2 Resilience as a multidimensional trait.

 

 

References 143 Conclusion/summary

Despite the high prevalence of trauma exposure, most individuals do not develop signif- icant symptoms of PTSD. It is important to better understand how so many trauma-exposed individuals do not develop significant symptoms, as well as how some have PTSD but are able to function despite these symptoms. Resilience research allows for the examination of factors that not only confer less risk for PTSD but also contribute to the resilience trait itself. Current measures for assessing resilience include the CDRISC, the RSA, the BRS, and the PANAS. Biological measures that are relevant to resilience following trauma include several genetic variants, brain regions, and physiological phenomena. Resilience studies may be improved by more incorporation of resilience-specific measures in addition to the study of group differences (PTSD vs. no-PTSD). Studying resilience as a trait can enhance future research and contribute to a better understanding of how individuals recover from trauma even in the face of PTSD symptoms.

Acknowledgments

The work was supported by NIH grants R01MH108665, R01MH094757, and R21MH112956 and the Frazier Founda- tion Grant for Mood and Anxiety Research. APW is supported by grants IK2CX000601, R01AG056533, and U01HG009807.

Disclosures

Dr. Ressler is on the Scientific Advisory Boards for Resilience Therapeutics, Sheppard Pratt-Lieber Research Institute, Laureate Institute for Brain Research, The Army STARRS Project, UCSD VA Center of Excellence for Stress and Mental HealthdCESAMH, and the Anxiety and Depression Association of America. He provides fee-for-service consultation for Biogen and Resilience Therapeutics. He holds patents for use of D-cycloserine and psychotherapy, targeting PAC1 receptor for extinction, targeting tachykinin 2 for prevention of fear, targeting angiotensin to improve extinction of fear. Dr. Ressler is also founding member of Extinction Pharmaceuticals to develop D-cycloserine to augment the effectiveness of psychotherapy, for which he has received no equity or income within the past 3 years. He receives or has received research funding from NIMH, HHMI, NARSAD, and the Burroughs Wellcome Foundation.

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CHAPTER

11

Stress resilience as a consequence of early-life adversity

Jakob Hartmann1, Mathias V. Schmidt2
1McLean Hospital e Harvard Medical School, Mailman Research Center, Neurobiology of Fear

Laboratory, Belmont, MA, United States; 2Max Planck Institute of Psychiatry, Munich, Germany

Introduction

Living in Western societies seems to become ever more unpredictable and uncontrollable, and therefore people are being exposed to substantial stressors throughout their lives. In par- allel, there is a growing awareness that stress exposure can be harmful and promote a variety of diseases (de Kloet et al., 2005). As a consequence, stress has been labeled the “bad guy,” and the response to stress is often seen as maladaptive. However, it should be considered that humans evolved in a highly unpredictable and uncontrollable environment and that life during the millennia of human evolution was unlikely to be less stressful than it is today. It is therefore not surprising that even today most people are highly resilient in the face of adversity and, despite continuous exposure to a multitude of stressors, stay healthy until old age. But what differentiates individuals that suffer from stress exposure from those that are resilient? In this chapter, we will discuss evidence that suggests the answer to this question may lie in the developmental history and the interplay of experiences early and later in life.

Early-life stressddefinition of the term

Before discussing the consequences of early adversity, one has to clearly define what exactly is meant by “early” and how “adversity” or “stress” is defined. For the purpose of the chapter, the early-life period will be considered to cover the prenatal and postnatal period until adoles- cence, both in animals and in humans. It is clear that the developmental trajectory of mice and humans is quite different depending on the physiological system or brain circuit of interest (Rice and Barone, 2000; Semple et al., 2013). However, overall, it is well accepted that during

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00011-2 149 Copyright © 2020 Elsevier Inc. All rights reserved.

   

 

150 11. Stress resilience as a consequence of early-life adversity

phases of intense brain development, the organism is most sensitive to environmental stimuli that can lastingly affect the individual (Chen and Baram, 2016; Yam et al., 2015).

The term “stress,” on the other hand, is here defined in the sense of unpredictable and uncontrollable adversity, rather than a challenge to body’s homeostasis per se. Here, we are following the arguments laid out by Koolhaas and colleagues, arguing that especially the unpredictable and uncontrollable nature of a challenge is of the essence when interpreting stress in the context of disease or disease risk (Koolhaas et al., 2011).

Early-life stress is a risk factor for psychiatric disorders

Stress and traumatic events are well-established risk factors for various pathologies including cardiovascular disease, obesity, diabetes, alcohol and drug abuse, and most prominently psychiatric diseases such as mood and anxiety disorders. Many epidemiological studies strongly support an association of adverse life events particularly during childhood, with increased susceptibility to develop psychopathology later in life (Lupien et al., 2009; Nemeroff, 2016; Kim and Cicchetti, 2006; Larkin and Read, 2008; Weber et al., 2008). More precisely, early-life stress, defined as neglect, physical abuse, sexual abuse, and emotional maltreatment, has been associated with an increased prevalence of depressive dis- orders such as major depressive disorder (MDD) (Goldberg, 1994; Chapman et al., 2004; Kaufman, 1991; Widom et al., 2007; Scott et al., 2010; Benjet et al., 2010; Maniglio, 2010; Teicher et al., 2006; Anda et al., 2002; Green et al., 2010; Danese et al., 2009), bipolar disorder (Anda et al., 2007; Gilman et al., 2015; Daruy-Filho et al., 2011; Agnew-Blais and Danese, 2016), and with increased rates of anxiety disorders including general anxiety disorder and panic disorder (Copeland et al., 2013; Scott et al., 2010; Green et al., 2010; Cougle et al., 2010). In addition, a history of childhood maltreatment has been linked to subsequent devel- opment of posttraumatic stress disorder (PTSD) (Duncan et al., 1996; Widom, 1999; Cabrera et al., 2007; Fritch et al., 2010; Scott et al., 2010) and to an increased risk for suicide attempt (Felitti et al., 1998; Dube et al., 2001; Maniglio, 2011). Notably, psychiatric disorders tend to emerge earlier in previously maltreated individuals, with greater severity, higher comorbidity rates, and with a less favorable response to treatment (Nanni et al., 2012; Alvarez et al., 2011; Leverich et al., 2002; Widom et al., 2007; Benjet et al., 2010). All of this suggests that childhood adversity can lay a fragile foundation for health across the life span.

Early-life stress shapes adult phenotypes

Although the exact molecular mechanisms underlying the effects of early-life stress are not fully understood, there is strong evidence for an impairment of the hypothalamic-pituitary- adrenal (HPA) axis (Lupien et al., 2009).

In response to stressful stimuli, circulating glucocorticoids (GCs), which are the main hormonal endpoint of the HPA axis, act on numerous organ tissues to execute a wide range of functions involving the immune, digestive, and endocrine systems and including the regulation of the negative feedback of the stress response mostly at the level of the hypo- thalamus and pituitary (de Kloet et al., 2005). GCs also affect the morphology and

 

 

Early-life stress shapes adult phenotypes 151

functionality of central nervous system target tissues, including those responsible for mood and cognitive functions relevant to psychiatric disorders (Abercrombie et al., 2011; de Quer- vain et al., 2003; Karst et al., 2002; Mitra and Sapolsky, 2010; Hartmann et al., 2017; Gershon, Sudheimer, Tirouvanziam, Williams and O’Hara, 2013; Barik et al., 2013; Tronche et al., 1999; Gass et al., 2001; Anacker et al., 2011). In fact, various types of early-life stress can alter HPA responsiveness and regulation. For instance, HPA axis hyperactivity has been docu- mented in depressed individuals as a consequence of childhood adversity associated with social, physiological, and pharmacological stressors (Heim et al., 2000, 2002; Heim et al., 2001; Heim et al., 2008; Carvalho Fernando et al., 2012). In contrast, other studies point to blunted HPA axis activity, both in healthy subjects and in individuals with mood disor- ders or PTSD following early-life adversity (Ouellet-Morin et al., 2011; Carpenter et al., 2009; Carpenter et al., 2011; King et al., 2001). Thus, the direction and pattern of such HPA alterations may depend not only on various factors including, but not limited to, the nature and timing of the stressor, and severity and number of traumatic events, but also on genetic and epigenetic markers.

It is indisputable that not all individuals who are exposed to early-life adversity will develop psychiatric pathology later in life. So what makes some individuals more susceptible to early-life adversity than others? It is well established that stress-related psychiatric disor- ders such as PTSD and MDD often originate from gene-environment interactions. Besides genetic variants (e.g., risk alleles), epigenetic modifications, such as histone modifications and DNA (de-)methylation, are thought to mediate long-lasting effects of adverse life events on gene regulation by shaping the transcriptional activity of genes without changing the underlying genetic code (Klengel and Binder, 2015; Pena et al., 2014). These molecular changes induce long-lasting alterations in gene expression and ultimately behavior. Thus, specific genetic and epigenetic markers may moderate the effects of early adversity on later psychopathology.

By studying a single nucleotide polymorphism (SNP) within the gene encoding the FK506 binding protein 51 (FKBP51), Klengel et al. (2013) present compelling evidence for an epige- netic mechanism mediating gene environment interactions that ultimately results in an increased risk to develop stress-related psychiatric disorders. FKBP51 participates in inhibi- tion of glucocorticoid receptor (GR) activity, which is the main mediator of the HPA axis. At the same time, GR activation is involved in the induction of FKBP51 transcription, creating an intracellular, ultrashort feedback loop that regulates GR sensitivity (Wochnik et al., 2005; Touma et al., 2011; Hartmann et al., 2012; Binder, 2009). Klengel et al. elegantly showed that a functional SNP altering chromatin interaction between the transcription start site and long- range enhancers in the FKBP51 gene increases the risk of developing stress-related psychiatric disorders in adulthood through allele-specific, childhood trauma-dependent DNA demethy- lation in functional glucocorticoid response elements of FKBP51. This demethylation was associated with increased stress-dependent gene transcription followed by a long-term dysregulation of the HPA axis (Klengel et al., 2013). Along these lines, there is a large body of literature linking other genetic risk factors with increased vulnerability to early-life stress, including SNPs in 5-HTT, PACAP, PAC1, Nr3c1, and Crhr1 (Tyrka et al., 2016; Bradley et al., 2008; Caspi et al., 2003; Ressler et al., 2011). Interestingly, Arloth et al. (2015) showed that different sets of genetic variants may be involved in baseline transcriptional regulation versus regulation following environmental impact, such as trauma exposure.

 

152 11. Stress resilience as a consequence of early-life adversity

In addition to HPA axis dysregulation and specific genetic/epigenetic risk factors, there is increasing evidence for persistent structural and functional consequences of adverse early-life events on specific brain structures and circuits. Indeed, MRI-based studies revealed decreased connectivity between the amygdala and insula/hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), as well as between the hippocampus and vmPFC in individuals with a history of childhood maltreatment (van der Werff et al., 2013; Burghy et al., 2012; Herringa et al., 2013). Structural variations in the prefrontal cortex have also been shown to mediate the relationship between early childhood stress and spatial working memory (Hanson et al., 2012). Moreover, previous work has repeatedly shown that hippocampal atrophy in depressed patients is associated with a history of early-life stress (Vythilingam et al., 2002; Buss et al., 2007; Frodl et al., 2010). This raises the question whether psychiatric disorders that are linked to early-life stress occur in response to epigenetic and/or gene expression changes in specific brain circuits.

Despite the presented examples, the effects of early-life stress on psychopathology in adulthood remain a challenging process to study in humans. Some of the major difficulties are the duration of such studies, the genetic diversity of humans as well as biases in the perception and reporting of early adversity. Preclinical studies using rodent models have been helpful and crucial in improving our basic knowledge about the consequences of adverse events during development on psychopathology later in life. Such models can offer better control over genetic backgrounds (e.g., inbred strains), onset, type and intensity of stressors and provide much shorter study times. Nevertheless, it is important to note that stress-related psychiatric disorders represent very complex diseases, making it impossible to model certain symptoms in rodents, for example, features of MDD (e.g., feelings of guilt, low self-esteem, or suicidality). However, other core aspects such as anhedonia, loss of motivation, sleep disturbances, anxiety, cognitive deficits, and a dysregulation of the HPA axis do have equivalents in rodents. Thus, it is possible to reach a certain level of face validity with such animal models.

Various rodent early-life stress paradigms have been developed in the past. Maternal separation, models based on naturally occurring differences in maternal care, impoverished postnatal environment as well as pharmacological approaches rank among most frequently used.

Numerous studies with rats have linked early maternal separation with lifelong neuroen- docrine alterations, changes in HPA axis activity, and anxiety-related behavior (Ladd et al., 1996; Rots et al., 1996; Sutanto et al., 1996; Workel et al., 2001; Workel et al., 1997; Suchecki et al., 2000; Kalinichev et al., 2002; Benekareddy et al., 2011). Another model that is based on individual differences of maternal care was first introduced by the group of Michael Meaney (Liu et al., 1997). In this paradigm, abnormal maternal care is defined as increased or decreased (one standard deviation above or below the group mean) licking, grooming, and/or arched-back nursing during the first 10 days of life. Liu et al. (1997) demonstrated that as adults, the offspring of mothers that exhibited more licking and grooming of pups (LG mothers) during the postnatal observation period showed reduced HPA axis responses to acute stress, increased hippocampal GR mRNA expression, and decreased levels of hypothalamic CRF mRNA. Strikingly, each measure was correlated with the frequency of maternal licking and grooming (Liu et al., 1997). In addition, Caldji et al. (1998) reported that individual differences in the frequency of maternal care during infancy regulate the

 

Early-life stress shapes adult phenotypes 153

development of neural systems mediating the expression of fearfulness in the rat. Interest- ingly, this paradigm also suggests that maternal effects may modulate optimal cognitive functioning in environments varying in demand in later life, with offspring of high and low LG mothers showing enhanced learning under contexts of low and high stress, respec- tively (Champagne et al., 2008).

The limited nesting material paradigm was first introduced by the group of Tallie Baram. In this model, the mothers (rats and mice) are provided with a limited quantity of bedding and nesting material during postnatal day 2e9 (Ivy et al., 2008; Rice et al., 2008). This manip- ulation induces perturbed dam-pup interactions reflected in frequent changes of maternal behavior and inconsistent or fragmented maternal care, resulting in a higher stress exposure of the offspring. This adverse environment leads to elevated basal HPA axis activity, increased anxiety-related behavior, and impaired learning and memory functions in adult mice and rats (Rice et al., 2008; Ivy et al., 2008, 2010; Wang et al., 2012; Brunson et al., 2005).

Other studies focus on the postnatal application of GCs such as the synthetic GC dexameth- asone (Dex) to mimic an early-life stress exposure. Neonatal Dex treatment leads to altered HPA axis activity in response to stress in adolescent and adult rats (Flagel et al., 2002; Neal et al., 2004). Moreover, rats with early-life Dex exposure also show increased anxiety- and depression-like behavior later in life (Neal et al., 2004; Ko et al., 2014; Felszeghy et al., 1993).

Again, many psychiatric disorders are caused by interactions between a (epi-) genetic predisposition and environmental factors. Thus, studies assessing the joint contribution of genetic and environmental factors in the etiology of mental disorders have become increas- ingly important in the field of psychiatry. Rodent models of early-life stress are often com- bined with additional genetic or environmental (risk) factors, for example, a specific genetic knockout or a second trauma/stress exposure later in life. Applying such experimental designs, corticotropin-releasing factor (CRF) and its receptor, CRFR1 have been shown to modulate the negative effects of early-life stress on cognition and structural plasticity in mice (Wang et al., 2011). Along these lines, we were able to demonstrate that the cell adhesion molecule nectin-3 is required for the effects of CRFR1 on cognition and structural remodeling after early-life stress exposure (Wang et al., 2013). In another study, the limited nesting material paradigm led to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of the neuronal cell adhesion molecule neuroligin-2 in the hippocampus. Although hippocampal overexpression of neuroligin-2 in adult mice mimicked the early-life stresseinduced alterations, knockdown of neuroligin-2 in adulthood attenuated the early-life stresseinduced behavioral changes (Kohl et al., 2015). Recently, Peña and colleagues reported that mice subjected to a model of maternal separation were less resilient to chronic defeat in adulthood. In this study, they demonstrated that genes regulated by the transcription factor orthodenticle homeobox 2 (Otx2) in the ventral tegmental area (VTA) primed the response toward susceptibility in adulthood. Although transient juvenile knockdown of Otx2 in VTA mimics the effects of early adversity by increasing stress vulnerability, its overexpression reduces the effects of early-life stress (Pena et al., 2017).

Although alterations in HPA axis activity as well as (epi-)genetic risk factors have been implicated in mediating the effects of early-life stress on later psychopathology, there is increasing belief that these changes may occur in a circuit-specific manner. Such circuit- level framework has been extensively investigated in adult stress models. For example, the

 

154 11. Stress resilience as a consequence of early-life adversity

combination of optogenetic technology and chronic social defeat stress has identified impor- tant structural and functional alterations within the brain’s reward circuits that are associated with aspects of depression and addiction (reviewed in Russo and Nestler (2013); Han and Nestler, (2017); Sparta et. al., (2013)). However, studies focusing on circuit-specific changes in animal models of early-life stress are still largely lacking. Consequently, the utilization of novel technologies including optogenetics, chemogenetics, and diverse viral tools will be instrumental in identifying distinct neuronal populations and brain networks that are affected by early-life stress.

Above we highlighted a number of pioneering human and preclinical studies on the com- plex subject of early-life adversity and its contribution to psychopathology in adulthood. Additional excellent examples are reviewed in Krugers et al. (2017); Nemeroff (2016); Schmidt (2010); Yam et al. (2015); Sandi and Haller (2015); Teicher et al. (2016). All of these studies underscore the ability of early-life stress to exert drastic effects on neurodevelopment and consequently impact health in adulthood. This occurs through interaction with genetic factors and/or reprogramming of the epigenome, which can induce changes in gene expression, cellular and synaptic function, circuit connectivity, and ultimately behavior.

What is the rationale for shaping adult phenotypes by early-life experiences?

Although it is clear that adversity during early life has a lasting impact on an individual, the underlying rationale behind such a costly programming is often neglected. As the involved mechanisms of early-life programming have evolved over millennia and are conserved across species, it is likely that they serve an adaptive purpose. In this context, Ellis and Del Giudice proposed the adaptive calibration model (ACM) as an evolutionary- developmental theory of individual differences in stress responsivity (Del Giudice, Ellis and Shirtcliff, 2011; Ellis and Del Giudice, 2014). At its core, the ACM states that exposure to stress does not so much impair development per se but directs or regulates it toward strategies that are adaptive under similarly stressful conditions. As a consequence, the ACM suggests that under high-stress conditions animals adapt to a “fast lifestyle,” where, for example, heightened aggression (males) or enhanced vigilance increases individual fitness. Along the same lines, the ecologists Sheriff and Love have argued that the conse- quences of early-life stress exposure should be viewed under the broad concept of a life his- tory perspective, both for the mother and the offspring (Sheriff and Love, 2013). Phenotypic traits following early-life adversity, for example, heightened anxiety, are not determining individual fitness per se but instead alter fitness upon interaction with the environment. A classic example is the predator-prey population cycle of snowshoe hares, where the maternal environment shapes the number and phenotype of the offspring in a highly adaptive fashion. Thus, the multiple examples of adverse early-life stress effects collected in both humans and animals as reviewed earlier may represent just one side of the coin and predominantly occur when early-life and adult-life environments do not match. This concept is especially relevant for psychiatric disorders, arguing that a mismatch of early-life and adult-life stress exposure might be the crucial risk factor for depression, rather than stress exposure per se (Schmidt, 2011). As the consequences of environmental stress exposure are directly related to the

 

Evidence for the match/mismatch theory in animal studies 155

genetic susceptibility of an individual (Belsky et al., 2009; Belsky, 2016), one would expect that only individuals with a high (epi)genetic flexibility (environmental sensitivity) would thrive under matched environmental conditions, whereas for individuals with a lower envi- ronmental sensitivity, stress effects may be rather cumulative over time (Nederhof and Schmidt, 2012). It is important to point out, however, that there is a difference between the evolved, adaptive function of the stress response and apparent pathological consequences for the individual (Flinn et al., 2011). Thus, natural selection that favors evolutionary (reproductive) fitness may not maximize short-term physical and mental health. With these considerations in mind, the question arises of whether there is evidence from human or preclinical studies to support the match/mismatch hypothesis.

Evidence for the match/mismatch theory in humans

Although few studies directly addressed the possibility that exposure to adversity early in life may enhance stress resilience in adulthood, there are still a number of examples where such an effect was indeed observed. Especially, exposure to moderate levels of early-life stress protects children from an overshooting HPA axis in response to the Trier Social Stress Test (TSST), compared with both severe and no early-life stress exposure (Gunnar et al., 2009). A very nice example for the beneficial effects of adversity even in healthy controls is the study from Seery and colleagues, who show that individuals with some lifetime adversity report better mental health and well-being outcomes than people with high or no lifetime adversity (Seery et al., 2010). Accordingly, healthy volunteers with a moderate history of lifetime adversity displayed less negative responses to pain and more positive psychophys- iological responses compared with individuals with no or high history of lifetime adversity (Seery et al., 2013). Along the same lines, a history of moderate childhood adversity was shown to be associated with an enhanced capacity of emotional regulation that was also reflected in an active suppression of the activity in limbic brain circuits (Schweizer et al., 2016). Shapero et al. (2015) demonstrated that adolescents with a history of moderate stressful life events are significantly protected from depressiogenic effects of proximal stressful events (Shapero et al., 2015). In contrast, especially, individuals with mismatched childhood and recent stress levels have been shown to display abnormal resting state functional connectivity in pathways responsible for social and cognitive functioning (Paquola et al., 2017).

Stress exposure can also still have adaptive consequences when it occurs later during development, especially during adolescence. For example, adults who are exposed to work stress as adolescents have been shown to exhibit fewer negative psychiatric health side effects from work-related stress as adults (Mortimer and Staff, 2004). Furthermore, adolescents with a history of early adversity were protected from a stress-induced increase in depression vulnerability as adults, if their attention style was categorized as highly flexible (Nederhof, 2013). Thus, people with a genetic background favoring fast and flexible adaptation benefit from matching environments early and late in life, even if both are stressful. Taken together, these examples demonstrate that early exposure to especially moderate levels of adversity may indeed facilitate the development of stress resilience, especially in individuals that are highly susceptible to environmental influences.

 

156 11. Stress resilience as a consequence of early-life adversity
Evidence for the match/mismatch theory in animal studies

Although most studies in humans suffer from retrospective assessment of early-life adver- sity and high variability of environmental conditions, animal studies can be designed much more stringently and allow the exact control of environmental conditions. Unfortunately, most studies addressing a possible interaction of early-life and adult-life environments have not utilized a continuous exposure to moderate adversity but rather single exposures of mostly severe stressors over a short developmental period, with the majority of the devel- opmental time consisting of standard housing without adversity. The consequent results are then often interpreted in the light of cumulative stress exposure or the two-hit hypothesis (Pena et al., 2017). An alternative explanation would be that these study designs enhance the mismatch situation of environmental conditions, as programming during the nonstress periods, which also takes place during potentially essential developmental phases, suggested a safe and stress-free environment. Nonetheless, there are still numerous examples in the preclinical literature that support the mismatch hypothesis and argue for an adaptive role of early adversity by enhancing stress resilience.

Already the early and seminal work of Levine and colleagues suggested that moderate levels of stress exposure early in life may have beneficial effects when animals were exposed to threats in adulthood (Levine, 1959, 1962). Later on, Dienstbier (1989) proposed the concept of psychophysiological toughness, where defined and controllable adversity early in life fosters subsequent stress resilience. Even environmental enrichment during early life and adolescence can be viewed as form of chronic mild stress, resulting in stress inoculation and consequently resilience to stress exposure in adulthood (Crofton et al., 2015). Also more recently, these concepts could be confirmed and extended. For example, female Balb/C mice have been shown to be less affected by social isolation in adulthood when exposed to erratic maternal care because of limited nesting and bedding material following birth (Santarelli et al., 2014). Interestingly, these results were dependent on the estrous cycle phase the animals were tested in. Furthermore, early-life stress in the form of limited nesting and bedding material dampened the behavioral and endocrine response to chronic social stress in adolescence (Hsiao et al., 2016). Similarly, male mice exposed to the same early- life stress paradigm displayed a heightened resilience to chronic social defeat stress in adult- hood (Santarelli et al., 2017). Brockhurst et al. (2015) reported that experience of early chronic social stress reduced HPA axis activity and improved stress-coping and anxiety-like behavior following subsequent repeated restraint. Along these lines, prenatally stressed offspring are more likely to become subordinate in a social group as adulthood but are more resilient to that social status compared with offspring from nonstressed mothers (Scott et al., 2017). Beneficial effects seem also evident in combination with treatment, as, for example, lympho- cytes from chronically stressed mice confer antidepressant-like effects to stress-naïve mice (Brachman et al., 2015), arguing that especially the immune system benefits from some form of stress inoculation early in life. There even seem to be transgenerational effects of early-life stress to promote a proresilient phenotype (Gapp et al., 2014).

