Stress Resilience: Molecular and Behavioral Aspects

Stress Resilience

Molecular and Behavioral Aspects

Editor

Alon Chen

Table of Contents

Cover image

Title page

Copyright

Dedication

Contributors

About the editor

Preface

Acknowledgments

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

Introduction

What is stress?

Definition of stress