Stress exposure early in life also seems to be beneficial for cognitive performance, especially under challenging conditions. In rats, chronic unpredictable stress during adoles- cence was shown to improve foraging-related problem solving under high-threat conditions

 

Conclusions 157

(Chaby et al., 2015). Along these lines, repeated social stress improves performance in an attentional set-shifting task (Chaijale et al., 2015). Furthermore, exposure to moderate peripu- bertal stress, where the effects of chronic mild stress were buffered by social partners in the home cage, was shown to result in an improved cognitive phenotype in aged female mice (Morrison et al., 2016).

The molecular underpinnings that are responsible for the beneficial effects of moderate stress exposure for later stress resilience are far from understanding, and only a few studies have addressed this question. For example, Biggio et al. (2014) showed that maternal deprivation dampens corticosterone response to adult social isolation in rats, which was paralleled by not only hippocampal brain-derived neurotrophic factor (BDNF) expression. BDNF but also the depression risk factor SLC6A15 (Hyde et al., 2016; Kohli et al., 2011), which were also implicated as potential mechanism in the study by Santarelli et al. (2014) in female mice. Moreover, in another study, prenatal stress induced anxiety and HPA axis hyper-reactivity, which could be normalized by exposure to adolescent chronic mild stress, together with a normalization of hippocampal tryptophan hydroxylase 2 expression (Van den Hove et al., 2013). However, all of these findings are just correlational observations, and so far there is a clear lack of mechanistic studies that would shed some light on the causal relationships that lead to enhanced stress resilience following adversity during development.

Conclusions

Taken together, there seems to be compelling evidence from human and animal studies that supports the match/mismatch hypothesis, while at the same time there are of course numerous reports that rather argue for a cumulative stress effect. Part of this apparent discrepancy can be explained by the different study designs, and as so often the devil is in the details. Most importantly, especially for animal studies, one has to consider the severity of the stressors and their chronicity. To trigger an adaptive long-term response, stressors likely need to be in the mild to moderate range and be present over developmen- tally meaningful time frames. If stress exposures are short (but severe) and interlaced with long periods of stress-free environments, successful adaptation is less likely. Finally, the genetic heritage of an individual will be decisive in their adaptive capacity to stress, so that some individuals will be more prone to suffer under chronic stress conditions, whereas others adapt and thrive (Fig. 11.1). It will be challenging to unravel the molecular and cellular mechanisms that determine this complex gene early environment adult environment interaction. One caveat in most of the current stress-related research is the limitation to only a few species and selected genetic backgrounds, which by itself limits the diversity and possible outcomes of stress exposure. However, these challenges can be overcome, and in the end a better understanding of the risks as well as the benefits of stress exposure will also advance our understanding of stress-related disorders and improve options of successful intervention.

 

158 11. Stress resilience as a consequence of early-life adversity

FIGURE 11.1 Schematic representation of two extremes in the reaction to early-life adversity. The black line represents a condition where the individual has a genetic background that is insensitive to environmental experiences and therefore prone to adverse cumulative effects of stress exposure. Consequently, such an individual would thrive under mild stress conditions and become more and more vulnerable to stress with higher levels of developmental stress exposure. The blue line represents the other extreme, namely an individual that has a high sensitivity to the environment. Such an individual would benefit from moderate stress levels during development and become stress resilient. In contrast, with no meaningful stress exposure during development, such an individual will have no chance to adapt its physiology to an adverse environment and will therefore be highly vulnerable to stress in adulthood. Severe early-life stress exposure is expected to be harmful under most circumstances, largely independent of the genetic background of an individual.

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CHAPTER

12

Mechanisms by which early-life

experiences promote enduring stress

resilience or vulnerability

Annabel K. Short1, 2, Jessica L. Bolton1, 2,

Tallie Z. Baram1, 2
1Department of Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, United States; 2Department of Pediatrics, University of California-Irvine, Irvine, CA, United States

Introduction

A predisposition to emotional and cognitive disorders originates early in life (Kessler et al., 2005; Insel, 2009). The concepts of gene-environment interaction, and the importance of early- life experience for resilience or vulnerability to mental illness, have been demonstrated in both preclinical rodent studies and clinical studies in human populations (Insel, 2009; Bale et al., 2010; Gunnar, 2010; Fox et al., 2010; Juul et al., 2011; Bale, 2015). Resilience is defined as an active and adaptive biological, psychological, and social response to an event that may otherwise impair one’s normal function (Dudley et al. 2011; Russo et al., 2012). Vulnerability is the susceptibility of an individual to a disorder and is often related (in addition to genetics) to early experiences. Resilience or vulnerability to a stressor tends to be regulated by molec- ular, cellular, synaptic, and finally, behavioral changes that determine the level of coping and normal function. Early-life experiences that contribute to resilience or vulnerability may consist of stimuli from the general environment (poverty, wealth, war). Notably, in view of the crucial importance of interaction/attachment with the primary caretaker for survival (Bowlby, 1950), there is compelling evidence to suggest that sensory signals from the primary caretaker during the neonatal period are vital in determining an individual’s vulnerability or resilience to cognitive and emotional disorders later in life (Meaney and Szyf, 2005; Fenoglio et al., 2006; Lupien et al., 2009; Korosi, 2009; Fox et al., 2010; van Hasselt et al., 2012; Wang et al., 2014). Thus, early-life adversity/stress, as well as beneficial early-life experiences, may be “filtered” by the mother and conveyed to the infant via altered maternal signals.

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00012-4 165 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

166 12. Mechanisms by which early-life experiences promote enduring stress resilience or vulnerability

There is now a large body of evidence in humans associating early-life adversity with emotional and cognitive disorders later in life. These publications range from epidemiological studies of famine or war (Brown et al., 1995; Eriksson et al., 2014) to prospective, cross-sectional, and case-control analyses (e.g., Bremner et al., 1993; Kaplan et al., 2001). To elucidate both direct causal and mechanistic relationships between early-life experiences and outcomes later in life, rodent models have been utilized. A variety of prenatal and post- natal manipulations have been employed in these studies (Molet et al., 2014; Walker et al., 2017). Studies inducing early-life stress are associated with negative emotional consequences, including behaviors that typically signify depression, anxiety, and social isolation. The consequences of early-life (prenatal as well as postnatal) stress on emotional and social be- haviors have been a subject of several recent reviews (Lucassen et al., 2013; van Bodegom et al., 2017; Walker et al., 2017). Although not as widely studied, manipulations that result in a more positive early-life environment are associated with increased learning and memory, and decreased anxiety-like phenotypes (Weaver et al., 2004; Fenoglio et al., 2006; Champagne, 2008; Korosi, 2009; Korosi et al., 2010).

The type and severity of early-life perturbations determine their consequences. In humans, this effect is highlighted in studies of institutionally raised children. These studies show chronic impoverished care was associated with cognitive and emotional problems. However, the associated consequences were somewhat reversed by fostering into more positive environments, thus highlighting the importance of early interaction with a primary caregiver (Fenoglio et al. 2005, 2006; Gunnar, 2010; Chen et al., 2012; Wang et al., 2014). Abnormal patterns of maternal care, ranging from unpredictable neglect to inconsistency and lack of sensitivity, can be a major cause of early-life stress (Fenoglio et al., 2005; Bota and Swanson, 2007). This is in contrast to repeated, predictable barrages of maternal care. To study early-life experiences, animal models have aimed to recapitulate these conditions by manipulating maternal interactions with the developing individual.

The degree of predictability of maternal care influences long-lasting cognitive and emotional resilience or vulnerability

Experimental model studies, in conjunction with human studies, have found that maternal input is the most significant environmental experience during development (Bowlby, 1950; Baram et al., 2012; Kundakovic and Champagne, 2015). Thus, most animal models of early-life stress have manipulated maternal interaction, disrupting either the quantity or quality of maternal care early in life (see Molet et al., 2014; Walker et al., 2017; van Bodegom et al., 2017 for recent reviews).

Studying early-life experiences experimentally

Disrupted maternal care

Some of the earliest and most informative translational work on early-life stress associated with disrupted maternal care has been performed in nonhuman primates. These models have the advantage of modeling the development of complex psychiatric disorders. Initial nonhuman primate studies were the first to demonstrate the association of intact

 

The degree of predictability of maternal care influences long-lasting cognitive and emotional resilience or vulnerability 167

maternal-infant interactions with appropriate development of cognitive and emotional phenotypes (Mason and Harlow, 1958). In addition to these studies of disrupted maternal care, a model of physical separation in nonhuman primates has been used. With this approach, Sanchez and colleagues associated adverse early-life experience with altered devel- opment of the stress response. This abnormal development resulted in emotional reactivity and manifested as poor maternal care when these infants reached adulthood and became mothers themselves (Maestripieri et al., 2006; Drury et al., 2017).

Due to the difficulties associated with nonhuman primate work, most studies of disrupted maternal care are performed in rodents. Although it is difficult to measure sophisticated cognitive and emotional disorders in rodents, appropriate testing and analyses yield tractable results when studying the developmental and behavioral outcomes of early-life stress. Given the similarities in the role of maternal care across species, and the significant parallelism of brain development especially the development of synaptic connectivity and brain circuits, ro- dents are a suitable model for studying the effects of maternal careerelated stress on neuro- psychiatric outcome.

Comparable with the maternal role in humans, the rodent dam is the primary source for nutrition and pup well-being. This includes providing protection and safety in the nest, which involves the communication of vital environmental signals from the dam to the pups (Levine, 1957; Eghbal-Ahmadi et al., 1999; Lucassen et al., 2013). Although removing the mother from the pup will effectively disrupt these signals, doing so for extended periods of time will lead to obvious physical stressors such as hypothermia and starvation. To over- come this, studies of disrupted maternal care may employ intermittent maternal separation, for variable lengths of time. This decreases the quantity of time available for maternal care in addition to causing a repeated stress (Millstein and Holmes, 2007). These approaches have been widely employed in the field and have provided an understanding of how directly decreasing maternal care influences early development and outcomes later in life. Yet, these approaches have yielded variable results (Shalev and Kafkafi, 2002; Aisa et al., 2007; Hill et al., 2014). Furthermore, adverse conditions that are commonly experienced by human infants and children include situations such as severe poverty, famine, war, maternal drug abuse, where the child is with the mother and receiving maternal signals. Because of the over- whelming importance of maternal signals, including their nature and patterns, there is a rationale to study early-life adversity in the presence of the mother. To recapitulate poverty in the presence of the mother, a now prevalent approach uses manipulations of the home cage while both the dam and pups are present. During postnatal days (P)2e9, nesting and bedding materials are limited (LBN) (Gilles et al., 1996; Molet et al., 2014; Naninck et al., 2015), and this manipulation reliably and reproducibly causes fragmented and unpredictable maternal behaviors toward the pups (Molet et al., 2016a). This is likely because the imp- overished environment induces stress in the dams (Ivy et al., 2008). Notably, the duration or quality of the nurturing behaviors of the dams is minimally altered: it is the patterns of maternal care that are disrupted (Ivy et al., 2008; Rice et al., 2008; Molet et al., 2016a; Walker et al., 2017). This fragmented maternal care causes chronic, unpredictable, and uncontrollable “emotional stress” in the pups (Gilles et al., 1996; Ivy et al., 2008; Rice et al., 2008; Moriceau et al., 2009; Wang et al., 2011; Molet et al., 2014; Naninck et al., 2015). The pups’ stress is apparent in persistent elevation of plasma corticosterone and adrenal hypertrophy, which is associated with emotional and cognitive vulnerabilities in adulthood (Brunson et al., 2005;

 

168 12. Mechanisms by which early-life experiences promote enduring stress resilience or vulnerability

Rice et al., 2008; Molet et al., 2016b). These cognitive and emotional outcomes produced by the LBN approach have been reliably reproduced by numerous laboratories and multiple outcome measures (Moriceau et al., 2009; Roth et al., 2009; Dalle Molle et al., 2012; Raineki et al., 2012; Gunn et al., 2013; Malter Cohen et al., 2013; Naninck et al., 2015; Walker et al., 2017).

Augmented/predictable maternal care

Important biological phenomena run along a spectrum. If unpredictable maternal care pro- vokes enduring vulnerability, then highly predictable patterns of maternal-derived sensory signals to the developing brain should promote cognitive and emotional resilience long-term.

Nurturing maternal care is typically quantified by licking and grooming behaviors. The handling paradigm (Levine, 1957; Plotsky and Meaney, 1993; Korosi, 2009) has been extensively used to modulate maternal licking and grooming quantity, as well as patterns. This involves a brief (15 min) daily separation of rat pups from the mother during the first weeks of life. The timing of these bouts of separation is crucial, and brief separations will promote increased, predictable sensory input to the pups upon reunion with their mothers (Liu et al., 1997; Fenoglio et al., 2006; Korosi et al., 2010). The recurrent predictable maternal signals lead to increased resilience to depressive-like behavior (Meaney and Szyf, 2005; Singh- Taylor et al., 2017) and improved learning and memory (Fenoglio et al., 2005). Notably, it is not simply the increase in maternal care that drives resilience. A single day of handling or irregular handling is insufficient to promote the molecular and behavioral outcomes (Fenoglio et al., 2006). Recurrent, predictable, repetitive brief separations (typically in the same circadian phase) seem to be required (Fenoglio et al., 2006; Karsten and Baram, 2013).

Cognitive and emotional outcomes of early-life experiences

The effects of early-life experiences on resilience or vulnerability in adulthood can be examined in rodents using standardized cognitive and emotional tests that are also translational to humans. Tests of emotional behavior such as the forced-swim test are used to identify depressive-like phenotypes in rodents, as when used in conjunction with routinely prescribed antidepressants, there is a reduction in depressive-like behaviors (Slattery and Cryan, 2012).

Measures of anxiety have relied on tests such as the open field and elevated-plus maze. Cognitive tests have typically involved memory and especially hippocampus-dependent spatial memory. Available standardized tests for this function include both the well- characterized Morris water maze and the object location memory test. The former involves stress/adversity in itself (forced swimming, cold water), whereas the object location relies on natural curiosity and is devoid of stress, as well as the potential confounding effect of early-life experience on stress-related behavior later in life. Thus, spatial memory tests are best when these considerations are included. An additional important caveat is that the large majority of studies have employed males, and many of the tests have been developed and standardized for males. Here, we note if reported studies and outcome pertain to females.

A spectrum of cognitive consequences of early-life experiences

Memory impairments have been the common outcome in rodents exposed to chronic early-life adversity. For example, in a rigorous and hippocampus-dependent test of object

 

The degree of predictability of maternal care influences long-lasting cognitive and emotional resilience or vulnerability 169

location memory, an overt impairment in spatial memory was found as early as adolescence in rats reared for a week in the simulated poverty environment (LBN rats) (Molet et al., 2016b). A less rigorous memory task involving object recognition (OR) found comparable performance in LBN versus control adolescent rats during adolescence. However, an acute-stress “challenge” imposed 24 h prior to the test led to memory problems only in the LBN rats, thus unmasking a latent cognitive vulnerability (Molet et al., 2016b). The memory deficits after chronic early-life stress also progressed over the life span of LBN rats, so that deficits in OR memory emerged by middle age (Molet et al., 2016b). At this age, hippocampus-dependent memory deficits were also present using the Morris water maze task (Brunson et al., 2005; Ivy et al., 2010). These data, obtained in males, are intriguing, because the emergence of memory problems during middle age has been found in men experiencing early-life adversity in well-controlled epidemiological studies (Kaplan et al., 2001).

Conversely, rats receiving predictable augmented maternal care had improved hippocampus- dependent cognitive function (Tang, 2001; Fenoglio et al., 2005; Lesuis et al., 2016). Together, these studies indicate that either naturally occurring or experimentally recurrent, predictable or enhanced sensory stimulation that pups receive from the dam improves hippocampus- dependent learning and memory later in life (Korosi and Baram, 2008).

Emotional consequences of early-life experience

A variety of emotional problems, based on rodent tasks considered indicative of depres- sion or anxiety, have been reported after early-life stress (McEwen, 2003; Molet et al., 2014; Chen and Baram, 2016). Increased anxiety-like behaviors in the elevated-plus maze test were found later in adulthood (Dalle Molle et al., 2012, but see Molet et al., 2016a), Conversely, predictable barrages of maternal care early in life was related to decreased anxiety-like phenotypes in adult rats (Singh-Taylor et al., 2017).

Anhedonia, a reduced capacity to experience pleasure, which commonly heralds depres- sion or schizophrenia in humans (Whitton et al., 2015), has been identified in rodents following perturbations of early-life experiences. Already during adolescence, anhedonia, apparent both as a significant reduction in sucrose preference and a reduction of peer play, was found in late-adolescent LBN rats (Molet et al., 2016a; Bolton et al., 2018). This anhedonia was not accompanied by overt anxiety-like behavior or depressive-like behavior. Adolescent anhedonia after early-life stress has since been confirmed in a separate LBN cohort in a different laboratory, as indicated by decreased consumption of palatable food (M&Ms) (Bolton et al., 2019). Furthermore, LBN rats self-administered lower levels of cocaine, consistent with a reduced hedonic set point (Bolton et al., 2019). These changes were shown to be selective to anhedonia, as early-life adversity did not affect other measures of addiction, such as sensitivity to self-administered cocaine dose; responding for cocaine under extinction conditions; or cocaine- or cue-induced reinstatement of cocaine seeking. Early-life adversity did not induce anxiety-like behavior or augmented locomotor response to acute cocaine. Together, these findings demonstrate enduring effects of early-life adversity on reward/ pleasure-circuit function.

In contrast, rats that have been handled in the first week of a life, thus receiving recurrent barrages of maternal care signals, when given a similar task, had an increase in the consump- tion of palatable food, in the absence of an anxiety-like phenotype (Silveira et al., 2005).

 

170 12. Mechanisms by which early-life experiences promote enduring stress resilience or vulnerability

Although the majority of emotional consequences of chronic early-life adversity have been negative, there is some evidence for positive outcomes following stressful experiences that are challenging but not overwhelming, so-called “stress inoculation” (Lyons, 2009). For example, Lyons and colleagues have demonstrated that exposure of newly weaned squirrel monkeys to brief intermittent maternal separations decreased subsequent anxiety and stress responsiv- ity. This resilience to later stress did not seem to be maternally mediated or related to changes in maternal care, unlike the rodent models discussed above (Parker et al., 2006).

It is possible that some discrepancies reported on the emotional consequences of early-life stress may be due to inadvertent generation of recurrent, predictable bouts of maternal care, which may counteract or reverse the stress effects. For example, a recent powerful paper by Peña et al. (2017) did not find major emotional outcomes after early-life stress in the simulated poverty paradigm. Yet, in aiming to improve the approach, Peña et al. added daily maternal separations, which, upon the subsequent return of the dams to the cages, may have provided predictable, recurrent daily episodes of maternal tactile signals (licking) to the pups (Korosi et al., 2010; Singh-Taylor et al., 2015, 2017). Thus, the potential negative consequences of unpredictable and fragmented sensory signals from the mother in the LBN cages on the devel- opment of brain circuits were most likely mitigated by the predictable daily barrages of maternal care when the dams were returned to the cages. These variations highlight the complexities inherent in all of our experimental approaches to the human condition.

Importantly, the consequences of early-life experiences are clearly further modulated later in life. In humans, fostering at 2 years or earlier clearly ameliorated the effects of institution- alization (Nelson et al., 2007). In rodents, enrichment (Bredy et al., 2003) or pharmacological manipulations (Ivy et al., 2010) at least partially reversed cognitive deficits promoted by early-life adversity. Understanding the basis of these consequences of early-life stress should enable targeted and logical interventions to improve lifelong outcomes.

Mechanisms by which early-life experiences elicit enduring changes in neuronal, circuit, and behavioral functions

How altered early-life experience promotes resilience or vulnerability to emotional and cognitive disorders in adulthood is yet to be fully elucidated. An attractive hypothesis is that, in analogy to the development of the visual and auditory brain circuits, early sensory signals from the mother alter synaptic development and pruning, thus influencing the matu- ration of brain networks involved in emotional and cognitive processing (Bogdan and Hariri, 2012; Burghy et al., 2012; Maras and Baram, 2012; Karsten and Baram, 2013; Singh-Taylor et al., 2015; Chen and Baram, 2016; Davis et al., 2017). Changes in synaptic connectivity, in turn, have recently been shown to influence epigenetic programs in stress-sensitive neurons (Singh-Taylor et al., 2017).

Stress-sensitive neurons in the hypothalamus are influenced by early-life stress as well as by augmented early-life experience

Early-life stress and fragmented maternal care have significant effects on the developing and adult stress response system. Abnormal maternal care in the simulated poverty environ- ment provokes an increased number and function of excitatory synapses to stress-sensitive neurons in the hypothalamus (Gunn et al., 2013). In contrast, recurrent predictable maternal

 

Mechanisms by which early-life experiences elicit enduring changes in neuronal, circuit, and behavioral functions 171

signals reduce the number of excitatory synapses to corticotropin-releasing factor (CRF)e expressing cells in the paraventricular nucleus (PVN) of the hypothalamus (Korosi et al., 2010). Recent exciting data indicate that the change in synapse number and function is suffi- cient to turn on massive epigenetic/transcriptomic programs in the PVN CRF cells (Singh- Taylor et al., 2017). These changes include lifelong reduction in CRF expression in the PVN.

Reduced expression of CRF in the PVN is classically associated with reduced CRF release in response to stress throughout life. Thus, there is now a direct mechanistic connection be- tween early-life experiences, development of circuitry of a key element of the stress system, and enduring epigenetic change in the level of expression and function of a stress hormone.

Notably, reduced or increased CRF expression and release influences the levels of circu- lating glucocorticoids, thus providing multiple pathways by which early-life stress or optimal experience will influence the brain long-term (Liu et al., 1997; Eghbal-Ahmadi et al., 1999; Korosi et al., 2010). Rodents, reared in LBN cages have elevated basal levels of serum corticosterone (Brunson et al., 2005; Rice et al., 2008). These changes are present immediately following the stress and may or may not persist into adulthood. Although there is also adrenal hypertrophy described in pups following LBN, these changes do not persist into adulthood (Gilles et al., 1996; Avishai-Eliner et al., 2001; Brunson et al., 2005; Ivy et al., 2008). Conversely, predictable maternal care is associated with decreased release of serum corticosterone in response to stress (Liu et al., 1997; Eghbal-Ahmadi et al., 1999; Meaney and Szyf, 2005; Singh-Taylor et al., 2017).

Memory consequences of early-life stress and experiencesda hippocampal story

There is clear vulnerability or resilience accorded by early-life experience to hippocampus- dependent tasks. In rodents, early-life stress causes reduction in dorsal hippocampal volume associated with a reduction in dendritic arborization (Brunson et al., 2005; Ivy et al., 2010; Molet et al., 2016b). This is comparable with observations in humans. For example, children raised in orphanages have reduced hippocampal volume (Hodel et al., 2015). Rodent data allow speculation that reduced hippocampal volume in humans is also a result of a decrease in synaptic growth and branching of neuronal dendrites, contributing to the observed func- tional deficits (Brunson et al., 2005; Radley et al., 2008; Ivy et al., 2010; Maras and Baram, 2012; Chen and Baram, 2016). In addition to structural changes in the hippocampus of rodents following early-life stress, significant reduction in LTP has been observed, which progresses as the animal ages (Brunson et al., 2005). These structural and functional changes in the hippocampus following early-life stress are also associated with lasting molecular changes (Gilles et al., 1996; Avishai-Eliner et al., 2001; Bath et al., 2016). Both elevated plasma corticosteroids and enhanced CRF gene (Crh) expression in hippocampus (Ivy et al., 2010; Maras and Baram, 2012) might play a role in these hippocampal changes. Glucocorticoids powerfully modulate dendritic and synapse growth in hippocampus (Magarinõs and McE- wen, 1995; Alfarez et al., 2009; Jafari et al., 2012; Liston et al., 2013), and chronic increases in CRF, via binding to local CRF receptors (Chen et al., 2013) impair dendritic branching and pruning early in life (Chen et al., 2004; Joëls and Baram, 2009).

In contrast to the adverse consequences of early-life stress, augmented maternal care may have beneficial influences on the hippocampus, and these also seem to progress with age. Aged rats that have undergone handling at an early age show less hippocampal cell loss when compared with control animals and maintain better cognitive function (Fenoglio et al., 2005).

 

172 12. Mechanisms by which early-life experiences promote enduring stress resilience or vulnerability Early-life experiences affect a number of brain systems

Early-life experiences provoke enduring changes in the expression of multiple molecules throughout the brain. This is likely mediated via large-scale transcriptional/epigenetic programs (Singh-Taylor et al., 2017; Peña et al., 2017; Gray et al., 2017).

Evidence for altered gene expression and function are found in anxiety-fear circuits, including the central nucleus of the amygdala (ACe), and bed nucleus of stria terminalis (BnST). In these regions, changes in Crh gene expression are an eloquent example of broad transcriptional change. In addition, the changes in Crh expression probably directly contribute to altered functional outcomes in behaviors subserved by the underlying circuits. For example, increased Crh expression has been found in amygdala (Dubé et al., 2015) already during adolescence after early-life stress; in contrast, high levels of predictable maternal care promote reduced Crh expression in the ACe (Fenoglio et al., 2004). Notably, the same experience promotes reduction of glucocorticoid receptor (GR) in ACe. As GR occupancy increases CRF expression in the amygdala (Makino et al., 1994), these findings support a coordinate effect of early-life experience on two mediators of the stress system. A second, intercalated circuit influenced by early-life experience encompasses the mesolimbic reward/pleasure circuit. As mentioned above, dysregulation of these systems has been observed following early-life stress. Mechanistically, social play, a pleasurable task, provoked Fos activation of CRF neurons within the ACe, in contrast to controls (Bolton et al., 2018). These findings suggest aberrant connectivity of pleasure/reward and fear/anxiety circuits. Importantly, knockdown of CRF expression in the ACe was sufficient to completely reverse the observed anhedonia in individual LBN rats, suggesting mechanistic roles for CRF-expressing neurons in the amygdala in the abnormal emotional function induced by early-life stress.

Aberrant patterns in Fos activation are apparent in LBN rats also following cocaine. The abnormal activation was found in other reward-related regions, such as the core of the nucleus accumbens (NAc) and the lateral habenula (LHb) (Bolton et al., 2019). This evidence for network disruptions following adverse early-life experiences is supported by high- resolution MRI studies. Tractography revealed increased tracts/streamlines connecting the amygdala to the medial prefrontal cortex in LBN rats (Bolton et al., 2018). Together, these results suggest that projections in both pleasure/reward- and anxiety/aversion-related circuits are enduringly altered because of early-life stress, which may have functional implications.

Although there is currently limited evidence for a role of augmented maternal care in pleasure and reward-seeking behavioral changes, there are reported changes in related brain regions. Fos mapping studies have suggested that the pathway of neuronal activation by repeated barrages of maternal care travels to the hypothalamic PVN via the ACe and BnST (Fenoglio et al., 2006). These high levels of neuronal activation result in robust and enduring suppression of Crh gene expression in these neurons (Fenoglio et al., 2006; Karsten and Baram, 2013), which further supports a role for the CRF neurons in the amygdala in resilience or vulnerabilities to emotional disorders in adulthood.

How the consequences of early-life experience are encoded long-term: transcriptional and epigenetic mechanisms

The critical importance of events taking place during sensitive developmental periods is their influence on developmental trajectories and hence their enduring effects (Russo et al., 2012;

 

Mechanisms by which early-life experiences elicit enduring changes in neuronal, circuit, and behavioral functions 173

Regev and Baram, 2014; Peña et al., 2017). In the context of early-life stress, this is clearly apparent from the ability of interventions, including pharmacological, to alter the course of these consequences if undertaken directly after the stress epoch (Bredy et al., 2003; Ivy et al., 2010). However, interventions several months later were ineffective in reversing the effects of early- life stress on hippocampal functions (Ivy et al., unpublished observations). There is also evidence for the crucial importance of the sensitive period in humans. Early-life stress is associated with an increased risk of dementia and cognitive problems in middle age (Kaplan et al., 2001; Nelson et al., 2007). Interventions were found only to be effective prior to the first 3 years of life, suggest- ing that mechanisms behind these behavioral changes decrease in plasticity over time (Nelson et al., 2007; Regev and Baram, 2014).

There is increasing evidence that the larger changes in brain circuit behavior induced by early-life stress may occur through molecular changes via epigenetic mechanisms. Commonly described epigenetic mechanisms include DNA methylation, histone modifica- tions, and chromatin remodeling. Alterations to gene expression can occur via noncoding RNAs, which is often also regarded as an epigenetic mechanism.

Multiple studies in rodents have shown that aberrant maternal care, whether biological or fostered, will produce permanent changes in behavior and gene expression patterns (Roth et al., 2009). These changes in gene expression patterns have been associated with multiple epigenetic modifications both on a genome-wide level and to specific target genes (for a full review, see Kundakovic and Champagne, 2015). Although the majority of work has focused on the effects of early-life experiences on the hippocampus, there is also evidence for altered epigenetic states in the prefrontal cortex (Roth et al., 2009) and hypothalamus (Murgatroyd et al., 2009; Peña et al., 2013).

Weaver et al. (2004) were the first to link differences in maternal care to levels of GR promoter methylation. Analogous changes in methylation after early-life stress have been sought in humans (McGowan et al., 2009; Naumova et al., 2012; Suderman et al., 2014). Yet, it is unclear if DNA methylation, argued by Weaver to be a mechanism for lasting changes, is a cause or consequence of gene expression changes. Changes in gene expression in neuronal populations that drive the function of these neurons can be triggered and main- tained via numerous mechanisms. Initiation of transcriptional changes is often secondary to transcription factors (Peña et al., 2017; Singh-Taylor et al., 2017), which might be activated in response to early-life sensory signals and/or changes in calcium entry to the cell resulting from changes in synaptic numbers (Chen et al., 2017). The mechanisms for stable changes in the chromatin that endure for life (and even transgenerationally, Chan et al., 2018) are complex. In addition to these epigenetic changes, there is also some evidence for a role for altered miRNA expression in encoding stress resilience or vulnerabilities from the early-life environment (Bai et al., 2012; Zhang et al., 2013), which may also be heritable across generations (Rodgers et al., 2013; Gapp et al., 2014; de Castro Barbosa et al., 2016; Short et al., 2016; Short et al., 2017). Histone modifications are also likely to play a role, and multiple histone modifications have been associated with differences in early-life experience (Weaver et al., 2004; Peña et al., 2017).

These types of chromatin modifications follow both early-life adversity (see above) and beneficial early-life experiences. Repressive histone modifications were recently observed after augmented early-life experience (Singh-Taylor et al., 2017). In this instance, large-scale epigenetic changes were initiated by increases in the function of a transcriptional repressor, NRSF. Later in life, NRSF binding to target genes was no longer observed. Rather, there

 

174 12. Mechanisms by which early-life experiences promote enduring stress resilience or vulnerability

FIGURE 12.1 A unifying theoretical framework for how early-life experiences can induce long-term changes in behavior. The inciting event is the experience of early-life adversity (green) or repeated, predictable barrages of maternal care (pink), represented in the overlapping circles. Changes in early-life experiences cause a cascade of changes acutely during the perinatal period that results in altered neuronal development and changes in gene expression, which are maintained long-term via epigenetic modifications of the chromatin (represented in the dark grey inner concentric circle). These molecular- and cellular-level changes build upon each other to create altered synaptic connectivity and circuit development at the level of the network, ultimately resulting in the observed al- terations in cognition, emotion, and pleasure/reward (represented by the three nodes within the light grey outer concentric circle). Adapted from Bolton, J.L., Molet, J., Ivy, A., Baram, T.Z., 2017. New insights into early-life stress and behavioral outcomes. Current Opinion in Behavioral Sciences 14, 133e139 with permission.

were increases in histone modifications associated with repression of these target genes, including Crh (Singh-Taylor et al., 2017). These results suggest a transition of epigenetic states across the life span in response to changes in the early-life experiences.

Conclusions

Early-life experiences modulate risk and resilience to stress-related emotional and cogni- tive disorders in adulthood. The mechanisms by which experiences during the sensitive developmental period early in life translate into enduring molecular, cellular circuit, and behavioral phenotypes are emerging (Fig. 12.1). This chapter reviews available knowledge. It proposes a unified mechanistic scenario, where patterns of sensory input from the mother influence the number and function of synapses onto stress-sensitive neurons (in analogy to similar processes in visual and auditory systems). Synapse changes regulate transcriptional and epigenetic programming in distinct neuronal populations, which modulate how these

 

References 175

neurons wire together into circuits and the levels of expression of numerous genes. Together, the altered circuitry and altered neuronal behavior in response to future stimuli promote a phenotype of resilience or vulnerability to stressful signals throughout lifedand perhaps across generations.

This framework requires much additional work to affirm or refute. However, it provides a common mechanistic understanding for the enduring consequences of both adverse and beneficial early-life experiences, leading to resilience and vulnerability, respectively, to stress-related emotional and cognitive disorders.

Acknowledgments

This work was supported by the National Institutes of Health (grant numbers R01MH073136, R01NS028912, P50MH096889) and the George E. Hewitt Foundation for Medical Research.

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CHAPTER

13

Child abuse and neglect: stress responsivity and resilience

Shariful A. Syed1, Matthew Cranshaw2,

Charles B. Nemeroff1
1Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, Miami, FL, United States; 2University of Miami, Miller School of Medicine, Miami, FL, United States

Child abuse and neglect is one of the most prevalent forms of trauma experienced in the modern world (Anda et al., 2006). In the United States alone there were approximately 4 million reports of child maltreatment in 2015 (increased from 3.4 million in 2012), including 1,585 fatalities, with only 1 in 10 victims receiving any form of postabuse care/service. Furthermore, since 2008, the overall incidence of childhood maltreatment appears to be steadily increasing. Of the child fatalities, 72.9% were neglected children, 43.9% physically abused, and 1.2% sexually abused (Health USDo and Human S, 2015). National reports (Fig. 13.1) have consistently shown that early-life trauma predisposes individuals to develop a number of psychiatric syndromes, particular mood and anxiety disorders, and as such, is a significant public health problem (Molnar et al., 2001). The mechanisms by which various forms of child abuse increase the risk of developing psychiatric disorders are believed to stem from their profound short- and long-term effects on the central nervous system (CNS) and a multitude of peripheral organ systems (Heim et al., 2000a). The neurobiological mechanisms that mediate the consequences of early developmental stress have been studied in humans and laboratory animals. The increased rates of several psychiatric disorders after exposure to early-life stress (ELS) suggest a persistent sensitivity to the effects of stress in later life (Heim and Binder, 2012). More specifically, child abuse and neglect have been posited to permanently sensitize and dysregulate various components of the stress response, both centrally and peripherally. Although the goal of this book is to generate a neurobiological paradigm of stress resilience, in this chapter we focus on one of the most pivotal aspects of this paradigm, namely stress responsivity and how we may discern resilience mechanisms from the stress neurobiology of childhood abuse and neglect.

To begin, we present the functional definition of “stress responsivity” to be “variability in reaction to stressful stimuli.” We have chosen such a definition, as it appears to be congruent

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00013-6 181 Copyright © 2020 Elsevier Inc. All rights reserved.

 

 

182 13. Child abuse and neglect: stress responsivity and resilience

FIGURE 13.1 Number of cases of child abuse in the United States in 2015, according to the type of abuse. Adapted from the U.S. Department of Health and Human Services.

with the theory of evolution as well as the physiology subserving the human stress response. A challenge, which we will elaborate on later in the chapter, although necessary to address from the start, is the difficulty of developing a generalizable definition for “resilience.” To date, the field of stress neurobiology has largely presumed it to mean the absence of psychopathology after extreme stress. This is, in part, a product of the simple fact that we are still in the early stages of “stress resilience” neurobiological research. As the scientific community continues to further elucidate mechanisms via advancement in methodological approaches as well as innovative methods of investigation, we are optimistic that a more refined and comprehensible definition will be operationalized. Before delving into the various mechanisms involved in stress responsivity, a brief overview of the two major systems, which mediate the human stress response, is necessary, namely, the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SAM) system.

Before beginning this discussion, we would highlight a fact of the utmost importance. The age group most vulnerable to abuse (neonatesdchildren aged 2 years) is also the group abused the most (Health USDo and Human S, 2015).

Stress responsivity physiology

The two main components of the mammalian stress response are the SAM system and the HPA axis (Gunnar and Quevedo, 2007). CNS circuits involving areas of the prefrontal cortex, hippocampus, amygdala, hypothalamic, and brain stem nuclei modulate both systems.

Corticotropin-releasing factor (CRF)eproducing neurons oversee the entire mammalian stress response, coordinating the autonomic, endocrine, immune, and behavioral responses to stress (Arborelius et al., 1999). The highest concentrations of CRF are found in the paraven- tricular nucleus (PVN) of the hypothalamus, which primarily regulates the HPA axis

 

Stress responsivity physiology 183

response to stress (Antoni et al., 1983). CRF-producing neurons located in the central nucleus of the amygdala are involved in processing emotional stress responses and the SAM response as well. CRF neurons in the central nucleus of the amygdala project to locus coeruleus norepi- nephrine cells, which in turn project to the lateral thalamus, leading to subsequent activation of the sympathetic preganglionic neurons that ultimately stimulate release of epinephrine from the adrenal medulla. CRF cells of the central nucleus of amygdala are involved in stress-induced activation of the HPA axis (Shekhar et al., 2005), via an indirect pathway through the bed nucleus of the stria terminalis, where CRF neuronal projections innervate the PVN neurons of the hypothalamus (Herman and Cullinan, 1997; Herman et al., 2002; Swanson and Sawchenko, 1983). Following activation of the HPA axis, CRF is released from the PVN in to the adenohypophysial-portal circulation from nerve terminals in the me- dian eminence where it stimulates adrenocorticotropin hormone (ACTH) release from the anterior pituitary.

ACTH in turn stimulates release of glucocorticoids (GCs) from the adrenal cortex (Gutman and Nemeroff, 2002). Able to permeate the blood-brain barrier, GCs reduce activation of the HPA axis via stimulation of GC receptors (GRs) within the hippocampus, hypothalamus, and anterior pituitary (Jacobson and Sapolsky, 1991). The critical role of amygdalar CRF has brought to attention the widespread localization of CRF receptors throughout the CNS and their converging pathways in orchestrating stress reactions (Swiergiel et al., 1993; Nemeroff, 1996). Two G proteinecoupled subtypes of CRF receptors, CRFR1 and CRFR2, have been found in the anterior pituitary, as well as in subcortical and cortical brain areas (Chalmers et al., 1996; Steckler and Holsboer, 1999). In general, the stress response appears to be medi- ated largely by CRFR1 receptors, whereas CRFR2 activation appears to actually diminish the stress response (see Chapter 16 for more information).

The response to psychosocial stress, of which ELS represents a specific subtype, also involves “higher appraisal” by cortical and subcortical regions of brain containing CRFR1 receptors, namely, cingulate cortex, orbital/medial prefrontal cortex, and hippocampus (Bale and Vale, 2004); all these areas comprise part of the converging pathways described above. Much evidence points to the role for CRF as a neurotransmitter coordinating immune, autonomic, endocrine, and behavioral stress responses, supported by the finding that CRFR1 receptors are more abundant in corticolimbic pathways that mediate fear- and anxiety-related behaviors (Sanchez et al., 1999). With this basic framework of stress response neurobiology, the concept of “stress responsivity” may be viewed through a model of posttraumatic stress disorder (PTSD).

In many ways, as discussed in more detail in other chapters of this book, individuals diagnosed with PTSD exhibit dysregulation of the stress response system. Criteria D for diagnosing PTSD in DSM5 requires that an individual demonstrates “marked alterations in arousal and reactivity associated with traumatic event(s)” in the form of hypervigilance, exaggerated startle response, increased irritability, problems with concentration, and/or sleep disturbance. The fact that many individuals with PTSD have experienced traumatic events that occurred in the form of child abuse and neglect comes as little surprise and further strengthens the argument for using PTSD-derived neurobiological research in developing the construct of “stress responsivity.”

 

184 13. Child abuse and neglect: stress responsivity and resilience

In the space below, we will examine in further detail the available evidence from human studies on the role of child abuse and neglect that contribute toward a model of “stress responsivity.”

Hypothalamic-pituitary-adrenal axis physiology

The HPA axis represents the major neuroendocrine stress response system that serves to adapt the organism to change in life demands and thereby maintain homeostasis (McEwen, 2004). Studies of the influence of ELS on HPA axis activity have shown that the effects of child abuse and neglect are variable in that it is associated with either increased or decreased HPA axis activity. This variability is dependent on several factors including age at the time of the trauma, subtype of abuse/neglect, magnitude, duration, etc.

Childhood maltreatment influence on hypothalamic-pituitary-adrenal/ sympathetic nervous system response to stress

Using various validated human stress models of provocative adrenal testing, HPA axis hyperactivity was demonstrated in depressed women and men with ELS by increases in both the ACTH and cortisol response as well as increased cerebrospinal fluid (CSF) CRF concentrations (Heim and Nemeroff, 2001; Heim et al., 2000b, 2002; Carpenter et al., 2004). In an early study, we tested the hypothesis that ELS in humans is associated with persistent sensitization of the HPA axis (Heim et al., 2003). To induce stress, we employed a standard- ized psychosocial stress protocol, the Trier Social Stress Test (TSST) that consists of public speaking and mental arithmetic tasks in front of an “audience” that has been shown to reli- ably induce HPA axis and sympathetic nervous system activation (Kirschbaum et al., 1993). Parallel to results from animal models, women with a history of childhood abuse (with and without) current major depressive disorder (MDD) exhibited increased ACTH responses to stress compared with controls. Overall the ACTH response was more than sixfold greater in abused women with current MDD than in controls. These women also demonstrated increased cortisol and heart rate responses to psychosocial stress. Abused women who were not currently depressed exhibited normal cortisol responses, despite their increased ACTH response, perhaps suggesting adrenal adaptation to central sensitization as a marker of resilience against depression after early stress. Depressed women without abuse demonstrated normal neuroendocrine responses. Our findings suggested that HPA axis and autonomic nervous system hyperactivity, likely due to CRF hypersecretion, may be a persistent consequence of childhood abuse that may contribute to the diathesis for adulthood psychopathology (Monroe and Simons, 1991). In a study of patients with MDD and border- line personality disorder, higher baseline and postdexamethasone cortisol concentrations were found in those who had a history of childhood trauma (Fernando et al., 2012).

In a nonclinical sample of women with minimal or no current psychopathology, childhood physical abuse was associated with a blunted cortisol response to psychosocial stress task (Carpenter et al., 2011). In another sample of 230 adults without a primary affective disorder,

 

Glucocorticoid feedback regulation of stress responsivity 185

a history of self-reported childhood emotional abuse predicted a significantly diminished cortisol response after administration of the dexamethasone/CRF test (Carpenter et al., 2009). In contrast, individuals with child abuse have been reported to exhibit reduced basal cortisol levels, as well as a blunted cortisol response to provocative stimuli (Carpenter et al., 2007). Likewise, ELS is well documented to increase the risk for development of PTSD, which is characterized by an “endocrine signature” of GR hypersensitivity and

reduced cortisol signaling (Bradley and Blakely, 1997). Sympathetic nervous system

Perceived threat activates the sympathetic (SNS) and parasympathetic (PNS) nervous systems and recurrent high levels of threat exposure, particularly early in life, can signifi- cantly affect an individual’s long-term ability to modulate the SNS and PNS response to future stressors (McEwen, 1998). Although the majority of studies have been focused on the HPA axis, others have examined childhood abuse and SNS reactivity. Of these, some report increased SNS reactivity following high levels of family adversity, whereas others observe no such association (Ellis et al., 2005; Oosterman et al., 2010; El-Sheikh, 2005; Elzinga et al., 2008). Women with a history of childhood sexual abuse also demonstrate relatively high SNS activity (Weiss et al., 1999), particularly in response to sexual cues (Rellini and Meston, 2006). Child abuse is associated with maladaptive patterns of cardiovas- cular reactivity to psychosocial stress in adolescence (McLaughlin et al., 2014). Taken together, these described HPA axis and SNS changes are consistent with an abnormal increase of CNS CRF activity as a function of childhood abuse and neglect. In fact, childhood stress has been suggested to be more predictive of increased CSF CRF concentrations than either a syndromal diagnosis of a depressive disorder or a suicide attempt (De Bellis and Thomas, 2003). Further highlighting the importance of the timing of stressors, Carpenter et al. (2004) reported that a history of adverse life events before age 6 years predicted elevated CSF CRF concentrations better than the diagnosis of MDD (Schoedl et al., 2010).

Glucocorticoid feedback regulation of stress responsivity

Enhanced stress responsiveness after childhood trauma might be further influenced by changes in GC-mediated feedback control of the HPA axis. In an initial study, we observed increased suppression of cortisol in a low-dose dexamethasone suppression test in abused women with depression and concurrent PTSD (Newport et al., 2004). Such hypersuppression indicates enhanced sensitivity of the pituitary to negative feedback and is a prominent finding in PTSD, believed to contribute to stress sensitization (Yehuda, 2006). In fact, the re- sults found in this study might be best attributable to comorbidity with PTSD. We sought to determine the effects of childhood abuse on results in the dexamethasone/CRF test in adult men with and without current MDD. Abused men demonstrated markedly increased cortisol

 

 

186 13. Child abuse and neglect: stress responsivity and resilience

responses to dexamethasone/CRF administration when compared with nonabused men, regardless of diagnosis. When stratifying groups by MDD and childhood trauma, only those abused men with current MDD, but not depressed men without childhood trauma, demon- strated increased cortisol responses. Increased response was associated with exposure to both sexual and physical abuse and the severity of the abuse (Heim et al., 2008). Importantly, this effect was not attributable to comorbid PTSD. These results suggest that childhood trauma is associated with impaired GC-mediated feedback control of the HPA axis during stimulated conditions (Heim et al., 2008).

Epigenetics of stress responsivity

It is firmly established that genetics contribute to the risk for the development of major psychiatric disorders. In addition, child abuse and neglect serve as important risk factors for the development of psychiatric disorders (Agid et al., 1999; Nestler et al., 2002). A novel approach utilized in recent years tests the hypothesis that gene variants may modulate the effect of ELS on the longitudinal risk for mental illness. Diathesis-stress theories of depression suggest that individual’s sensitivity to stressful events depends, in part, on their genotype (Costello et al., 2002). Investigations to date have largely supported this theory, with many studies demonstrating gene environment (G E) interactions that predict psychiatric disorder risk. A handful of such genetic polymorphisms are reviewed here: serotonin transporterelinked polymorphic region (5HTTLPR), monoamine oxidase A (MAOA), FK506-binding protein 51 (FKBP51), CRFR1, brain-derived neurotrophic factor (BDNF), and opioid-related nociceptin receptor 1 (OPRL1). Much research has focused on the interac- tion between serotonin transporter polymorphisms, ELS, and depression. In a pioneering study using the Dunedin cohort, Caspi et al. (2003) were the first to demonstrate an association between depression, ELS, and the 5-HTTLPR genotype. Individuals exposed to childhood maltreatment, possessing the s/s genotype, were shown to have the highest probability of developing a MDD episode and/or exhibit suicidality, followed by the s/l ge- notype. The l/l genotype was associated with resiliencedno increased risk for depression or suicide even in the presence of severe childhood abuse or neglect. In a general population study, a three-way interaction among childhood abuse adult traumatic experience s allele carrier status was found to be associated with higher Beck Depression Inventory-II (BDI-II) scores (Grabe et al., 2012).

A meta-analysis by Karg et al. (2011) found strong evidence supporting the association between childhood maltreatment and the s allele and increased stress sensitivity. This G E discovery leads to an interesting question, namely, whether we can use a patient’s genotype for the serotonin transporter promoter polymorphism, as well as other polymor- phisms coupled with a history of child abuse/neglect as criteria for early intervention to prevent the development of MDD in vulnerable individuals. Caspi et al. (2002) were also among the first to suggest that individual differences at a functional polymorphism in the promoter region of the MAOA gene may modulate children’s response to maltreatment.

 

Stress responsivity neural circuits 187

As noted previously, the association between child abuse and adult PTSD is well estab- lished (Bremner et al., 1993). Given that PTSD is strongly associated with long-lasting alter- ations in HPA axis sensitivity and increased GR sensitivity, a natural extension of G E research has examined whether HPA axis gene candidates mediate the increased susceptibility to PTSD after ELS (Yehuda, 2001; Yehuda et al., 1991). FKBP51 codes for a cochaperone protein that modules signal transduction of the GR. Four FKBP51 SNPs were found to significantly predict the PTSD Symptom Score (PSS) in individuals with a history of child abuse. All four SNPs have been associated with the presence of higher levels of FKBP51, consistent with the physiological mechanisms mediating GC sensitivity (Binder et al., 2008).

Bradley et al. (2008) demonstrated that genetic variants of the CRFR1 moderate the effect of child abuse on adult depressive symptoms. Laucht et al. (2013) found that the impact of childhood maltreatment on adult depressive symptoms was higher in individuals with two copies of the CRFR1 TAT haplotype. A haplotype of three SNPs in intron 1 of the CRFR1 gene was associated with a diminished effect of child abuse on adult depressive symptoms (Bradley et al., 2008). Thus, a genotype/haplotype may serve as a predictor of risk/resilience in those with history of child abuse and neglect.

Ressler et al. found that variants in the 5-HTTLPR interact with CRFR1 genotypes to predict current adult depressive symptoms. Individuals carrying a “risk” allele in both genes demonstrated more severe depressive symptoms at lower levels of child abuse (Ressler et al., 2010). Another G G interaction with implications of vulnerability to depres- sion is between 5-HTTLPR and BDNF. Meta-analyses have suggested that alteration in serotonergic activity may serve as a prodrome for later changes in neural plasticity of which BDNF is essential (Munafo et al., 2005; Urani et al., 2005). One study suggested that the BDNF Met allele may serve as a protection against the adverse effects associated with the 5-HTTLPR s allele in healthy individuals. However, in maltreated children, the combination of BDNF Met with the 5-HTTLPR s allele was associated with an increased risk for MDD (Kaufman et al., 2006).

Stress responsivity neural circuits

That ELS, including child abuse and neglect, produces persistent increases in CSF CRF concentrations, a measure of activity of CRF-containing neural circuits, a hallmark of HPA axis hyperactivity, and dysregulation of corticolimbic circuits places it in a position of fundamental importance in exploring pathogenic mechanisms that may underlie major psychiatric illnesses such as MDD and PTSD. Within the context of ELS, emerging data are all congruent in demonstrating persistent structural and functional changes to CNS structures and circuits including the prefrontal cortex, hippocampus, amygdala, and other cortical/ subcortical areas of brain, with increasing evidence that the ELS-specific subtypes result in specific neuroanatomical alterations. The hippocampus has long been an area of interest for a multitude of reasons, one being that it is known to play a pivotal role in efficient termi- nation of the HPA axis stress response by its rich density of GRs.

 

188 13. Child abuse and neglect: stress responsivity and resilience

Moreover, hippocampal volume reductions have been repeatedly reported in those suffering from MDD, PTSD, and other psychiatric disorders. Reports of reduced hippocam- pal volume in depressed women with a history of childhood maltreatment but not in equally depressed women without ELS have also been confirmed by others (Vythilingam et al., 2002; Buss et al., 2007; Frodl et al., 2010) and in a comprehensive meta-analysis (Nanni et al., 2012). Teicher et al. (2012) found that childhood maltreatment was significantly associated with reduced volume in the hippocampal dentate gyrus, subiculum, and subfield CA3. Another study compared depressed patients and age- and sex-matched healthy controls and found that childhood maltreatment, but not depression, was associated with hippocampal atrophy (Opel et al., 2014). Victims of childhood sexual and emotional abuse showed marked thinning in specific areas of cortical representation, respectively, suggesting that type-specific ELS has select effects on neural plasticity that persist into adulthood (Heim et al., 2013).

The preeminent role of the amygdala in stress responsivity has appropriately rendered it a central focus in research on mood and anxiety disorders. Both amygdala volume and responsiveness to stressors in those exposed to child abuse and neglect versus controls have been explored. Childhood maltreatment (assessed by the Childhood Trauma Question- naire) was shown to be positively associated with amygdala responsiveness in a standard emotional face-matching paradigm. This effect was not confounded by recent life stressors, current depression, or sociodemographic factors (Dannlowski et al., 2012).

Stress responsivity and inflammation

A neurodegenerative hypothesis of depression and psychiatric disorders of which inflam- mation is central has started to gain significant support in the stress neurobiology literature (Maes et al., 2009).

Briefly, the mechanisms of action of cytokines on the brain include the ability to mediate “sickness” behavior, alterations in serotonergic/glutamatergic/dopaminergic neurotransmis- sion, reduction in neurotrophic factors (e.g., BDNF), and increased neuronal glutamate exci- totoxicity, as well as neuronal vulnerability to oxidative reactive species (Maes et al., 1993, 2009, 2011; Raison et al., 2006, 2010; Qin et al., 2007; Irwin and Miller, 2007; Borland and Michael, 2004; Zhu et al., 2010; Neurauter et al., 2008; Felger et al., 2013; Steiner et al., 2011; Raison and Miller, 2003; Krügel et al., 2013). This has refined the original monoamine hypothesis of depression (Reichenberg et al., 2001; Maes, 1995; Capuron et al., 2002; Harrison et al., 2009; Bonaccorso et al., 2002) with a chronic neuroinflammatory and neurodegenerative theory of depression (Maes et al., 2009). Childhood abuse has been convincingly shown to produce a proinflammatory state (Coelho et al., 2014). Individuals with depression and a history of childhood maltreatment were more likely to have elevated C-reactive protein concentrations compared with controls (Danese et al., 2007, 2011). In response to daily stressors, child abuse history moderated levels of IL-6; those with a positive history of childhood abuse had IL-6 levels 2.35 times greater than those without any early abuse history. Childhood abuse was significantly associated with increased NF-kb pathway activity in individuals with PTSD, providing additional pathways to the previously discussed HPA axis alterations in the context of child abuse and neglect (Pace et al., 2012).

 

Resilient stress responses: CRFR1/OPRL1/5HTLPR/BDNF/NPY/DHEA 189 Stress responsivity and resilience

As discussed earlier, the concept of resilience has proven remarkably challenging to operationalize, as it encompasses a variety of behavioral phenotypes, which further complicates the characterization of neurobiological mechanisms in resilient individuals (Russo et al., 2012). If we consider resilience to be an active process of adaptation that precludes the development of psychopathology in the context of extreme duress, then the study of stress responsivity may be one pathway to advancing our understanding of resilience.

To date, it is clear that the scientific literature has amassed a considerate database on the neurobiological consequences of child abuse and neglect and its associated cascade of perturbations associated with increased vulnerability to developing affective and anxiety disorders. However, it may be that through the elucidation of “risk neurobiology,” we may indirectly arrive at ways to reduce risk and thus increase resilience. In several animal models and in some human studies, resilience is associated with rapid activation of the stress response and its efficient termination (DeRijk and de Kloet, 2005; De Kloet et al., 2005) and is further characterized by the capacity to constrain stress-induced increases in CRF and cortisol through an elaborate negative feedback system.

There are clinical data in select populations that exemplify stress resilience (i.e., military personnel, victims of trauma), of which there are multiple biological factors that appear to play a role: CRFR1, 5HTLLPR, BDNF, neuropeptide Y (NPY), and dehydroepiandrosterone (DHEA) to name a few.

Resilient stress responses: CRFR1/OPRL1/5HTLPR/BDNF/NPY/DHEA

Mediating the bulk of the CNS action of CRF, the CRFR1 receptor gene has demonstrated a haplotype of three SNPs in intron 1 of the CRFR1 gene that was associated with a diminished effect of child abuse on adult depressive symptoms (Bradley et al., 2008).

Specific CRFR1 polymorphisms appeared to uniquely moderate the effect of child abuse on the prospective risk for depressive symptoms in adulthood. Thus, a genotype/haplotype may serve as a predictor of both risk and resilience in those with history of child abuse and neglect.

To add to the ELS-HPA axis gene interaction story, an SNP found in the opioid receptore like 1 (Oprl1) gene in patients with PTSD symptoms after a traumatic event is associated with a self-reported history of childhood trauma (Andero et al., 2013). The same SNP is associated with altered fear learning and fear discrimination, mechanisms including differential amygdala-insula functional connectivity that has been linked to PTSD (Stein et al., 2007). Kaufman et al. (2004) showed that a supportive environment protected children with the s/s serotonin transporter promoter genotype and a history of maltreatment from developing depression. BDNF, a vital growth factor, promotes healthy function of the adult hippocam- pus. Induction of BDNF has been implicated in relative vulnerability and resilience to stress (Krishnan et al., 2007). NPY is a peptide neurotransmitter that modulates the acute stress response, and laboratory animal studies have provided evidence that increased NPY

 

 

190 13. Child abuse and neglect: stress responsivity and resilience

signaling in the central nucleus of the amygdala is associated with lower anxiety levels (Rasmusson et al., 2003). DHEA is released with cortisol from the adrenal cortex, and studies suggest it may play an antiinflammatory/antioxidant role during an acute stress response. DHEA increased under acute stress and a higher DHEA-to-cortisol ratio is associated with fewer dissociative symptoms in healthy subjects during military survival training (Rasmusson et al., 2003; Mulchahey et al., 2001).

There is evidence to suggest that testosterone promotes resilient behavior in males with MDD and PTSD, an observation congruent with the epidemiological data that women are at significantly higher risk than men to develop such disorders (Pope et al., 2003).

One area of work that will significantly advance resilience research will be human brain imaging, as the elucidation of brain circuits involved in stress resilience is vital. Although this avenue of exploration still remains in its infancy in human studies, there already are some promising findings. Steffens et al. (2017), in the NBOLD study, have found significant differences in the Default Mode Network vmPFC/dlPFC that are thought to play a regulato- ry role in corticolimbic circuits mediating stress vulnerability (Steffens et al., 2017).

Treatment/implications/future

Stress resilience neurobiology research, at its core, deals with the human evaluational response to verbal and nonverbal stimuli (aka “stressors”) in connection with their unique meanings to the “person.” Maladaptive evaluations result in abnormal stress responses, which lead to a cascade of negative consequences including poor coping skills, reduced tolerance for stressful stimuli, and higher risk of developing a psychiatric disorder (Hammen et al., 1985). As briefly discussed in this chapter, and further elaborated upon in others, genetic variants appear to interact with environmental variables to modulate how a human’s reaction to stress predisposes or protects against development of psychiatric disturbances.

Studies suggest that the molecular mechanisms of childhood abuse and neglect as well as other forms of early-life adversity are potentially reversible in adulthood (Meaney and Szyf, 2005). That behavioral interventions have been shown to directly affect 5-HT neurotransmission, leading to changes in GR expression, which allow for effective termination of stress response bodes well for the field of stress resilience research. Not to be excluded, exercise training has also had consistently positive results suggesting utility in the area of stress resilience, specifically for those with clinical depression (Martinsen et al., 1985; Blumenthal et al., 1999; Singh et al., 2001).

Exercise monotherapy for mild to moderate depression showed comparable rates of remission to the SSRI monotherapy group. Furthermore, during the follow-up period, those who exercised on their own had a 50% reduction in probability of relapse compared with those who did not continue exercise after study completion (Babyak et al., 2000; Salmon, 2001). In relation to stress responsivity, it is of interest that exercise-trained individuals showed attenuated HPA axis responses to mental stress (Luger et al., 1987) and that exercise has been shown to prevent stress-induced changes in gene expression of neurotrophic factors vital to hippocampal function (Russo-Neustadt et al., 2001).

 

References 191

The neurobiology of stress resilience will hopefully make possible the induction of natural mechanisms of resilience in vulnerable populations including victims of child abuse and neglect. One of the intrinsic and unavoidable challenges that researchers must navigate in the realm of stress resilience neurobiological research is that those who are able to maintain a high level of function and psychiatric stability despite exposure to trauma do not come to the attention of clinicians. As a result, other than some studies in niche populations (military personnel), the field remains challenged to discern resilient mechanisms from those that have been shown to have higher risk/vulnerability such as those who develop MDD/ PTSD in the context of childhood abuse and neglect. A plausible methodological approach that may better demonstrate the neurobiological mechanisms mediating resilient behavior would include a model that prospectively examines the impact of a stressor such as natural disaster with comparisons to nonetrauma-exposed individuals. Determining what factors contribute to psychiatric vulnerability and morbidity in these two groups in a long-term longitudinal paradigm is of interest. Decreasing the CRF response both centrally and periph- erally to stress represents an important component of the therapeutic response in mood and anxiety disorders (Nemeroff and Vale, 2005). Alternatively, discovery of resilience biomarkers that translate into novel interventions that can alleviate the suffering of those afflicted by stress-related disorders and/or prevention is the ultimate goal.

Financial Disclosures

The author(s) declared the following financial relationships over the past 3 years. Charles B. Nemeroff, MD, PhD, Research/Grants: National Institutes of Health (NIH), Stanley Foundation. Consulting: Xhale, Takeda, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Navitor, Intracellular therapeutics, Bracket (Clin- tara), Gerson Lehrman Group (GLG) Healthcare & Biomedical Council, Sunovion Pharmaceuticals Inc., TC-MSO, Janssen Research & Development, LLC, Magstim, Inc.; Stockholder (or options): Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Bracket Intermediate Holding Corp., Network Life Sciences Inc.; Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF) (formerly named National Alliance for Research on Schizophrenia and Depression [NARSAD]), Xhale, Anxiety Disorders As- sociation of America (ADAA), Skyland Trail, Bracket (Clintara), Laureate Institute for Brain Research, Inc.; Board of Directors: AFSP, Gratitude America, ADAA; Income sources or equity of US$10,000 or more: American Psychiatric Publishing, Xhale, Bracket (Clintara), CME Outfitters, Takeda; Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1) and method of assessing antidepressant drug therapy via transport inhibition of mono- amine neurotransmitters by ex vivo assay (US 7,148,027B2).

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CHAPTER

14

How genes and environment interact to shape risk and resilience to stress-related psychiatric disorders

Lilia Papst1, Elisabeth B. Binder1, 2
1Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; 2Department of Psychiatry and Behavioral Sciences and Department of Psychology, Emory University School of Medicine, Atlanta, GA, United States

Introduction

Mental disorders are multicausal and diagnostically overlapping and typically take a chronic course over prolonged periods of time, with recurring symptoms often triggered through stressful experiences. Although the identification of definitive causal factors has proven difficult, the diathesis-stress model has garnered widespread acceptance in the field with its general assumption that psychiatric disorders are caused by a combination of genetic and environmental factors. The contribution of genetic variation to pathogenesis differs between diagnoses but is mainly polygenic with many genes contributing with small effect sizes as opposed to single gene large effects. Twin and family studies and now also genome-wide association studies (GWAS) report the genetic contribution to psychiatric dis- orders to range from about 80% for autism to about 30%e40% for major depressive disorder (MDD) (Sullivan et al., 2012). Environmental factors, especially adverse life events, can both trigger or exacerbate disease course. Among these, childhood adversity has been most consis- tently associated with increased risk for a range of psychiatric symptoms. In a study including data from 21 countries, childhood adversities, in particular when associated with maladaptive family functioning, strongly associated with psychiatric disorders, with little specificity across disorders and explaining up to 30% of disease variance across diagnoses (Kessler et al., 2010).

Given that exposure to stressful life experiences can often not be avoided, building resil- ience constitutes an integral part of preventive and therapeutic efforts. Understanding

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00014-8 197 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

198 14. How genes and environment interact to shape risk and resilience to stress-related psychiatric disorders

resilience-promoting factors as well as interindividual differences in resilience may help to optimize these efforts. Resilience-promoting factors include caring and supportive relation- ships, communication and problem-solving skills, and the ability to manage strong feelings and impulses (American Psychological Association, 2018). The mechanisms underlying resil- ience may be primed early on by the interplay of environmental factors, including the quality of caregiving and the degree of adversity, and genetic factors that impact on the regulation of the stress response, which in turn may influence the development of brain circuits relevant for emotion regulation (Blair and Raver, 2012). In this chapter, we will discuss how the inter- play of genetic and environmental factors shapes the developing organism to ease or perturb resilience-promoting qualities through their influence on intermediate phenotypes. The chap- ter structures the findings by giving specific examples for such mechanisms along develop- mental periods. A focus will be on genetic polymorphisms in select candidate genes that moderate the impact of adversity to predict adult psychiatric disorders (see Halldorsdottir and Binder, 2017 for review). We will highlight examples of mechanisms of how these genetic polymorphisms influence specific biological mechanisms throughout development. These include but are not limited to genes involved in regulating the stress hormone system (FKBP5 and CRFR1), the oxytocin system (oxytocin receptor gene [OXTR] and the gene encod- ing the oxytocin peptide [OXT]) as well as the monoamine system (SLC6A4 and COMT).

Prenatal development

The human embryonic stage is a highly dynamic phase of brain development, governed by a complex interplay of intrinsic and extrinsic cellular signaling. Extrinsic signaling events may hereby involve external perturbances, such as increased glucocorticoid levels, which can significantly alter brain development trajectories (O’Donnell and Meaney, 2016). Although the unborn child is usually protected from high glucocorticoid levels by a barrier of placental 11b-hydroxysteroid dehydrogenase type 2, an enzyme that degrades cortisol to inactive metabolites, this mechanism can be compromised as a result of maternal stress (Mairesse et al., 2007) or depression (Seth et al., 2015). Genetic factors act as moderators of these processes by altering the impact of glucocorticoids at the level of the placenta or the developing embryo. Schizophrenia, for instance, has long been known to have a strong genetic background, while obstetric complications have been shown to be a strong environ- mental risk factor for this disorder. A recent study revealed that the interaction of polygenic risk scores derived from large GWAS for schizophrenia with obstetric complications best explained variance in disease risk (Ursini et al., 2018). In fact, genes within this polygenic score were enriched for transcripts with strong expression in the placenta and also differen- tially expressed in placentae from complicated in comparison with normal pregnancies. This suggests that genetic polymorphisms predisposing to schizophrenia may in part mediate this risk by making the placenta more vulnerable during obstetric complications.

In addition to obstetric complications, maternal stress and adversity during pregnancy have also been shown to increase risk for later psychiatric disorders, especially mood and anxiety disorders (Brannigan et al., 2018). Such effects may be mediated by alternating the trajectory of brain development. In interaction with prenatal adversity, a polygenic risk score for MDD was associated with reduced frontocortical gray matter, larger amygdala volumes,

 

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and altered hippocampal volume and shape at birth (Qiu et al., 2017). The same brain regions were affected in neonates by variation in candidate genes FKBP5, a gene influencing glucocorticoid receptor sensitivity, and the catechol-O-methyltransferase COMT, essential for catecholamine metabolism, in interaction with maternal mental health. A set of 19 FKBP5 SNPs predicted larger hippocampal volume in newborns (Wang et al., 2018), whereas a protein coding variation in COMT rs4680 resulted in reduced ventrolateral prefrontal cortex thickness in homozygotes for the lower activity methionine allele (Qiu et al., 2015).

Such altered morphology in the frontal cortex and amygdala may contribute to behavioral problems observed in youth exposed to prenatal stress, who were more likely to exhibit negative emotionality, internalizing and externalizing behavior, disturbed motor develop- ment, and attentional and cognitive deficits (van den Bergh et al., 2017).

Prenatal stress together with genetic risk factors may thus predispose children to a reduced capacity for frontally mediated emotion regulation very early in life. Additionally, both delay in motor functions and deficiencies in attention and general cognitive functions observed in exposed children may lead to early experiences of failure or inadequacy in the school setting. Altogether, these experiences are likely to amount to feelings of helplessness and low self-esteem from an early age. Understanding these mechanisms of prenatal risk may offer an opportunity for early intervention, using targeted environmental and behavioral support in the postnatal environment.

Infancy

The first years of postnatal life are associated with sustained high plasticity, signifying both ongoing vulnerability and the chance for early interventions following prenatal adver- sity. Although gene expression in the brain of transcripts associated with cell proliferation decreases, genes related to myelination, synapse, and dendrite development continue to rise in expression levels (Kang et al., 2011). Meanwhile, social development is characterized by the formation of attachment to a primary caregiver (Bowlby, 1954). In fact, positive parental attention and physical contact were shown to attenuate or even eliminate the nega- tive influence of prenatal stress (Sharp et al., 2012, 2015), although its effects persisted in most studies where these behaviors were not explicitly encouraged (Velders et al., 2011).

An interesting candidate gene for G E interactions in this context is the oxytocin receptor gene (OXTR) and the gene encoding the oxytocin peptide (OXT). Oxytocin is a hormone that biologically serves a function in cervix dilation before birth and stimulating lactation during breastfeeding but has been implicated in a much wider range of maternal and nurturing behaviors, emotional bonding, and social interactions. Genetic variation in OXT and OXTR may contribute to differences in the capacity for social interactions, both on the parental and on the offspring’s side. For instance, a gain-of-function genetic polymorphism in rhesus macaque OXTR was shown to partially protect from the negative behavioral consequences of early maternal deprivation in infants (Baker et al., 2017). In humans, genetic variation has also been shown to alter infant attachment, with OXTR SNP rs2254298 A allele carrier infants being more often securely attached than G homozygotes (Chen et al., 2011a). These polymor- phisms in OXTR may therefore help infants to establish close relationships and may indirectly determine the extent of care and affection they are likely to receive from caregivers.

 

200 14. How genes and environment interact to shape risk and resilience to stress-related psychiatric disorders

OXTR polymorphisms were also shown to influence maternal behavior, with mothers with a specific OXTR genotype combination and adult separation anxiety showing significantly reduced levels of maternal sensitivity during free play with their infant (Mehta et al., 2016). Genetic variation in the gene encoding the OXT peptide was shown to interact with a mother’s own early parenting experience to predict the quality of her mothering (Mileva- Seitz et al., 2013). The literature thus depicts a complex interaction of maternal and infant genetic variation in the oxytocin system to predict the quality of maternal care as well as the susceptibility of infants to poor care.

As mentioned previously, caring and supportive relationships as well as good communi- cation skills are important resilience factors with regard to mental health. Carriers of certain polymorphisms in OXT or OXTR may therefore be more resilient to adverse experiences. More importantly, however, physical contact and positive parental attention may be a suffi- cient means to counteract the effects of early stress and by extension the likelihood of offspring psychopathology. In fact, both in animal models and humans, it has been shown that close physical contact early in life can reduce later consequences of early adversity (Barrett et al., 2015; Hunziker and Barr, 1986).

Childhood

According to the WHO World Mental Health Survey, childhood may be a uniquely sensitive phase for psychological development, as childhood stress accounts for about 30% of the variance of all psychiatric disorders (Kessler et al., 2010). While newborn infants predominantly rely on external stress regulation by means of their caretaker, children increas- ingly develop their own and more diverse strategies to cope with distress. Maladaptive coping in children is often broadly grouped into internalizing strategies, including rumina- tion, worrying, and social withdrawal, and externalizing strategies, such as verbal or physical aggression. These behavioral coping strategies have been shown to associate with genetic polymorphisms in genes within the monoamine as well as stress-hormone system, thus providing a mechanism for genetic influence on later psychiatric risk. Both internalizing and externalizing symptoms were more common in children carrying a lower function (short) allele of a promoter polymorphism of the serotonin transporter gene SLC6A4 who were exposed to harsh parenting and traumatic events. Exposed children carrying the opposite allele were less affected and showed beneficial distraction coping strategies (Cline et al., 2015). Beneficial coping strategies in children were furthermore reported for car- riers of alleles of other genes associated with adult mental health following childhood adversity. These included CRFR1, a gene encoding for the corticotrophin-releasing factor receptor important in the regulation of stress signaling (Cicchetti and Rogosch, 2012; Cline et al., 2015), OXTR (Cicchetti and Rogosch, 2012; Apter-Levy et al., 2013; Baribeau et al., 2017) or COMT (Hygen et al., 2015). These findings support that specific genotypes may increase resilience by promoting beneficial coping strategies when exposed to adversity.

During childhood, the brain undergoes a phase of maturation marked by progressive loss of gray matter, starting in limbic brain areas and concluding with the frontal cortex (Gogtay et al., 2004). Interestingly, stressful experiences early in life may promote these struc- tural changes. Childhood adversity has been associated with reduced gray matter volumes in

 

Adolescence 201

the frontal cortex, anterior cingulate cortex (ACC), insula, and hippocampus (Dannlowski et al., 2012), and these effects were more pronounced in individuals carrying specific risk alleles in FKBP5 (Grabe et al., 2016) or the SLC6A4 short allele (Frodl et al., 2010). Decreases in gray matter volume have been associated with processes of integration and specialization during this period. Exposure to early-life stress may therefore strengthen stimulus-response contingencies between a stressor and internalizing or externalizing behaviors that are adap- tive at this time. However, by reducing developmental plasticity, learning of alternative coping strategies later in life could be reduced in exposed children. In fact, a multilocus score of genetic variations predicting higher HPA axis activity in FKBP5, CRFR1, and the mineral- ocorticoid receptor (NR3C2) was shown to associate with high amygdala reactivity to threat in young adults exposed to early-life stress. Since the amygdala is involved in the encoding of emotional memories, including negative ones, this process seems to be enhanced in individuals with experiences of early-life stress ranking high on this biologically informed multilocus profile score (Di Iorio et al., 2017).

The hypothesis that early-life stress may promote reduction in gray matter is further corroborated by a genome-wide molecular study that integrated blood transcriptome data from humans exposed to childhood trauma with hippocampal microRNA and mRNA data from a prenatal stress rat model. Using this convergent transspecies approach, the authors identified FoxO1, a gene promoting neural cell death and TGFb1, which controls SMAD signaling, important for brain homeostasis and neural proliferation and differentiation, as dysregulated by early adversity. These two genes are representative of major processes in child brain maturationdapoptosis and neuronal differentiation. The relevance of FoxO1 could be further corroborated using a gene environment interaction analysis in a large human cohort, where six polymorphisms in FoxO1 interacted with early-life stress to predict adult depressive symptoms (Cattaneo et al., 2018).

With regard to possibilities of intervention, coping strategies might be suitable targets in spite of preexisting genetic preferences. For instance, children may feel encouraged to employ more adaptive stress regulation strategies when observing positive consequences in social role models (Bandura et al., 1963). An early establishment of such competencies, especially in children at genetic risk, could prevent trajectories of risk.

Adolescence

Although early-life experiences significantly shape the risk to psychopathology, a remark- able number of psychiatric disorders do not have their onset until adolescence (Kessler et al., 2005). This may be due to both an increased exposure to social stressors and unique develop- mental features of adolescence. For instance, sex-dependent differences in susceptibility to individual diagnoses are not reported at younger ages (Angold et al., 1999), suggesting an important role of gonadal steroids, possibly in interaction with glucocorticoids. Genetic variation in the estrogen receptor alpha gene (ESR1) are, for example, associated with the likelihood to suffer from premenstrual dysphoric disorder (Huo et al., 2007) and interact with traumatic life events to predict PTSD symptomatology (Feng et al., 2018).

In addition to hormonal changes, adolescence is characterized by heightened reward sensitivity, sensation-seeking, and immature impulse control (Steinberg and Chein, 2015),

 

202 14. How genes and environment interact to shape risk and resilience to stress-related psychiatric disorders

likely because of the fact that frontal cortex regions associated with cognitive control mature last, after limbic brain areas are already fully myelinated (Pfefferbaum et al., 1994). Differ- ences in frontolimbic structures are therefore presumed at the core of problems in adolescence associated with the reward and emotion regulation systems. Females carrying genotypes associated with an extreme reduction in COMT (22q11 deletion and carrying the low activity rs4680 methionine allele), for example, exhibited excessive cortical thinning and deficits in executive function, but only after puberty (Sannino et al., 2017). Such complex interactions between brain maturation, stress, and genetic risk have been elegantly described by Niwa et al. where glucocorticoids link adolescent stressors to epigenetic control in neurons. Specif- ically, isolation stress in adolescence led to hypermethylation of the tyrosine hydroxylase promoter in mesolimbic dopamine projections, but only in animals carrying a dominant- negative DISC1 mutation, associated with neuropsychiatric risk in humans. This led to increased dopamine levels, heightened dopamine receptor expression in the frontal cortex, and behavioral impairments, which were successfully prevented by the application of a GR antagonist (Niwa et al., 2013).

Well-established coping strategies to regulate feelings and impulses may help to contain some of these stress-induced biological alterations. However, especially, adolescents with specific genetic risk variants already described above, such as in FKBP5, OXTR, and the serotonin transporter may be less able to employ such strategies. For example, adoles- cents carrying the FKBP5 risk alleles growing up in households characterized by lower socioeconomic status and family adversity were more prone to employ negative strategies such as rumination or catastrophizing and develop symptoms of anxiety and depression (Halldorsdottir et al., 2017). Carriers of the 5-HTTLPR short allele had a higher risk of emotional dysregulation, lowered positive affect, and aggressive behavior when attachment was low or if they were exposed to unsupportive parenting (Zimmermann and Spangler, 2016; Hankin et al., 2011). However, securely attached OXTR rs2254298 A allele carriers also exhibited more depressive symptoms if their mothers experienced depression (Thompson et al., 2011), stressing the context specificity of adaptive genotypes.

The latter finding stresses the importance of targeting intervention in adolescence not only to the individual but also to the whole family. Adolescents were shown to profit from inter- ventions promoting supportive parental behavior as well as skills training, resulting in improvements on the behavioral level, which were accompanied by morphological changes in brain structure (Brody et al., 2009).

Adulthood

All mechanisms discussed in the previous sections will impact on resilience in adulthood. Although gross morphological brain maturation processes are complete at this point, some adult neurogenic niches remain, such as in the subgranular zone of the hippocampal dentate gyrus (Eriksson et al., 1998). Being associated with the encoding of memory and learning of new behavior in adulthood (Deng et al., 2010), it may provide a possible gateway for both pharmacological and psychotherapeutic interventions (Alboni et al., 2017). In addition, synaptic plasticity allows learning and memory into old age. Among the most stressful life events in adulthood are the death of a child or other close family member, divorce, personal

 

Conclusions 203

illness, and unemployment (Holmes and Rahe, 1967). Whether exposed individuals go on to develop symptoms of psychiatric symptoms, however, is highly dependent on the availabil- ity of social support or lack thereof (Kilpatrick et al., 2007; McQuaid et al., 2016). Indeed, social support and physical contact have shown measurable consequences on physiological parameters in reducing stress-induced cortisol and norepinephrine levels, as well as blood pressure (Grewen et al., 2005). These beneficial effects are possibly moderated by the oxytocin system, as OXTR rs53576 G allele homozygotes seem to particularly benefit from social support (Chen et al., 2011b). Several studies also support that polymorphisms in oxytocin system genes moderate social sensitivity (McInnis et al., 2015, 2017). As previously noted, the very availability of social support to an individual might be mediated by OXTR genotype. Similar to their younger counterparts, adult individuals homozygous for the OXTR rs53576 G allele exhibited higher empathy (Rodrigues et al., 2009), were judged to be more prosocial by others (Kogan et al., 2011), and ultimately had a higher tolerance for stress than individuals carrying an A allele (Lucas-Thompson and Holman, 2013). Differential sensitivity to adult stressful life events has also been reported for the other candidate genes, as reviewed in Halldorsdottir and Binder (2017).

For adult life events, not only candidate genes have been investigated, but also genome- wide interaction patterns using different strategies. For example, polygenic risk scores derived from GWAS for MDD show inconsistent interactions with stressful life events in predicting depressive symptoms (Mullins et al., 2016; Peyrot et al., 2017). On the other hand, polygenic risk scores for bipolar disorder and schizophrenia interacted with trauma exposure to predict alcohol abuse in more than 10,000 US-Army soldiers (Polimanti et al., 2018b). In addition to mapping polygenic risk scores, gene-environment wide interaction studies (GEWIS) have been attempted. In study within more than 10,000 participants, GEWIS identified a SNP 14 kb from CEP350 interacting with stressful life events to predict depressive symptoms in the larger African-American subset (Dunn et al., 2016). The functionality of CEP350 is not well characterized yet, but it is known to be involved in the organization of microtubules and may therefore play a role in adult neuroplasticity. Another GEWIS in two independent cohorts of over 24,000 individuals identified SNPs in PRKG1, a gene involved in learning and memory, to interact with trauma exposure to predict alcohol abuse (Polimanti et al., 2018a). Genes moderating the capacity of neural plasticity may thus be relevant candidates for resilience mechanisms in adulthood.

Conclusions

We here outlined how genetic factors in interaction with changing environmental stressors shape the developing brain toward disease or resilience. Studying gene environment inter- actions may thus be informative for understanding resilience mechanisms providing informa- tion on relevant molecular and cellular mechanisms, brain circuits, and behavioral strategies. A detailed mapping of gene environment interactions in large longitudinal cohorts with repeated biological, neuroimaging, behavioral, and symptomatic measures may allow to dissect mechanisms of resilience at different developmental stages and to inform strategies for enhancing resilience.

 

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CHAPTER

15

Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

Orna Issler, Zachary S. Lorsch, Eric J. Nestler

Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Introduction

There are profound individual differences in the response to stress. In some people, stress induces a range of behavioral abnormalities, whereas in the majority of individuals, exposure to the same stressor has no discernible effect. This variability contributes to differing suscep- tibility to several psychiatric disorders such as major depressive disorder (MDD), during the development of which only a subset of individuals exposed to chronic stress will exhibit clin- ical symptoms (reviewed in (Russo et al., 2012; Franklin et al., 2012; Feder et al., 2009)). In this context, the individuals who do not develop behavioral changes that impede social and occu- pational functioning, despite exposure to severe stress, are termed “resilient.” Because stress in life is inevitable, understating what makes specific individuals stress resilient is of great interest, as this knowledge could provide a foundation for efforts to prevent and treat syn- dromes such as MDD. Of particular interest is elucidating the molecular processes that under- lie resilience, as these molecular changes could be mimicked by therapeutics to treat or prevent pathological states in susceptible individuals.

In the laboratory, animal models involving controlled applications of different types of stress can be used to explore individual differences in behavioral and physiological responses (Fig. 15.1). These models are predicated on individual differences in stress reactivity, which result from genetic, epigenetic, or other factors. For example, selective breeding of rodents has resulted in distinct reactive and nonreactive strains that show altered behavioral readouts (Touma et al., 2008; Stead et al., 2006) and molecular profiles (Chaudhury et al., 2014; Hamilton et al., 2014). Other models such as chronic social defeat stress (CSDS) (Berton et al., 2006; Krishnan et al., 2007), chronic variable stress (CVS) (Ota et al., 2014), and learned

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00015-X 209 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

210 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

FIGURE 15.1 Experimental framework to identify and validate molecular changes associated with stress resilience in animal models. A chronic stress paradigm, stain differences, or selective breeding of rodents are used to induce depression-like behavioral abnormalities in individual animals. Such abnormalities are assessed using a battery of behavioral and neuroendocrine tests, which can differentiate susceptible versus resilient phenotypes in some paradigms. Brain, blood, and other peripheral tissue are collected from control, susceptible, and resilient animals and analyzed to identify molecular and biochemical changes. This can occur either by a candidate gene approach or through unbiased, high-throughput screens. Bioinformatic tools are then utilized to integrate and compare the molecular changes associated with resilience and to identify key target genes and molecular pathways. Finally, it is essential that such predictions are validated in vivo to confirm a causal role in mediating stress resilience. Reprinted with permission from © Mount Sinai Health System.

 

Introduction 211

helplessness (Su et al., 2016), among others, utilize inbred mouse lines that show individual variations in stress reactivity (Box 15.1). As these mice share a common genetic background, models such as these are useful to pinpoint epigenetic changes associated with resilience.

BOX 15.1
Chronic stress paradigms in rodents

Depression is a devastating psychiatric disorder that affects nearly 10% of the pop- ulation. Individuals with depression suffer from a range of emotional, cognitive, and physiological symptoms such as sadness, anhedonia, guilt, energy changes, problems concentrating, changes in appetite, psycho- motor alterations, and thoughts of suicide (Akil et al., 2017; Nestler, 2014). Given the heterogeneity of the human depression syndrome, and the prominence of many abnormalities that are uniquely human, it is impossible to fully recapitulate depression in a rodent (Nestler and Hyman, 2010). Rather, the goal is to expose rodents repeatedly to different types of stresses and identify those individuals (susceptible) that develop behavioral abnormalities that are reminiscent of human depression and other individuals (resilient) that avoid some or all of these ab- normalities and maintain normal behavioral and physiological functioning despite the stress. Ultimately, it is essential to validate findings from rodent models in humans through the study of postmortem brain tissue. The following are examples of chronic stress paradigms used to study resilience.

CSDS is a widely used procedure to distinguish between susceptibility and resil- ience in mice (Berton et al., 2006; Krishnan et al., 2007). In this procedure, a C57BL/6 mouse is placed into the home cage of a bigger retired CD-1 breeder. During this session, the intruder mouse is subjected to physical aggression by the CD-1 for 5 e10 min. Next, the two mice are separated by a perforated divider for the remainder of the

day. This divider prevents any further phys- ical interactions but exposes the C57BL/6 mouse continuously to the aggressive mouse. This procedure is repeated daily for a total of 10 days, with a new aggressor each day (see (Golden et al., 2011) for protocol). Several assays are used to measure behavioral ab- normalities after CSDS. The social interaction (SI) test is used to probe social avoidance. In this test, mice are allowed to explore an arena twice. First, while alone, and second, with a novel CD-1 breeder mouse that is placed in a confined space called the interaction zone. Susceptible mice avoid interacting with the novel mouse, whereas control and resilient mice spend more time in the interaction zone when the novel mouse is present than when the confined space is empty (Krishnan et al., 2007). Importantly, the social avoidance exhibited by susceptible mice generalizes to all mice, including conspecific C57BL/6 mice. Susceptibility versus resilience established by the social interaction test correlates strongly with performance in several other assays, such as sucrose preference, sexual behavior and high-fat food consumption. (Berton et al., 2006; Krishnan et al., 2007). Although CSDS was developed originally for male mice, several paradigms have been established for females (Harris et al., 2017; Steinman and Trainor, 2017; Takahashi et al., 2017).

CSDS has proven particularly useful for three main reasons. First is its ability to so clearly differentiate susceptible versus resil- ient subpopulations of animals. Second, many of the behavioral abnormalities induced by CSDS are essentially permanent,

Continued

 

212 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

BOX 15.1

which makes it possible to test the ability of experimental manipulations to reverse stress- induced abnormalities (Berton et al., 2006; Tsankova et al., 2006). This is in contrast to several other paradigms, which induce more transient behavioral abnormalities and can only be used to study the ability of a manipulation to prevent the deleterious ef- fects of concomitant stress. Finally, standard antidepressants exert therapeutic-like effects after CSDS only with chronic administration, and with acute antidepressant-like effects seen with ketamine as observed in humans. (Donahue et al., 2014).

CVS refers to several procedures, also known as chronic unpredictable stress or chronic mild stress, in which rodents are exposed to different stresses each day (Will- ner et al., 1987; Hill et al., 2012). The stress regime is performed for several weeks and comprises stressors ranging from cage tilting and/or flooding in the milder protocols, and foot shock and/or restraint stress in the more harsh protocols. The usage of multiple stressors in random order is to prevent habituation to the stressors. CVS has been shown to induce increased depression-like behaviors in rodents, particularly anhedonia (Willner et al., 1992). However, there are also reports of no effect or decreased depressive- like phenotypes following CVS (Willner, 2005). A strength of the CVS model is that it can be performed in multiple age groups. There are also sex differences in the effects of CVS, as a shorter stress exposure is sufficient to induce a depressive phenotype in female but not male mice (Hodes et al., 2015). These characteristics make CVS a compelling model

(cont’d)

for studying the increased risk of females for mood disorders and the relative resilience of males to this particular type of stress.

Learned helplessness is a model in which exposure of rodents to repeated inescapable shock leads to the development of passive responses to future shocks in a subset of an- imals (Maier, 1984). Such passive responses are associated with cognitive, motivational, and emotional deficits and have also been linked to certain neurobiological changes that mimic aspects of depression (Willner, 1986). Individual differences in escape latency have been used as proxy for stress susceptibility and resilience (Berton et al., 2007; Su et al., 2016).

Early-life stress: Exposure to stress in early life, such as neglect or abuse, increases the risk for developing depression later in life (Felitti et al., 1998). This phenomenon is mimicked in rodents by exposure to stressors such maternal separation or reduced cage nesting materials in critical periods in early life (Francis et al., 1999; Heim et al., 2008; Bale et al., 2010). In some protocols, subsequent exposure to stress in adulthood is needed to reveal the enhanced stress susceptibility (Pena et al., 2017). Notably, there are reports that maternal care contributes to stress resil- ience by long-term programming of the off- spring’s stress responses (Liu et al., 1997; Korosi et al., 2010).

Several other chronic stress or other procedures (e.g., chronic corticosterone administration) have been used to study stress-related pathologies, but have not been used widely to date to study resilience.

 

Introduction 213

Using these animal models, a wide range of molecular changes have been associated with stress resilience (Fig. 15.1). In particular, studies have identified resilient-specific changes at the levels of RNA (Krishnan et al., 2007; Bagot et al., 2016), protein (Henningsen et al., 2012; Palmfeldt et al., 2016), chromatin (Wilkinson et al., 2009; Dias et al., 2014), and DNA (Elliott et al., 2010; Feng et al., 2017), all of which can have an impact on brain function. Many studies of resilience to date have examined effects on candidate genes or molecular pathways known to be perturbed in stress-susceptible animals or in human MDD. An increasing number of studies, however, are the result of unbiased genome-wide profiling ap- proaches. Such approaches, when combined with advanced systems biology and bioinfor- matics analysis, have the potential to reveal novel regulators of stress resilience. For these cases, in vivo validation is essential to provide causal evidence that a given target molecule is indeed pro-resilient. Such validations involve direct genetic manipulations in a given brain region, such as viral-mediated gene transfer, which induce behavioral resilience upon mimicking a molecular change associated with resilience, as well as blocking of behavioral resilience by occluding that molecular change (Hamilton et al., 2017). Such tactics have the potential to establish the involvement of specific pathways in pro-resilient behavior and to provide more mechanistic detail as to the role of the individual molecules and pathways in stress resilience (Fig. 15.1).

The molecular changes associated with stress resilience arise from a combination of genetic and environmental factors. To date, most studies of genetic contributions to stress suscepti- bility have focused on the underlying genetics of MDD with minimal investigation of factors that directly promote resilience. Even though twin studies have long suggested that heritability in MDD approaches 40% (Sullivan et al., 2000), only recently have genome- wide studiesdinvolving the examination of tens and hundreds of thousands of subjects, been able to identify variants associated with MDD that achieve genome-wide significance (Hyde et al., 2016) (CONVERGE Consortium, 2015). It is possible that these or other genetic variants apply to resilience, but have not yet been elucidated because it is difficult to clearly define a large population of resilient individuals. Epigenetics refers to a host of biological mechanisms that can explain the complex interactions between life experiences and molecular changes at the cellular level and has been proposed to mediate individual differences in response to stress (Akil et al., 2017). Epigenetic changes through DNA methylation, chro- matin modifications, and noncoding RNAs can contribute to alternations in gene expression and therefore affect cellular processes, neural circuits, and behavior (Fig. 15.2).

In this chapter, we focus on literature from animal stress models to elaborate upon the known molecular mechanisms that promote stress resilience. We emphasize studies that concentrate on stress exposure in adulthood and the resulting adaptive changes that prevent the development of behavioral abnormalities reminiscent of MDD. We highlight only the literature that specifically studies the mechanisms of stress resilience and not that of stress susceptibility. Furthermore, we differentiate between resilience, which we associate with active molecular processes that help to mitigate the deleterious influences of stress, from antidepressant-induced molecular changes, which reverse deleterious changes associated with stress susceptibility. Finally, we organize our review by molecular mechanism, examining the broad categories of changes that have been suggested to be involved in stress resilience.

 

214 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

FIGURE 15.2 Epigenetic processes that influence gene expression. Simplified schematic representing epigenetic modifications. DNA exists across the spectrum from tightly spaced nucleosomes (repressed heterochromatin) to more sparsely spaced nucleosomes (active euchromatin), which affects the accessibility of DNA for transcription factor binding and thereby helps set the level of transcription at a given locus. This is regulated in part by DNA modifi- cations such as generally repressive cytosine methylation catalyzed by DNMTs, and generally activating cytosine hydroxymethylation mediated by TET enzymes. Histones tails are also modified in numerous ways, with functional effects on transcription occurring according to the “histone code.” Changes in histone tail methylation are controlled by PRMTs and HMTs, and many HDMs, although changes in histone acetylation are controlled by HATs and HDACs. Noncoding RNAs such as microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are additional epigenetic mechanisms that regulate gene expression. MiRNAs are posttranscriptional regulators that act in the cell cytoplasm to repress target genes through mRNA destabilization or translational repression. lncRNAs work throughout the cell and interact with DNA, RNA, or protein and function as scaffolds, decoys, or regulators. DNMT, DNA methyltransferase; HAT, histone acetyltransferases; HDAC, histone deacetylase; HDM, histone demethylases; HMT, histone methyltransferase; lncRNA, long-noncoding RNA; miRNA, microRNA; PRMT, protein arginine methyltransferases; Tet, tet methylcytosine dioxygenase. Reprinted with permission from © Mount Sinai Health System.

These include DNA and chromatin modifications, alterations in transcription factors, immune- related processes, and molecular changes associated with altered neuronal signaling.

DNA methylation

DNA methylation is a key epigenetic process that regulates gene expression through direct modifications to DNA (Fig. 15.2). DNA methylation is generally associated with diminished gene expression whereby unmethylated genes are more available for transcription (Meaney and Szyf, 2005). On the other hand, certain variant forms of methylation, for example, hydroxymethylation, of DNA are thought to activate gene expression (see below).

 

DNA methylation 215

Several studies suggest a role for changes in DNA methylation in stress resilience. Following CSDS, Elliott et al. found increased methylation in the promoter region of the corticotropin-releasing factor (Crf) gene, involved in stress responses, in control and resilient, but not susceptible, mice in the paraventricular nucleus (PVN) of hypothalamus (Elliott et al., 2010). This increased methylation was associated with lower expression level of Crf, and mimicking this process with shRNA to downregulate Crf in the PVN was pro-resilient in vivo (Fig. 15.3). As such, DNA methylation has the potential to reduce expression of key stress-promoting genes to contribute to stress resilience.

Alterations in DNA methylation enzymes have also been implicated in promoting stress resilience. For example, one correlative study using CSDS reported higher levels of DNA

FIGURE 15.3 Examples of site-specific genetic manipulations of target molecules implicated in behavioral resilience. Summary of the role of some of the specific targets that have been implicated in resilience organized by the brain site in which the molecule was evaluated. cKO, conditional knockout; DN, dominant negative; DR, dorsal raphe; Hipp, hippocampus; KD, knockdown; KO, knockout; NAc, nucleus accumbens; OE, overexpression; PVN, paraventricular nucleus; VTA, ventral tegmental area; Ac3I, EGFP-fused CaMKII inhibitory peptide (Robison et al., 2014); Baz1b, bromodomain adjacent to zinc finger domain 1B (Sun et al., 2016); ß-catenin (Dias et al., 2014); Bdnf, brain-derived neurotrophic factor (Taliaz et al., 2011; Duclot and Kabbaj, 2013; Krishnan et al., 2007); Caspase-1, caspase-1/interleukin-1 converting enzyme (Li et al., 2017); Cdk5, cyclin-dependent kinase 5 (Heller et al., 2016); Crf, corticotropin-releasing factor (Elliott et al., 2010); DFosB, delta FosB (Vialou et al., 2010b; Donahue et al., 2014; Vialou et al., 2010a; Berton et al., 2007; Ohnishi et al., 2015); Dnmt3A, DNA methyltransferase 3A (Hodes et al., 2015); Gdnf, glial cellederived neurotrophic factor (Uchida et al., 2011); GluR2, glutamate receptor 2 (Vialou et al., 2010b); Hdac2, histone deacetylase 2 (Uchida et al., 2011); Hdac6, histone deacetylase 6 (Espallergues et al., 2012); Hsp90, heat shock protein 90 (Jochems et al., 2015); IKK, IkB kinase (Christoffel et al., 2011; Christoffel et al., 2012); Otx2, orthodenticle homeobox 2 (Pena et al., 2017); miR-124 (Higuchi et al., 2016); p38a MAPK, P38 mitogen-activated protein kinases (Bruchas et al., 2011); PTPN5, protein tyrosine phosphatase, nonreceptor type 5 (Yang et al., 2012); Smarca5, SWI/ SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 5 (Sun et al., 2016); SC1, Sparc-like 1 (Vialou et al., 2010b); Tet1, tet methylcytosine dioxygenase 1 (Feng et al., 2017); xCT, cystine- glutamate antiporter (Nasca et al., 2017). Reprinted with permission from © Mount Sinai Health System.

 

216 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

methyltransferase 3A (Dnmt3a), which methylates DNA, in recently differentiated neurons in the dentate gyrus of resilient mice (Hammels et al., 2015). Using the CVS model, Hodes et al. expanded these findings to show a causal role for Dnmt3a in resilience in female mice. In this experiment, conditional knockout (cKO) of Dnmt3a in the nucleus accumbens (NAc) pro- duced pro-resilient effects after CVS, to which female, but not male mice, are normally more susceptible (Hodes et al., 2015) (Fig. 15.3). Interestingly, cKO of Dnmt3a in the NAc of female mice led to dramatic changes in gene expression that made the transcriptome appear more “male-like” (Hodes et al., 2015). As males are inherently more resilient to CVS, these transcriptional changes likely represent a broad pattern of resilience.

Recently, there have been reports on the role of enzymes mediating oxidized forms of DNA methylation, such as hydroxymethylation, as well as demethylation, such as tet meth- ylcytosine dioxygenase 1 (Tet1), in stress resilience (Feng et al., 2017). In this study, Tet1 was found to be downregulated following CSDS in the NAc of susceptible but not resilient mice. However, cKO of Tet1 in NAc had a pro-resilient effect in non-stressed mice (Fig. 15.3). RNAseq data showed an overlap between the transcriptional signature of resilience and cKO of Tet1 in this brain region.

Taken together, these studies suggest that DNA methylation processes play a role in supporting stress resilience. However, further work is needed to demonstrate the role of the enzymes mediating this process across brain regions, sexes, and cell types, as well as identifying the key genomic locations where DNA methylation promotes resilience. Whole-genome bisulfate sequencing approaches now make it possible to obtain this insight in an unbiased fashion.

Chromatin modifications

Histone acetylation and methylation are pivotal processes in switching between repressed heterochromatin and actively translated euchromatin (Fig. 15.2). Several studies have impli- cated histone modifications in promoting stress resilience. In one study, researchers profiled global changes in histone acetylation across multiple brain regions following CSDS in rats, and found that resilient rats show patterns of histone acetylation more similar to control than susceptible rats (Kenworthy et al., 2014). Interestingly, however, the authors also observed that levels of enzymes that modify chromatin were altered more in both susceptible and resilient than in control rats, suggesting that social stress induces certain chromatin mod- ifications independent of behavioral outcomes. In accordance with findings of unique histone modifications in resilient mice, global ChIP-chip analysis (an earlier iteration prior to the development of ChIP-seq; ChIP: chromatin immunoprecipitation followed by DNA sequencing) for the histone 3 (H3) dimethyl K9/K27 mark in the NAc of mice exposed to CSDS revealed opposite patterns of activity for stress resilience and susceptibility (Wilkinson et al., 2009). Moreover, susceptible mice that had been treated with the antidepressant imip- ramine showed a H3K9/H3K27 binding pattern that partly mimicked that of resilient mice. This finding suggests that antidepressants act in part via inducing mechanisms of natural resilience. However, additional studies of H3 subunit dynamics in the NAc have shown a response to chronic stress only in susceptible mice, although they do also demonstrate that blockade of this process promotes resilience in vivo (Lepack et al., 2016).

 

MicroRNAs 217

Enzymes modifying histones, such as histone deacetylase 6 (Hdac6), have also been implicated in stress resilience. Specifically, Hdac6 has been shown to be downregulated in the dorsal raphe (DR) in serotonergic neurons of resilient mice (Espallergues et al., 2012). Accordingly, cKO of Hadc6 in serotonergic neurons was sufficient to increase resilience and mitigated CSDS-induced electrophysiological and morphological alterations, a process that is believed to occur as a result of Hdac6’s interaction with the glucocorticoid receptor (GR) (Espallergues et al., 2012) (Fig. 15.3). Given the wide-ranging role of chro- matin dynamics in resilience, it is perhaps unsurprising that pharmacologic agents that modulate histones, such as the histone acetylation agent N-acetyl-cysteine or histone deace- tylase inhibitors administered into any of several brain regions, can increase resilience (Nasca et al., 2017).

More recent research has begun to focus on nucleosome positioning and the 3D structure of chromatin in response to chronic stress models in rodents (Jiang et al., 2017; Sun et al., 2015, 2016). For example, the chromatin remodeling factor, BAZ1B, which controls the spacing between nucleosomes, is induced in the NAc selectively in mice that are resilient to CSDS, and upon overexpression in this brain region, promotes behavioral resilience (Sun et al., 2016). ChIP-seq analysis of genomic targets of BAZ1B has provided initial insight into the underlying mechanisms involved.

In sum, there is considerable evidence for chromatin modifications playing a role in stress resilience. However, this line of research needs to be expanded by additional ChIP-seq and related genome-wide studies that provide global profiling of chromatin across several limbic brain regions in the context of stress to further elucidate genomic hot spots for resilience.

MicroRNAs

Noncoding RNAs play an important regulatory role in cells (Issler and Chen, 2015). In particular, the subclass of microRNAs (miRNAs), which act as posttranscriptional repressors, has been implicated as a molecular mediator of stress resilience across several brain sites. In the NAc, the miRNAome of mice resilient to CSDS shows substantial differences from that of mice susceptible to CSDS (Dias et al., 2014). With regards to specific transcripts, overexpres- sion of miR-135 in serotonergic neurons within the DR increases resilience to CSDS (Issler et al., 2014), whereas overexpression of miR-124 in the hippocampus increases resilience CVS (Higuchi et al., 2016) (Fig. 15.3). Interestingly, both miR-135 and miR-124 are upregu- lated by antidepressant treatment, but the proposed mechanisms of action for these two transcripts are distinct. Although miR-135 functions in part by repressing serotonin-related genes (Issler et al., 2014), miR-124 has been shown to target histone-modifying enzymes (Higuchi et al., 2016). In addition to miR-124, other miRNA transcripts have also been shown to play a role in stress resilience in the hippocampus, suggesting a broad role for different miRNAs even in the same brain region. For example, miR-455-3p is upregulated and miR30e-3p is downregulated in resilience in rat stress models (Pearson-Leary et al., 2017). Taken together, these diverging effects of stress on different miRNA transcripts suggest that miRNAs have a complex role in resilience. As such, further study of specific miRNA transcripts, as well as other classes of noncoding RNAs, is warranted.

 

218 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms Transcription factors

Binding of transcription factors regulates gene expression and partially explain the broad patterns of transcriptional changes seen in stress resilience (Bagot et al., 2016; Bagot et al., 2017). The transcription factor delta FosB (dFosB), a splice product of the FosB immediate early gene, has been shown to be upregulated in several brain regions in resilient animals following chronic stress (Nestler, 2015). For example, in the learned helplessness paradigm, resilient mice with low escape latency show higher levels of dFosB in the periaqueductal gray (PAG) than mice with high escape latency (Berton et al., 2007). Similarly, mice resilient to CSDS have elevated levels of dFosB in the NAc (Vialou et al., 2010b), which is localized more in medium spiny neurons expressing the dopamine receptor type 1 (D1) than in neu- rons expressing the dopamine receptor type 2 (D2) (Lobo et al., 2013). Viral-mediated gene transfer has provided causal evidence for a role of dFosB in stress resilience (Fig. 15.3). In one study, researchers overexpressed dFosB in the PAG and found it to promote resilient following exposure to inescapable stress, an effect that is mediated by dFosB suppression of substance P expression (Berton et al., 2007). Similarly, overexpression of dFosB in the NAc was found to be pro-resilient after CSDS (Vialou et al., 2010b; Donahue et al., 2014); the proposed mechanism in this case involves induction of the GluA2 AMPA receptor subunit (Vialou et al., 2010b). Interestingly, these effects are cell-type-specific: histone acetylation tar- geted to the FosB gene via use of synthetic zinc finger proteins in D1 neurons was pro-resil- ient, whereas targeted repressive histone methylation opposes resilience, with the opposite effects observed upon targeting D2 neurons (Hamilton et al., 2017). The induction of dFosB in the NAc of resilience mice is mediated in part by serum response factor (Srf), an upstream regulator of the FosB gene, which is activated in the NAc of resilient mice, where it was shown to promote behavioral resilience upon its own overexpression (Vialou et al., 2010a).

In addition to dFosB, transcription factors affecting well-studied molecular pathways, such as the Wnt signaling pathway, have been implicated in stress resilience. Research has shown that this action is also cell-type-specific, as CSDS increases WNT-ß-catenin activity in D2 neurons of the NAc only, with overexpression of ß-catenin selectively in D2 neurons promot- ing resilience (Dias et al., 2014). ChIP-seq of ß-catenin showed enrichment for binding sites in the NAc of resilient mice over susceptible mice, and Dicer 1 (which controls the biogenesis of miRNAs) and numerous specific miRNA targets have been proposed as molecular regulators of ß-catenin in this context (Dias et al., 2014).

Several transcription factors have to date been implicated in stress resilience across multiple brain regions, and it is likely that resilience is the product of numerous transcription factors that interact with chromatin-modifying mechanisms to fundamentally alter the gene expression profile in many brain regions that influence stress responses. Studies using advanced methods such as ChIP-seq, whole-genome bisulfite sequencing, ATAC-seq, and HiC, in combination with RNA-seq, are needed to identify more transcription factors with a role in stress resilience, as well as to define specific molecular interactions that result in the unique global transcriptional profile of resilience (Fig. 15.4).

 

Transcription factors 219

FIGURE 15.4 Schematic model of theoretical molecular changes associated with stress resilience. Behavioral resilience is defined by the preser- vation of a normal control-like phenotype despite stress exposure. For individual molecules, this process can be defined by the restoration of control levels of susceptibility-associated changes (patterns (A) and (B)); by a gradient whereby pro-resilient adaptations are in the opposite direction of susceptibility- associated changes (patterns (C) and (D)); or by changes that are unique to the resilient state (patterns (E )and (F)). The sum of these many changes, all of which have been observed experimentally, is that the molecular profile of stress resilience is not merely the restoration of the control state, but instead a unique, active adaptive response.

 

220 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms Immune-related processes

Alternations of the peripheral and central immune system have been linked to stress resil- ience across multiple studies. Within the brain, microglia, which are derived from peripheral macrophages, play a role in immune surveillance and synaptic pruning and have been impli- cated in resilience. For example, one study showed that although susceptible mice have elevated levels of microglia and proinflammatory cytokines in the prefrontal cortex (PFC), resilient mice have levels similar to those of nonstressed controls (Couch et al., 2013). Addi- tionally, several independent studies have shown that KO of the chemokine receptor Cx3cr1, which is expressed in the brain exclusively in microglia, promotes stress resilience (Hellwig et al., 2016; Rimmerman et al., 2017; Milior et al., 2016) by altering the expression of immunity-related genes, as well as synaptic function.

Peripheral immune regulators also have been implicated in resilience. Lower levels of the circulating proinflammatory cytokine IL-6 were found to be predictive of individual stress resilience in mice (Hodes et al., 2014). Interestingly, inhibiting IL-6 in the periphery by IL-6 KO, bone marrow transplantation from an IL-6 KO mouse, or treating mice systemically with antibodies against IL6, increases behavioral resilience to CSDS (Hodes et al., 2014). Similarly, transferring lymphocytes from mice that are resilient to stress to stress-naïve mice confers resilience, and is associated with increased hippocampal neurogenesis, reduced levels of proinflammatory cytokines and blunted microglia reactivity (Brachman et al., 2015).

Together, these findings provide evidence of the interplay between the immune system and the brain in the context of stress resilience. As such, the study of potential mechanisms and treatment avenues for stress-related disorders extends beyond the brain and should not be limited to targeting CNS mechanisms.

Neurotrophic factors

Neurotrophic factors such as brain-derived neurotrophic factor (Bdnf) and glial cellederived neurotrophic factor (Gdnf) have been shown to be important for stress resilience across several brain regions. For example, in the VTA-NAc projection, lower levels of Bdnf have been associated with stress resilience (Krishnan et al., 2007). Within the NAc, expression levels of Bdnf in resilient mice are similar to control levels, but susceptible mice show Bdnf induction in response to CSDS. Knocking down Bdnf in the NAc does not affect stress resil- ience, but knocking down Bdnf in the VTA is sufficient to increase behavioral resilience (Ber- ton et al., 2006). Moreover, mutant mice homozygous for the human variant Met/Met polymorphism (compared with the wild-type Val/Val at amino acid 66)dwhich display decreased Bdnf function in the VTA-NAc pathwaydalso show enhanced stress resilience (Krishnan et al., 2007).

In contrast to the mesolimbic dopamine system, Bdnf has been shown to be pro-resilient in the hippocampus across multiple studies (Duman et al., 1997; Monteggia et al., 2004, 2007; Taliaz et al., 2011; Duman, 2014). In rats, overexpression of Bdnf in the hippocampus increases resilience to CVS, and Bdnf knockdown in this region promotes susceptibility (Taliaz et al., 2011). This may be the result of epigenetic changes in Bdnf exon VI, which results in baseline upregulation of Bdnf in resilient animals (Duclot and Kabbaj, 2013).

 

 

Circuit-related molecules 221

The opposing effects of Bdnf in different brain sites may be due to the opposite consequences of its effects on strengthening glutamatergic synapses in different brain regions, as well as its unique role in promoting neurogenesis in the hippocampus.

Gdnf levels are reported to vary in mouse strains with different inherent levels of stress susceptibility. C57BL/6 mice, which are more resilient to CVS, show higher levels of Gdnf in the striatum than BALB/c mice, which are more susceptible to this form of stress (Uchida et al., 2011). Accordingly, overexpression of Gdnf in the NAc of BALB/c mice is pro-resilient. It has been proposed that these differences in Gdnf may be a result of epigenetic changes at the Gdnf promoter in resilient mice (Uchida et al., 2011).

Circuit-related molecules

Stress resilience and susceptibility are associated with numerous circuit-level changes, and specific molecular regulators have been directly implicated in mediating changes in neuronal circuitry in the context of stress. For example, susceptibility to CSDS has been linked to increased phasic firing in VTA dopamine neurons that project to the NAc, a phenomenon not seen in resilient mice (Chaudhury et al., 2013). Optogenetic suppression of the activity of this circuit promotes resilience, whereas its activation mimics susceptibility. The increased excitability of VTA dopamine neurons seen in susceptible mice is mediated in part by increased hyperpolarization-activated cation current (Ih), and direct inhibition of Ih in these neurons exerts pro-resilient and antidepressant-like effects (Cao et al., 2010). Paradoxically, resilient mice show an even larger increase in Ih current, as well as activation of several potassium channels, as compared with either control or susceptible mice, demonstrating that resilient mice have unique adaptations in several types of ion channels that actively promote behavioral resilience (Friedman et al., 2014). Importantly, very different adaptations occur in VTA dopamine neurons in response to different types of chronic stress (see (Tye et al., 2013)), underscoring the importance of considering the type, duration, and severity of the stress used in a rodent model.

Molecular regulation of different inputs to the VTA-NAc reward circuit has been shown to contribute to resilience. Optogenetic stimulation of ventral hippocampus (vHIP) inputs to the NAc increases susceptibility to CSDS, while stimulating inputs to the NAc from either the PFC or basolateral amygdala (BLA) promotes resilience (Bagot et al., 2015). Accordingly, mol- ecules that enhance signaling, such as sidekick cell adhesion molecule 1 (Sdk1), which increases the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in affected pyramidal neurons, increases susceptibility when overexpressed in the vHIP, but resilience when overexpressed in the PFC (Bagot et al., 2016).

Molecular adaptations seen in the context of behavioral resilience have been associated with changes in neuronal morphology, particularly dendritic spines, in several brain regions. For example, Yang et al. (2012) identified reduced dendritic spine density in the rat hippocampus 1 week after acute stress in susceptible, but not resilient, rats (Yang et al., 2012). By examining levels of protein tyrosine phosphatase nonreceptor 5 (PTPN5) in this region, they found that spine density was positively correlated with PTPN5 expression, which was significantly reduced in susceptible compared with resilient rats. Furthermore, shRNA knockdown of PTPN5 produced a susceptible-like reduction in spine density, whereas overexpression of PTPN5 mimicked the spine density profile of resilience. However, the

 

222 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

consequence of changes in spine density in affecting susceptibility-resilience is region specific. In the NAc, CSDS increases spine density in susceptible compared with resilient mice (Christoffel et al., 2011). This effect was driven largely by increases in immature stubby spines and was associated with higher frequencies of mini EPSCs in susceptible versus resilient mice. These morphological and functional changes were linked to increased expression of IkB kinase (IKK), a downstream target of Bdnf. Viral overexpression of a dominant negative IKK mutant in NAc was sufficient to reverse CSDS-induced increases in spine density in previously susceptible mice and to enhance behavioral resilience.

Similarly, in the BLA, rats susceptible to a prolonged course of restraint stress showed increased dendritic arborizations (Vyas et al., 2006). Other studies have shown that repeated stress is associated with BLA hyperexcitability and that this process is not seen in resilient rats (Hetzel and Rosenkranz, 2014). These changes in morphology and electrophysiology may be a direct result of neurotransmitter function, as mutations of the NMDA receptor N2A subunit, but not the AMPA GluA1 subunit, reduce dendritic spine density in the BLA and are associated with a reduction in anxiety-like responses to stress in mice (Mozhui et al., 2010). Taken as a whole, these studies indicate that dendritic density in the BLA is inversely related to stress resilience, with progress being made in identifying some of the molecular mediators involved.

Glutamatergic modifications in other brain regions have been functionally linked to stress resilience. In the hippocampus, higher expression of the AMPA receptor subunit GluA1 and decreased AMPA binding have been associated with behavioral measures of stress resilience in mice, with polymorphisms in the GluA1 gene correlating with stress susceptibility (Schmidt et al., 2010). Similarly, GluA2 knockout increases susceptibility and individual variations in GluA2 levels in the hippocampus explain endophenotype differences among high-susceptible and low-susceptible mice following CVS (Nasca et al., 2015). Interestingly, inhibitory circuitry appears to play a role in stress resilience; for example, heterozygous mutations in the GAD65 GABA-synthesizing enzyme confer resilience to behavioral stress in mice (Muller et al., 2014). Finally, as noted earlier, DFosB-mediated induction of GluA2 in D1 medium spiny neurons of NAc promotes behavioral resilience (Vialou et al., 2010b). These findings provide a mechanism by which individual molecular changes can directly alter neuronal morphology and circuit-level function to affect pro-resilient behavior.

Genome-wide studies

As mentioned throughout this chapter, high-throughput profiling approaches are now being utilized in the study of resilience. Unlike candidate gene approaches, tools such as microarrays, RNA-seq, ChIP-seq, and several other sequencing-based methods, and mass spectroscopy provide an unbiased view on the molecular, epigenetic, and biochemical land- scape associated with stress resilience within individual brain regions of interest. Such studies are a great resource for future investigations, particularly because they identify large-scale patterns of changes that can pinpoint similarities and differences across multiple brain sites and behavioral phenotypes. To date, however, these studies are limited in number (Table 15.1). A major need moving forward is to extend these genome-wide studies to individ- ual cell types within a targeted brain region, to capture the cell typeespecific changes that are likely associated with resilience in different types of neurons, glia, and endothelial cells.

 

Stress Animal model model

CSDS Male
mice VTA

CSDS Male
mice AMY Hip

CSDS Male
mice AMY Hip

CSDS Male mice

CSDS Male mice

CSDS Male mice

CSDS Male mice

CSDS Male mice

CSDS Male mice

SCVS Female mice

CUS Male mice

AUS Male rats

Repeated Male restraint mice

NAc

NAc NAc NAc NAc NAc

NAc Hip

PFC Hip

Hip AMY PFC

Brain site tested

Platform

microarray

RNA-seq

RNA-seq

RNA-seq

RNA-seq

Small RNA-seq

ChIP-seq ChIP-seq ChIP-seq

RNA-seq RNA-seq

microarray RNA-seq

Main findings

A larger number of genes are regulated in resilience than in susceptibility.
The transcriptional profile of susceptible and resilient mice shows limited overlap.

A larger number of genes are regulated in resilience than in susceptibility.
There is a high degree of correspondence between
gene changes in the NAc and PFC in resilient mice.

The transcriptional signature of the antidepressants imipramine and ketamine is similar to that of resilient mice, particularly in the PFC.

The blockade of H3.3 in the NAc promotes resilience and is mediated via regulation of synaptic-related genes.

There is a strong similarity between genes regulated in resilience and genes affected by cKO of Tet1.

B-catenin-dependent microRNA regulation is associated with resilience.

There is more binding of B-catenin to gene promoters in resilient mice versus susceptible mice.

Increased DNA binding by BAZ1B in resilient mice compared to both control and susceptible.

The binding profile of CREB and the H3 methylation profile in resilient mice is different from that of susceptible mice, but overlaps with that of imipramine treatment.

cKO of Dnmt3a in females is pro-resilient and shifts the transcriptome to more male-like state.

Cx3cr1 KO mice are stress resilient and this is associated with changes in interferon, MHC class I and estrogen receptor signaling pathways.

There is low overlap in genes regulated between resilient, susceptible, and control groups.

Strain differences associated with stress resilience and with robust changes in baseline gene expression. Stress is associated with induction of genes associated with the neurotransmitter glutamate.

Reference

Krishnan
et al. (2007)

Bagot et al. (2016)

Bagot et al. (2017)

Lepack et al. (2016)

Feng et al. (2017)

Dias et al. (2014)

Dias et al. (2014)

Sun et al. (2016)

Wilkinson et al. (2009)

Hodes et al. (2015)

Rimmerman et al. (2017)

Benatti et al. (2012)

Mozhui
et al. (2010)

(Continued)

NAc PFC

NAc PFC

Future directions 223

TABLE 15.1 Studies using high-throughput methods for profiling molecular changes associated with chronic stress resilience in animal models.

 

NAc

 

224 15. Molecular characterization of the resilient brain: transcriptional and epigenetic mechanisms

TABLE 15.1 Studies using high-throughput methods for profiling molecular changes associated with chronic stress resilience in animal models.dcont’d

Stress Animal model model

CMS Male rats

CMS Male rats

CMS Male rats

Brain site tested

Hip
Hip MS

PFC MS

Main findings

Resilient rats show increased expression of immune- related and signaling-related genes.

The global protein expression profile is different in resilient and susceptible rats.
Resilient rats show increased activity related to oxidative phosphorylation.

Protein changes associated with resilience involve glutamatergic transmission, the Na/K-transporter and cellular respiration.

Platform

Reference

Bergstrom et al. (2007)

Henningsen et al. (2012)

Palmfeldt et al. (2016)

  

microarray

AMY, amygdale; AUS, acute unavoidable stress; ChIP-seq, chromatin immunoprecipitation followed by DNA sequencing; cKO, conditional knockout; CMS, chronic mild stress; CSDS, chronic social defeat stress; CUS, chronic unpredictable stress; Cx3cr1, CX3C chemokine receptor 1; Dnmt3A, DNA methyltransferase 3A; H3, histone 3; Hip, hippocampus; KO, knockout; MS, mass spectrometry; NAc, nucleus accumbens; PFC, prefrontal cortex; RNA-seq, RNA sequencing; SCVS, subchronic variable stress; Tet1, tet methylcytosine dioxygenase 1; VTA, ventral tegmental area.

Future directions

The last decade has been very fruitful in terms of elaborating the molecular changes that define stress resilience. However, additional mechanistic studies are needed. For example:

–  There are profound sex differences in stress-induced psychiatric disorders, with females being more likely than males to develop these diseases (Hodes et al., 2017). However, most of the mechanistic studies to date focus exclusively on males. Key questions involve the following: Why are males more resilient than females to certain types of stress para- digms, but not others? Are the molecular mechanisms promoting resilience sex-specific? This is likely, given the results of a recent large-scale RNA-seq study of multiple brain regions in depressed men and women, and in chronically stressed male and female mice, which demonstrated dramatic sex differences in gene expression abnormalities associated with depression and stress (Labonte et al., 2017).

–  Most of the studies described in this review were performed on microdissection of bulk tissue. However, the brain is an extremely heterogeneous organ composed of multiple cell types with very different cellular functions. Methodological advances such as ribo- some affinity purification (TRAP) (Heiman et al., 2008), neuronal fluorescence-activated cell sorting (FACS) (Cahoy et al., 2008), and single cell drop sequencing (Drop-seq) (Macosko et al., 2015) should now be utilized to explore cell typeespecific molecular alternations associated with stress resilience.

–  A common methodological approach used to study the role of specific genes in stress resilience is viral-mediated overexpression or knockdown of that gene within a given brain region, or cell type. However, with this approach, the targeted gene is often manipulated to a much greater in extent (up or down) than the physiological change observed in vivo. Technological advances such as modified zinc finger proteins

 

References 225

(Heller et al., 2014), (Hamilton et al., 2017) or CRISPR/Cas9 can now be used to mimic endogenous molecular interactions to more clearly delineate the necessity and suffi- ciency of particular mechanisms of resilience.

Summary

The molecular basis of stress resilience is complex, with numerous brain regions and enumerable molecular mediators involved. Although resilience appears to restore control- like behavior, multiple studies point to active processes occurring at the molecular level to compensate for, bypass, or overcome the harmful effects of stress (Fig. 15.4). Such unique mechanisms of stress resilience are the product of interactions between genetics and the environment. Delineating the complex interactions between the genetic, epigenetic, and environmental factors promoting stress resilience is essential to understand this complex phenotype and can bring us one step closer to leveraging these molecular mechanisms to develop better ways to prevent and treat MDD and other stress-related conditions.

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CHAPTER

16

The role of the CRF-urocortin system in stress resilience

Marloes J.A.G. Henckens1, Jan M. Deussing2,

Alon Chen2, 3
1Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour,

Radboudumc, Nijmegen, The Netherlands; 2Department of Stress Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; 3Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

Introduction to the corticotropin-releasing factor/urocortin system

Decades of research indicate that corticotropin-releasing factor (CRF) is an essential medi- ator of the behavioral, endocrine, and autonomic response to stress (Dunn and Berridge, 1990). Upon stress exposure, CRF is rapidly released from the paraventricular nucleus (PVN) of the hypothalamus into the periphery to activate the hypothalamic-pituitary-adrenal (HPA) axis by stimulating the release of adrenocorticotropic hormone from the anterior pitu- itary, which then triggers the synthesis and secretion of corticosteroids (cortisol in humans, corticosterone in rodents) from the adrenal gland (Vale et al., 1981). CRF release also con- tributes to the sympathetic response to stress by activating noradrenergic neurons in the locus coeruleus (LC) (Valentino et al., 1993)dthe principal site for brain synthesis of noradrenalinedand acting on the adrenal medulla and peripheral sympathetic response system (Brown et al., 1982). However, besides the peripherally-mediated actions of CRF, its central release also contributes directly to the necessary adaptive behavioral response to stressful challenges by inducing increased vigilance, which eventually transitions into a state of anxiety (Bale and Vale, 2004). Increased central CRF levels induced either by intracere- broventricular administration or by genetic overexpression (OE) in transgenic mice are associated with an anxiogenic phenotype, whereas the suppression of CRF signaling (e.g., by the administration of CRF antisense oligodeoxynucleotides or receptor antagonists) induces anxiolytic effects and reduces stress-induced anxiety (see Reul and Holsboer, 2002, and Bale and Vale, 2004 for excellent reviews on this work). The observation of elevated

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00016-1 233 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

234 16. The role of the CRF-urocortin system in stress resilience

CRF levels in the cerebrospinal fluid (CSF), increased numbers of PVN CRF-expressing neu- rons, as well as PVN Crf mRNA in patients suffering from stress-related psychopathology, such as major depressive disorder (MDD) (Nemeroff et al., 1984; Raadsheer et al., 1994, 1995; Hartline et al., 1996; Wang et al., 2008) or posttraumatic stress disorder (PTSD) (Bremner et al., 1997; Baker and Shalhoub-Kevorkian, 1999), has implicated CRF/UCN sys- tem abnormalities in the pathophysiology of these disorders. Supporting this association, ab- normalities appear to normalize with electroconvulsive therapy (Nemeroff et al., 1991) and successful antidepressant treatment (De Bellis et al., 1993; Veith et al., 1993; Heuser et al., 1998). Notably, persistent elevations of CSF CRF concentration in symptomatically improved depressed patients are associated with early relapse of depression (Banki et al., 1992). The HPA axis hyperactivity reported in depressed patients (Ising et al., 2007; Holsboer, 2003) has further substantiated the interest in the role of the CRF/urocortin (UCN) system in sus- ceptibility to stress-related mental disease.

The corticotropin-releasing factor/urocortin system as a critical mediator of the behavioral stress response

The CRF ligand family members exert their actions by binding two G proteinecoupled receptors, CRF receptor subtype 1 (CRFR1) and 2 (CRFR2). CRF has highest affinity for CRFR1 and a >20-fold lower affinity for CRFR2, which is preferentially activated by urocortin 2 (UCN2) and 3 (UCN3), whereas urocortin 1 (UCN1) binds both receptors with equal affinity (Fig. 16.1A). The ligands all display unique, partially overlapping, expression patterns throughout the brain (Fig. 16.1B). Crfr1 mRNA is abundantly expressed in the anterior pituitary, steering HPA axis activation, but also throughout the brain, with highest levels in the cerebellum and neocortical, limbic, midbrain, and brainstem regions (Van Pett et al., 2000), whereas Crfr2 mRNA is more locally expressed and virtually confined to subcortical structures (Fig. 16.1C). The anxiogenic effects of CRF have traditionally been attributed to the activation of CRFR1; its inhibition by pharmacological means prevents the CRF-induced anxiogenic phenotype (Skutella et al., 1998; Liebsch et al., 1999; Habib et al., 2000; Zorrilla et al., 2002). Conversely, constitutive inactivation of CRFR1 in developmental knockout mice reduces anxiety-like behavior as assessed in a wide variety of behavioral tests (i.e., open field, elevated plus maze, light-dark box, or defensive withdrawal) (Smith et al., 1998; Timpl et al., 1998; Contarino et al., 1999; Muller et al., 2003). These findings, together with the observation of increased PVN CRFR1 mRNA levels in patients suffering from depression (Wang et al., 2008), suggested a causative role for CRFR1 hyperactivation in stress-related psychopathologies and fostered the development of CRFR1 antagonists as potential next- generation anxiolytics and antidepressants (Holsboer, 1999; Zobel et al., 2000). In contrast, CRFR2 was thought to contribute to stress coping behavior and termination of the stress response, opposing CRFR1-mediated actions and restoring homeostasis. Crfr2 knockout mice display elevated corticosterone levels in response to stress (Bale et al., 2000; Coste et al., 2000), an anxiogenic phenotype (Bale et al., 2000; Kishimoto et al., 2000), and impaired stress recovery (Issler et al., 2014). However, many findings seem to contradict these circu- lating views on CRFR signaling and rather suggest a higher degree of complexity with the effects of CRFR activation being brain region specific, cell type specific, and synapse specific

 

The corticotropin-releasing factor/urocortin system as a critical mediator of the behavioral stress response 235

FIGURE 16.1 The CRF/UCN family. Following the initial discovery of CRF, several other members of the mammalian CRF-related peptide family were identified; urocortin 1 (UCN1), UCN2 (or stresscopin-related peptide), and UCN3 (or stresscopin), and some nonmammalian peptides (Dautzenberg and Hauger, 2002). This family of CRF- related peptides exerts its actions by binding the G proteinecoupled receptors CRFR1 and CRFR2. CRFR1 and CRFR2 are expressed in various central and peripheral tissues and are produced from distinct genes and have several splice variants (CRFR1a,b, and CRFR2a,b,g) of which several are nonfunctional (Grammatopoulos and Chrousos, 2002; Keck, 2006; Perrin and Vale, 1999). The receptors exhibit w70% sequence homology, with predominant structural differences in the ligand-binding domain, inducing distinctive ligand-binding profiles. (A) CRF is a high- affinity ligand for CRFR1. UCN1 binds with equal affinity to both receptors, whereas UCN2 and UCN3 are exclusive ligands of CRFR2. However, specificity is lost at higher concentrations of the ligand, with CRF activating CRFR2 and UCN2 acting on CRFR1. CRF-binding protein (BP) binds CRF and UCN1 with an affinity equal to or even higher than that of its receptors and therefore is an important indirect regulator of CRFR activation. (B) Schematic representation of Crf, Ucn1, Ucn2, Ucn3 mRNA expression in a sagittal section of the rodent brain. (C) Schematic representation of Crfr1, Crfr2, and Crf-BP mRNA distribution in a sagittal section of the rodent brain. Key: 7, facial nucleus; 12, hypoglossal nucleus; A1, A1 noradrenaline cells; A5, A5 noradrenaline cells; Amb, ambiguous nucleus; Arc, arcuate nucleus; BAR, Barrington’s nucleus; Basel G, basal ganglia; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; Cereb, cerebellum; CingCx, cingulate cortex; CoA, cortical amygdala; DBB, diagonal band of Broca; DMH, dorsomedial hypothalamus; EW, Edinger-Westphal nucleus; FrCx, frontal cortex; GP, globus pallidus; Hip, hippocampus; IC, inferior colliculus; IO, inferior olive; IPN, interpeduncular nucleus; LC, locus coeruleus; LDTg, laterodorsal tegmental nucleus; LS, lateral septum; LSO, lateral superior olive; MeA, medial amygdala; MePO, medial preoptic area; MGN, medial geniculate nucleus; MS, medial septum; NAc, nucleus accumbens; NI, nucleus incertus; NTS, nucleus of the solitary tract; OB, olfactory bulb; OT, olfactory tubercle; OccCx, occipital cortex; PAG, periaqueductal gray; ParCx, parietal cortex; PB, parabrachial nucleus; PFA, perifornical area; PG, pontine gray; Pir, piriform cortex; PM, premammillary nucleus of the hypothalamus; PPTg, pedunculopontine tegmental nucleus; PVN, paraventricular nucleus of the hypothalamus; R, red nucleus; RN, raphe nucleus; RTN, reticular nucleus; SC, superior colliculus; SI, substantia innominata; SN, substantia nigra; SON, supraoptic nucleus; SP5n, spinal trigeminus nucleus; SPO, superior paraolivary nucleus; VMH, ventromedial hypothalamus; VTA, ventral tegmental area.

 

236 16. The role of the CRF-urocortin system in stress resilience

and moreover dependent on the organism’s (stress) history (Henckens et al., 2016). This might also relate to the observation that the latest clinical trials failed to demonstrate sufficient therapeutic efficacy of CRFR1 antagonists, although it is possible that more refined treatment strategies, including patient stratification, could help to overcome the currently halted CRFR1 antagonist development (Binneman et al., 2008; Paez-Pereda et al., 2011; Murrough and Charney, 2017; Dunlop et al., 2017).

The emergence of new neurobiological tools, such as conditional mutagenesis, viral manipulations, and optogenetics, has allowed site-specific investigation of CRFR activation to investigate the contribution of local CRF/UCN dysfunction in closer detail. In these studies, particular focus has been attributed to its role in the PVN, amygdala, and hippocam- pus. These regions are key in the initiation and control of the neuroendocrine and behavioral response to stress; they all express CRFR1 and are sources of CRF-containing neurons that are activated by stress (Koob and Heinrichs, 1999; Chen et al., 2004).

The PVN, a crucial hub in the regulation of the HPA axis, is characterized by high expres- sion levels of CRF, and also UCN1, UCN2, CRFR1, and CRFR2 mRNA expression is locally observed to some extent. Activation of PVN CRF-expressing neurons initiates the behavioral as well as the HPA axis response to stress, whereas their inhibition by negative glucocorticoid feedback importantly contributes to its termination (Liposits et al., 1987; Uht et al., 1988; Herman et al., 1990). Local CRFR1 expression in the PVN also has an anxiogenic effect, albeit only in male rats (Fan et al., 2013).

In the amygdala, CRF expression is restricted to the central nucleus (CeA) and the bed nucleus of the stria terminalis (BNST). The CeA is the major output nucleus of the amygdala, controlling the expression of innate behaviors and physiological responses (LeDoux et al., 1988), and the BNST is involved in sustained states of anxiety (Davis, 1998). CRFR1 is observed in all amygdalar subnuclei, with highest levels in the basolateral nucleus (BLA), which is involved in fear learning and fear memory consolidation (Roozendaal et al., 2009), and anterior BNST, followed by the medial and central nuclei (Van Pett et al., 2000). Amygdalar CRFR1 activation has been found to increase anxiety-like behavior during social interaction (Sajdyk et al., 1999; Gehlert et al., 2005; Spiga et al., 2006), augment pain responses (Ji et al., 2013) and pain-related anxiety (Ji et al., 2007), increase inhibitory avoidance behavior (Vicentini et al., 2014), reduce feeding and increase grooming behavior (Jochman et al., 2005), and induce fear-potentiated startle, while impairing prepulse inhibition (Bijlsma et al., 2011). Moreover, CRF in the BLA contributes to stress-enhanced fear memory consolidation (Roozendaal et al., 2002) through CRFR1 binding (Hubbard et al., 2007) by interacting with the b-adrenoreceptor-cyclic AMP cascade, facilitating modulation by noradrenaline in the region (Roozendaal et al., 2008). Interestingly, the anxiolytic effects of environmental enrichment were associated with very low Crfr1 mRNA levels in the BLA, implicating amygdala CRFR1 expression as a substrate by which diverse environmental factors can modify behavior.

Similar to the amygdala, hippocampal function is potentiated by local CRF signaling as well; both fear learning (Blank et al., 2002) and the retention of fear memory (Hung et al., 1992) are enhanced by hippocampal CRF. Moreover, local CRF increases defensive responses and anxiety during conditioned and unconditioned threat (Pentkowski et al., 2009).

Taken together, these studies implicate the CRF/UCN system in orchestrating the stress response by regulating both behavioral and neuroendocrine reactions to an acute challenge.

 

The corticotropin-releasing factor/urocortin system mediates stress vulnerability caused by chronic stress exposure 237

These responses enable an organism to optimally adapt to a threatening/changing environ- ment and benefit survival, but the maintenance of this stressed, anxiety-like state irrespective of the environment is highly maladaptive and can have severe consequences for general health. Prolonged exposure to stress, or stress exposure during critical periods in develop- ment, can induce such a state and are prominent risk factors for stress-related mental illness (de Kloet et al., 2005; Nestler et al., 2016). The behavioral, neuroendocrine, and neuroplastic consequences of both chronic stress and early-life stress (ELS) therefore provide an interesting substrate for interrogating stress resilience and susceptibility.

The corticotropin-releasing factor/urocortin system mediates stress vulnerability caused by chronic stress exposure

Two important animal models of chronic stress are chronic social defeat stress and chronic variable stress. Chronic social defeat stress is a paradigm in which an intruder animal is repeatedly placed in the cage of a dominant conspecific in a manner that allows for nonlethal conflict (McLaughlin et al., 2006). Chronic variable stress involves repeated exposure to physical stressors, such as restraint, foot shock, or cold (Willner, 2005). Both of these para- digms induce a behavioral state that mimics symptoms of depression, that is, social avoid- ance, anhedonia, weight loss, disturbed sleep, as well as increased CRF levels and HPA axis activation (Chappell et al., 1986; Krishnan et al., 2007; Pulliam et al., 2010; Page et al., 2016; Wells et al., 2017). Moreover, these chronic stressors increase anxiety and potentiate startle responses (Pulliam et al., 2010; de Andrade et al., 2013), resembling observations in PTSD (Glover et al., 2011). Furthermore, impairments in learning and memory are observed as a consequence of chronic stress (Wang et al., 2011a) and are also observed in stress-related psychiatric disorders (Brewin et al., 2007; de Kloet et al., 2005).

ELS exposuredfor example, prenatally by stress in the mother or postnatally by maternal separation or impoverished maternal care induced by the limited availability of nesting material (Rice et al., 2008)dinduces a similar behavioral phenotype (Graham et al., 2011), as well as increased CRF levels and HPA axis (re)activity in adulthood (for review, see van Bodegom et al., 2017).

In terms of mechanisms, exposure to ELS as well as chronic variable stress reduces the expression of the glucocorticoid receptor (GR) in the PVN, which may mediate the upregulation of CRF expression during chronic stress (Bingham et al., 2013; Makino et al., 1995; Herman et al., 1995). However, the observation of elevated CRF in the absence of GR mRNA downregulation in some stress regimens suggests that other mechanisms may also contribute to driving PVN gene expression (Herman and Tasker, 2016). A recent study pointed toward a potential role for local CRFR1-expressing neurons in modulating activation of local CRF neurons, as they reside in close proximity of the CRF neurons and are of an apparent GABAergic phenotype (Ramot et al., 2017). CRFR1 expression in these neurons is positively regulated by glucocorticoids, generating a second mechanism for feedback inhibition. Although PVN CRFR1 is not essential for the regulation of basal anxiety and HPA axis responses to acute stress, it can modulate the response to chronic stress and contribute to the resulting increase in corticosterone levels and anxiety-like behavior (Ramot et al., 2017). Besides the potential local inhibitory regulating circuits,

 

238 16. The role of the CRF-urocortin system in stress resilience

activity of CRF neurons is influenced by excitatory synaptic inputs. Early-life environment is capable of inducing synaptic rewiring, modifying the number and function of excitatory synapses onto these CRF neurons, and lastingly affecting their function (Korosi et al., 2010; Gunn et al., 2013). Chronic stress and ELS-induced alterations in the (local) CRF/UCN system in the PVN thereby seem to contribute to stress sensitivity.

In the amygdala, chronic stress exposure and ELS induce dendritic growth (Vyas et al., 2002, 2003; Henckens et al., 2015), increase spine density (Suvrathan et al., 2014), enhance amygdala excitability (Rau et al., 2015) and long-term potentiation (Suvrathan et al., 2014), and exaggerate amygdala activation in both safe and fearful contexts (Hoffman et al., 2014), while contributing to an anxiety-like behavioral phenotype (McEwen, 2012). Research investigating the effects of (sub)chronic CRF/UCN or CRFR1 antagonist infusion into the distinct amygdalar subnuclei has revealed a prominent role of the CRF/UCN system in mediating these amygdala-controlled behavioral effects. CRF knockdown (KD) or local blockage of CRFR1 signaling in the CeA was observed to reduce stress-induced anxiety (Regev et al., 2012; Liebsch et al., 1995), suppresse chronic pain-induced anxiety (Ji et al., 2007), and prevent stress-induced hyperalgesia (Itoga et al., 2016), whereas CRF-OE in the CeA increased anxiety- and depressive-like behavior (Keen-Rhinehart et al., 2009). CRFR1 inhibition in the BNST was found to reduce chronic stresseinduced anxiety, hyperalgesia, and HPA axis activation (Tran et al., 2014), whereas CRF-OE in the BNST induced depressive-like behavior and was associated with increased Crfr1 mRNA expression levels (Regev et al., 2011). In the BLA, specific KD of CRFR1 was shown to decrease anxiety levels (Sztainberg et al., 2010), whereas repeated administration of UCN1 in the BLA inducde a persistent state of anxiety- or panic-like symptoms in the rat (Sajdyk et al., 1999; Shekhar et al., 2003; Rainnie et al., 2004), which was associated with a hyperexcitable BLA network that was NMDA receptor dependent and calcium calmodulinedependent protein kinase II (CaMKII) dependent (Rainnie et al., 2004). Inter- estingly, previous chronic stress exposure changed the response of the amygdala to a new CRF challenge. The CRF-induced potentiation of afferent activation of the BLA as observed in stress-naïve animals was reduced in rats with a history of chronic stress, and this reduction predicted the development of depressive-like symptoms as a consequence of the stress procedure (Sandi et al., 2008). Further analyses revealed that this reduction was greatest in highly anxious rats. These rats displayed increased amygdalar Crfr1 mRNA levels and CRF-mediated potentiation prior to the stress procedure, which were both significantly reduced following stress. The administration of a CRFR1 antagonist prevented the attenuated CRF response. The reduced acute response to CRF as a consequence of chronic stress was previously linked to a depressive-like phenotype, as this response in stress-naïve animals typically reduces behavioral despair as displayed in the tail suspension and forced swim test (Swiergiel et al., 2008). Interestingly, treatment with a CRFR1 antagonist was most effective in the highly anxious rats, which is in line with other reports (Lancel et al., 2002; Heinrichs and Koob, 2004; Keck et al., 2005), implicating that anxious patients (or those with a history of stress) displaying sensitive CRFR1 signaling might actually benefit most from treatment with CRFR1 antagonists (Hauger et al., 2006; Sanders and Nemeroff, 2016). This association might also be modulated by differential genetic background, influencing the CRF/UCN system’s sensitivity to stress (Anisman et al., 2007).

 

Corticotropin-releasing factor/urocortin system mechanisms influencing resilience 239

Hippocampal function is impaired by chronic stress, which is reflected in learning and memory deficits, depressed hippocampal synaptic transmission, blocked activity-induced polymerization of spine actin, and impaired synaptic plasticity in hippocampal slices (for review, see Chen et al., 2013). Many of these effects have been attributed to CRF, as chronic CRF exposure was found to deplete thin dendritic spines (i.e., the so-called “learning spines”) in the hippocampus through destabilization, resulting in a reduction of small, potentiation-ready excitatory synapses (Chen et al., 2013). This reduction in dendritic spine density was dependent on CRFR1-induced activation of NMDA receptors, which recruit the calcium-dependent enzyme calpain, triggering the breakdown of spine actin-interacting proteins (Andres et al., 2013) and on the CRFR1-mediated reduction of the hippocampal cell adhesion molecule nectin-3 (Wang et al., 2013). The involvement of CRFR1 in mediating the behavioral consequences of chronic stress is further substantiated by a greatly suppressed chronic stresseinduced phenotype in conditional forebrain CRFR1 knockout (CRFR1-CKO) mice. Mice with forebrain CRFR1 deficiency showed much milder memory impairments and normal hippocampal dendritic morphology and nectin levels as a consequence of chronic stress than their wild-type counterparts (Wang et al., 2011a). Similarly, part of the ELS-induced phenotype was dependent on CRFR1 signaling; conditional CRFR1 deletion or CRFR1 antagonist treatment prevented the typical reduced body weight gain during development and adulthood and attenuated the anxiogenic effects of ELS. In addition, the forebrain-restricted CRFR1 deficiency restored cognitive function, hippocampal long-term potentiation, and spine density (Ivy et al., 2010; Wang et al., 2011b). Along these lines, the impairments in learning and memory were mimicked by postnatal forebrain-specific CRF-OE (Wang et al., 2011b). Importantly, acute trauma (i.e., severe stress) seems to induce a similar cognitive impairment and associated decrease in hippocampal neuronal excitability, which were prevented by repeated administration of a selective CRFR1 antagonist (Philbert et al., 2013).

Overall, chronic stress potently affects the CRF/UCN system and thereby increases an individual’s vulnerability to develop stress-related psychopathology. However, significant interindividual differences exist in one’s sensitivity to stress and its potency to long- lastingly alter brain function. Aforementioned effects of stress exposure are not observed in all individuals, but subgroups of resilient versus vulnerable animals can be identified and characterized by apparent differential sensitivity to stress. What are the differences in CRF/UCN system function and response to stress between these subgroups? And how are these established?

Corticotropin-releasing factor/urocortin system mechanisms influencing resilience

Corticotropin-releasing factor system genetic variance x environment interactions

Influential studies in monozygotic twins have demonstrated that stress vulnerability can be explained partially (30%e40%) by genetic variation, mainly mediated by single-nucleotide polymorphisms (SNPs) (Afifi et al., 2010; Pitman et al., 2012). In a search for such gene x

 

240 16. The role of the CRF-urocortin system in stress resilience

environment (G x E) interactions for the CRF/UCN system, Bradley et al. (2008) investigated the interaction between 15 genetic polymorphisms in the Crfr1 gene and measures of child- hood abuse on adult depressive symptomatology. They identified significant G x E interactions for several individual SNPs, as well as with a common haplotype spanning intron 1 of the Crfr1 locus that modified adult risk for MDD in the presence of childhood trauma. Whereas these SNPs did not modify depressive symptoms in the absence of ELS, they moderated the effect of childhood trauma, having either protective or harmful effects. Other studies underscore this influence of Crfr1 genotype on vulnerability for MDD, by showing either main effects of several yet different Crfr1 SNPs on risk for depressive symptoms and suicidality (Liu et al., 2006; Wasserman et al., 2009) or interactions with life stress (Liu et al., 2013; Davidow et al., 2014). Moreover, the Crfr1 genotype was found to predict antide- pressant treatment response in an anxiety-dependent manner; treatment was most effective in highly anxious individuals with a specific Crfr1 haplotype (Licinio et al., 2004; Liu et al., 2007).

A study in outbred mice performed to better understand these G x E interactions revealed a significant interaction between chronic stress and a Crfr1 SNP on basal HPA axis function (Labermaier et al., 2014). The risk haplotype carriers displayed an augmented increase in basal corticosterone levels as a consequence of chronic stress, whereas no differences in basal corticosterone levels were observed without a history of stress. Stress-naïve risk allele carriers showed increased Crfr1 mRNA expression in the pituitary, dentate gyrus, CA3 and all cortical layers, and increased CRFR1 binding in the pituitary, but not in the hippocampus or in the cortex. Treatment with a CRFR1 antagonist during the last 3 weeks of the 7-week chronic stress prevented the increase in HPA axis activity in the risk allele carriers. These data suggest that an individual’s Crfr1 genotype heavily determines not only one’s vulnera- bility to stress but also one’s sensitivity to treatment selectively antagonizing CRFR hyperac- tivity. Besides the Crfr1 gene, other reports suggest associations between genetic variation in the Crf and Crfr2 genes, although the evidence there is less compelling (for a review of these findings, see Binder and Nemeroff, 2010). In-depth characterization of all relevant variants will likely be important for improving our understanding of the interindividual differences in the long-term consequences of adverse experiences.

Epigenetic regulation of corticotropin-releasing factor system expression

Epigenetic modifications in the central nervous system have been identified as one of the main mechanisms by which environmental stimuli such as stress can induce long-lasting alterations in neurobiological systems by influencing gene expression (Provencal and Binder, 2015), including the neuroendocrine system (Auger and Auger, 2013). The term “epigenetics” refers to all reversible chemical modifications of the chromatin structure that alter gene transcription without altering the DNA sequence, including DNA methylation, DNA hydrox- ymethylation, and histone modifications. Alterations in epigenetic regulation resulting from ELS have been suggested to contribute to the increased risk on stress-related mental disease by changing gene expression and thereby brain maturation during sensitive developmental stages (Murgatroyd et al., 2009). Stress in adulthood is also capable of inducing such changes (Dirven et al., 2017), which seem to reflect stress vulnerability. For example, a recent study by Sipahi et al. (2014) showed that DNMT1 gene methylation was increased in PTSD patients, relative to trauma-exposed controls (relating it to pathology), whereas pretrauma

 

Corticotropin-releasing factor/urocortin system mechanisms influencing resilience 241

methylation of a single DNMT3b CpG site predicted the later development of a trauma- induced PTSD phenotype, indicative of preexisting vulnerability (Sipahi et al., 2014).

Of particular interest for this chapter are the epigenetic mechanisms mediating long- lasting alterations in the CRF/UCN system as a consequence of chronic stress. Previous work has indicated that chronic social stress long-lastingly decreased methylation of the Crf gene in the PVN, which was associated with increased basal Crf mRNA expression (Elliott et al., 2010). This demethylation was, however, only observed in animals that displayed social avoidance following defeat, and not in those resilient, implicating it as a mechanism for stress vulnerability. Immediately after defeat, decreased Dnmt3b (DNA methyltransferase 3b) and Hdac2 (histone deacetylase 2) expression and increased demethylation-promoting factor Gadd45 expression were found, with the latter potentially responsible for the demethylation. Antidepressant treatment attenuated social avoidance, as well as Crf expression and demethylation of its promoter. Thus, differential Crf gene demethylation reflects a mechanism mediating the behavioral consequences of stress, which explains other reports of increased PVN Crf mRNA expression in stress-susceptible mice only (Han et al., 2017) and is in line with the general demethylation of the Crf promoter region as a consequence of chronic variable mild stress (Sterrenburg et al., 2011). Similarly, the expression of Crfr1 is under epigenetic control. Chronic unpredictable stress was shown to reduce hypothalamic H3K9 trimethylation, which was associated with increased levels of local CRFR1 and avoidance behavior (Wan et al., 2014). In the amygdala, Crfr1 methylation suppresses Crfr1 mRNA expression by preventing the binding of the transcription factor Yin Yang 1 (YY1). Moreover, differences in methylation and thereby expression of Crfr1 in the amygdala were associated with both the distinct innate anxiety levels between animals and the anxiolytic and anxiogenic effects of environmental enrichment and chronic variable stress, respectively. Further evidence for the important role of epigenetic regulation of Crf expression is derived from studies on the stress resilienceepromoting effects of augmented maternal care. Augmented care reduced hypothalamic Crf expression by enhanced expres- sion of the transcriptional repressor neuron restrictive silencing factor (NRSF) and its recruitment to the Crf gene (Korosi et al., 2010). This increased occupancy of NRSF at the Crf gene was joined by the recruitment of methyl CpG-binding protein 2 (MeCP2) binding, which typically binds methylated DNA and contributes to the repression of gene expression (McGill et al., 2006). Although this enriched NRSF and MeCP2 binding was relatively short- lasting, it induced an early and enduring increase in repressive epigenetic (i.e., methylation) marks and thereby long-lasting suppression of Crf expression (Singh-Taylor et al., 2018). These findings propose DNA methylation as a prominent mechanism by which either a beneficial or adverse environment can induce long-lasting neural and behavioral changes in stress sensitivity.

MicroRNAs (miRs), which act as translational repressors, are considered another type of epigenetic modulator capable of influencing protein expression. Altered miR expression has in fact been proposed to mediate resilience to chronic stress (Issler and Chen, 2015). Inactivating miR processing by ablation of the Dicer gene in the CeA of adult mice was found to induce a robust increase in anxiety-like behavior (Haramati et al., 2011). As a follow-up, miR expression profiles were analyzed in response to stress, revealing several affected miRs with putative gene targets known to be associated with stress. One of the prominent stress-induced miRs found in this screen, miR-34c, was found upregulated after acute and

 

242 16. The role of the CRF-urocortin system in stress resilience

chronic stress and appeared to contribute to a reduction in anxiolytic behavior by targeting Crfr1 and thereby reducing neuronal responsiveness to CRF in neuronal cells endogenously expressing Crfr1. Considering the accumulating evidence for aberrant miR levels in patients suffering from stress-related psychopathology, such as PTSD (Zhou et al., 2014) and MDD (Lopez et al., 2014), as well as differences in other epigenetic regulators (Bagot et al., 2014), future research should further study the exact mechanisms by which these potent modulators encode stress vulnerability.

Stress regulation of CRFR1 availability

One mechanism by which the effects of excessive or prolonged exposure to stress/CRF can be minimized is by the suppression of CRFR-induced signaling. Receptor phosphoryla- tion, inducing its internalization and thereby rendering the cell relatively insensitive to CRF, is one of the main mechanisms by which this is established. Ligand binding triggers G proteinecoupled receptor kinases (GRKs) to rapidly phosphorylate the receptors, which desensitizes them and increases their affinity for b-arrestins by w30-fold. This ultimately triggers CRFR translocation to the cell surface, where b-arrestins uncouple the CRFR from the G protein and thereby “arrest” signal transduction. Moreover, b-arrestins enable the internalization of the desensitized CRFR1 (Gutknecht et al., 2009) and CRFR2 (Markovic et al., 2008), which are then either dephosphorylated in endosomes by specific phosphatases and recycled back to the plasma membrane, ordin case of prolonged exposure to high agonist concentrationsddegraded in lysosomes, resulting in a decrease in the total number of CRFRs (Kohout and Lefkowitz, 2003; Moore et al., 2007; Kelly et al., 2008). Importantly, not all phosphorylated receptors are internalized; some remain at the membrane to ensure proper response to recurrent exposure to stress (Krasel et al., 2005). Besides phosphoryla- tion, actual CRFR bindingeinduced signaling is also modulated by interaction of a C-terminal PDZ-binding motif that is found in CRFR1, but not CRFR2. The binding of this motif to PDZ domains of membrane-associated guanylate kinases (MAGUKs) (among which postsynaptic density protein 95 [PSD95], synapse-associated protein 97 [SAP97], SAP102, PDZ domain containing 1 [PDZK1], and membrane-associated guanylate kinase, WW and PDZ domain containing 2 [MAGI2]) influences receptor localization in the cell by anchoring CRFR1 to larger signaling complexes (Bender et al., 2015; Walther et al., 2015) and affects receptor endocytosis (Dunn et al., 2016). Moreover, binding to the cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) prevents CRFR1 trafficking to the cell surface and reduces its internalization via the modulation of the post- translational modifications that the receptor undergoes within the Golgi apparatus (Ham- mad et al., 2015). Moreover, PDZ domainebased interactions seem to modulate downstream kinase phosphorylation (Walther et al., 2015; Hammad et al., 2015), as well as functional cross-talk between distinct receptors (Magalhaes et al., 2012).

Besides these two main regulatory mechanisms, many other regulatory systems of CRFRs seem to modulate CRFR activity but are less well understood and deserve attention in the future, particularly with respect to modulation by prolonged/excessive stress expo- sure and vulnerability to stress-related psychopathology. That is, initial evidence implicates stress-induced alterations in these processes in the behavioral consequences of chronic stress exposure. Prolonged stress was found to desensitize CRFR1 and promote the

 

Corticotropin-releasing factor/urocortin system mechanisms influencing resilience 243

degradation of CRFR1s in the LC (Reyes et al., 2008). This region is activated by CRF and is hyperresponsive in MDD (Gold and Chrousos, 2002), which is characterized by increased LC CRF levels (Austin et al., 2003; Bissette et al., 2003; Merali et al., 2006). Local CRFR1 was internalized in response to CRF administration (Reyes et al., 2006), repeated stress exposure (Reyes et al., 2008), or chronic ethanol intake (Chaijale et al., 2013), which in turn attenuated the magnitude of the stress response by decreasing the postsynaptic sensi- tivity to CRF. This LC CRFR1 downregulation reflected an adaptive stress coping response to stress, as rats that displayed resilience to the learned helplessness model of depression were characterized by reduced CRFR1 levels in the LC and amygdala. Reduced receptor expression was associated with the maintenance of sufficient GRK3 levels, which were sup- pressed in helpless animals (Taneja et al., 2011). These suppressed levels of GRK3 could potentially be caused by increased sensitivity to oxidative stress in the helpless animals; protein carbonylation was increased in this subgroup specifically, and increased intracel- lular calcium as can be expected during excessive activation of neurons and oxidative stress is known to contribute to GRK3 degradation (Salim and Eikenburg, 2007). Notably, the reported internalization of LC CRFR1 only seems to occur in male rats, but not in female rats, in which the stress-induced CRFR association with b-arrestin 2, an integral step in receptor internalization, is not observed (Bangasser et al., 2010). This results in increased LC activity and suggests an impaired capacity for adaptation to stressors. However, the behavioral effect of CRF-induced CRFR1 desensitization is highly brain region specific. For example, in the BLA, chronic stressinduced a reduction in electrophysiological respon- siveness to CRF, which was associated with increased anxiety- and depressive-like behavior (Sandi et al., 2008), whereas in the CeA, reduced expression of CRFR1 and thus reduced sensitivity to CRF was related to anxiolytic effects following stress exposure, potentially reflecting stress coping (Haramati et al., 2011).

Stress-induced changes in CRFR2 expression

Differential levels of CRFR2 expression may also relate to interindividual differences in stress resilience. In a rat model for PTSD, the exposure to predator-associated cues (a psy- chological trauma) simulated several prevalent PTSD symptoms, including reexperiencing, avoidance, and hyperarousal, in a subset of susceptible animals, whereas others were rela- tively resilient (Elharrar et al., 2013). Interestingly, susceptible (PTSD-like) rats demon- strated not only an inability to suppress Crfr1 mRNA levels in the BNST but also a marked, long-term decrease in Crfr2 mRNA levels. Local upregulation of CRFR2 attenuated PTSD-like symptoms in the susceptible animals. In another study, (optogenetic) activation of CRFR2-expressing neurons in the posterior BNST reduced basal anxiety and contributed to stress and trauma recovery, reducing the risk on PTSD-like symptomatology afterward (Henckens et al., 2017). These findings seem in contrast to the observation of increased BNST Crfr2 mRNA expression associated with a PTSD susceptibility, which was rescued by BNST CRFR2-specific KD (Lebow et al., 2012). Potentially, these apparent inconsistencies can be explained by contrasting roles of different subnuclei and cell types within the BNST (Hammack et al., 2007) but nevertheless suggest a clear link between CRFR2-induced signaling and stress resilience. Other evidence for a role of interindividual differences in CRFR2 availability mediating stress sensitivity comes from studies in macaque monkeys,

 

244 16. The role of the CRF-urocortin system in stress resilience

where stress-sensitive animals tended to display lower CRFR2 mRNA expression in the dorsal raphe nucleus than highly stress-resilient ones. These levels were significantly unreg- ulated upon selective serotonin reuptake inhibitor treatment in the stress-sensitive animals only (Bethea et al., 2011). When and how these differential expression patterns are gener- ated and what their exact mechanistic base is remains unclear and deserves further investigation.

Corticotropin-releasing proteinebinding protein function

The CRF-binding protein (CRF-BP) binds CRF with an affinity equal to or even higher than that of its receptors and therefore is an important indirect regulator of CRFR activation. In mice, CRF-BP expression is mainly found in the pituitary, cortex, hippocam- pus, amygdala, and BNST (Seasholtz et al., 2001). It is upregulated in response to stress in both the pituitary (McClennen et al., 1998) and amygdala (Lombardo et al., 2001; Herringa et al., 2004; Roseboom et al., 2007) and is thought to buffer the action of CRF in response to a current or subsequent stressor by sequestering the peptide, thereby preventing its interac- tion with the receptor and possibly targeting CRF for degradation (Behan et al., 1995). Pituitary CRF-BP OE mice showed a rather anxiolytic behavioral profile, whereas CRF- BP-deficient mice displayed increased anxiogenic-like behavior in the elevated plus maze and defensive withdrawal tests (Burrows et al., 1998; Karolyi et al., 1999). However, these transgenic mouse lines are characterized by compensatory alterations in the CRF/UCN system (Burrows et al., 1998), limiting their value. Conversely, there is some indication that CRF-BPdwhen bound to CRFdmay act as a cellular signaling molecule, opening up the possibility that increased CRF-BP expression following stress exposure could in fact underlie the sensitization that occurs to some of the effects of stress (Ungless et al., 2003; Slater et al., 2016; Li et al., 2016).

Several studies have implicated genetic variance (SNPs) in the CRF-BP gene to altered vulnerability to stress-related disorders (Van Den Eede, 2005). A specific CRF-BP genotype was associated with the risk for MDD (Claes et al., 2003), suicidal behavior (De Luca et al., 2010), anxiety and alcohol use disorders (Enoch et al., 2008), MDD and PTSD symptoms following treatment in the intensive care unit (Davydow et al., 2014), and cortisol stress re- sponses in children (Sheikh et al., 2013). Moreover, the treatment response to antidepressants was modulated by genetic variance in the CRF-BP gene, an effect most pronounced in pa- tients with anxious depression (Binder et al., 2010). Amygdala CRF-BP levels were increased in patients suffering from bipolar disorder and schizophrenia, but not MDD (Herringa et al., 2006). In contrast to this upregulation, animal work investigating differences between stress- prone and stress-resilient genetic rat strains has found an overall downregulation of CRF-BP brain expression associated with increased stress sensitivity (Sabariego et al., 2011). Future studies investigating the link between CRF-BP availability and vulnerability to stress-related disease are therefore needed.

Alterations in intracellularly activated signaling pathways

Activation of CRFRs can induce several distinct signaling pathways depending on their localization and cellular context. CRFRs primarily signal by G protein coupling, resulting in

 

Conclusion 245

the induction of cyclic AMP-protein kinase A (PKA) and the extracellular signaleregulated kinase-mitogen-activated protein kinase (ERK-MAPK) pathways. These signals induce intracellular calcium mobilization (Gutknecht et al., 2009), and the transcription of down- stream target genes (Hauger et al., 2006), and thereby regulate synaptic plasticity processes such as dendrite stabilization, ion channel transmission, transcription of CREB and other genes, and receptor scaffolding, trafficking, and cross-talk. However, CRFRs also interact with other G protein systems, including Gq, Gi, Go, Gil/2, and Gz, by which they can activate phospholipase C (PLC) ultimately also resulting in the activation of ERK1 and ERK2 and an increase in intracellular calcium (Grammatopoulos et al., 2002). Chronic stress and drug exposure are capable of altering these downstream signaling pathways of CRFRs and modi- fying the effect of ligand-induced activation. This reflects another important mechanism by which chronic stress can long-lastingly alter the CRF/UCN system. For example, in the ventral tegmental area (VTA), CRFR1 activation typically initiates the PLC-protein kinase C (PKC) pathway (Wanat et al., 2008) but acts through the PKA pathway in drug-experienced animals (Hahn et al., 2009). Similar mechanisms may contribute to the observation that the effects of CRFR2 activation in the VTA are dependent on the prior history of an animal. Activation of presynaptic CRFR2 in naïve animals was found to facil- itate presynaptic release of GABA and thereby suppressed VTA excitatory postsynaptic currents (EPSCs). However, after chronic cocaine self-administration and extinction training, the ability of CRFR2 agonists to depress EPSCs and potentiate inhibitory postsyn- aptic currents was diminished. Administration of yohimbine (an a-receptor antagonist, increasing circulating levels of noradrenaline) and cue reinstatement reversed the effects of CRFR2 on GABA and glutamate release; EPSCs were increased as a result of a reduction of tonic GABA-dependent inhibition (Williams et al., 2014). Similarly, in the lateral septum, CRFR2 activation induces a PKA-dominant pathway, which is changed into a PKC-dominant pathway following chronic cocaine administration and withdrawal. This changes the functional consequences of receptor activation; the CRFR2-mediated depression of excitatory glutamatergic transmission induced by UCN1 was switched to a facilitation with a comparable potency (Liu et al., 2005; Gallagher et al., 2008). Such alterations in CRF/UCN-induced cellular signaling may be integral for developing resilience to stress- induced depression. Social defeat-susceptible rats developed adaptations in their HPA axis response more slowly following chronic stress than resilient animals, due to loss of response to CRF in the presence of normal CRFR concentrations, suggestive of receptor uncoupling or attenuation of cellular signaling (Wood et al., 2010).

Conclusion

Although an organism may benefit from the initial CRF/UCN system response in the presence of acute threat, prolonged stress exposure or stress experienced during critical periods in development lastingly alter the system, thereby contributing to an autonomic, neuroendocrine, and behavioral state very much resembling that of stress-related psycho- pathology. Abundant human evidence substantiates this presumed CRF/UCN system dysfunction in stress-related mental disorders such as MDD and PTSD. Mechanisms mediating the transition to disease seem to be subject to substantial interindividual variation

 

246 16. The role of the CRF-urocortin system in stress resilience

FIGURE 16.2 CRF/UCN system mechanisms influencing stress resilience versus susceptibility. Evidence suggests that a stressful environment increases risk for disease in susceptible individuals by interacting with one’s genetic background of the CRF/UCN system (e.g., in CRFR1) (1), as well as by inducing epigenetic changes regulating CRFR and ligand expression (2). Moreover, interindividual differences in stress-mediated regulation of CRFR1 (modulated by receptor phosphorylation and PDZ domain interactions (3)) and CRFR2 availability (4), as well as the regulation of available ligand by CRF-BP (5), contribute to risk on disease. Lastly, stress exposure can (lastingly) alter CRF/UCN-mediated activation of distinct signaling pathways (6), which might additionally contribute to stress-related mental disorders. A, acetylation; cAMP, cyclic AMP; DAG, diacylglycerol; ERK, extracellular signaleregulated kinase; GRK, G proteinecoupled receptor kinase; IP3, inositol-1,4,5-triphosphate; M, methylation; MAGUK, membrane-associated guanylate kinase; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; PLC, phospholipase C.

and determined by several factors (Fig. 16.2): first of all, the genetic background of the individual, which interacts with the environment in mediating the risk for disease; secondly, by stress-induced epigenetic changes regulating CRFR and ligand expression that may vary among individuals; thirdly, by differential regulation of CRFR1 (modulated by receptor phosphorylation and PDZ domain interactions) and CRFR2 availability and the regulation of available ligands by CRF-BP; and lastly, by stress-induced alterations in activated signaling pathways, which may mediate the interindividual differences in susceptibility to stress- related disease. Increased understanding of these exact mechanisms would aid identification of at-risk individuals and improve treatment options for those suffering from stress-related psychiatric disorders.

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CHAPTER

17

Intergenerational transmission of stress vulnerability and resilience

Mallory E. Bowers1, Rachel Yehuda1, 2, 3
1Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United

States; 2Mental Health Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, United States; 3Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Introduction

Severe stress exposure can precipitate long-term mental health problems, particularly in vulnerable individuals. It is now accepted that maladaptive behaviors and mental illness that may result from extreme stress exposure can be perpetuated intergenerationally. Although it is clear that familial psychopathology may have a genetic component, phenotypic alterations observed in subsequent generations could stem from trauma-mediated changes in parenting styles and other behaviors that are mirrored by offspring. Alternatively, adverse experiences in parents could be biologically transmitted to offspring via nongenetic mecha- nisms, subsequently altering offspring biology and/or behaviors in a way that precipitates or buffers against mental illness.

Here, we examine the evidence that suggests environmental exposure to psychological trauma that occur prior to conception or during gestation can exert long-lasting phenotypic changes in offspring. To date, studies have focused primarily on stress during pregnancy, which primarily reflects an understanding of stress transmission from mothers to offspring via placental signaling. Alternatively, preconception stress is thought to be transmitted by both mothers and fathers through epigenetic changes in gametes. Recent studies also demonstrate that offspring outcomes may vary according to timing of parental exposures.

Stress Resilience

https://doi.org/10.1016/B978-0-12-813983-7.00017-3 257 Copyright © 2020 Elsevier Inc. All rights reserved.

  

 

258 17. Intergenerational transmission of stress vulnerability and resilience Foundational populations: studies of the Dutch hunger winter and

holocaust survivor offspring

In considering the origins of the field of intergenerational transmission of stress, studies of the Dutch Hunger Winter and Holocaust survivor offspring (HSO) have been foundational and have prompted an increasing number of animal studies that provide insight into the potential biological mechanisms of stress transmission. The Dutch Hunger Winter and Holo- caust are dual instances of exposure to extreme environmental threat that were unrelated to the personal histories or behaviors of those affected. Study of the survivors of these pro- foundly adverse conditions, and of their offspring, are therefore devoid of the trauma- associated confounds that impact most naturalistic studies of trauma effects in humans. Observations of the effects of these exposures across generations have proved foundational in defining the range of physical and mental health sequelae that may be associated with exposure and have raised important questions regarding their mechanism(s) of transmission of these effects.

The Dutch Hunger Winter refers to the 6-month period from 1944 to 45 during which German occupiers in the Netherlands imposed a food embargo that resulted in severe and widespread famine among Dutch citizens. Despite a robust posteWorld War II recovery, Dutch adults who were in utero during the famine exhibited increased prevalence of type II diabetes, cardiovascular disease, and age-associated cognitive decline (Tobi et al., 2014). Poorer health outcomes among offspring who were famine-exposed in utero, regardless of socioeconomic status, lent evidence to the once controversial Barker hypothesis that has now been expanded into a broad field of study related to the developmental origins of health and disease (DOHaD) (Hoy and Nicol, 2018). For example, offspring exposed to the famine in utero exhibit differences in IGF2 methylation compared with unexposed, same-sex siblings. Thi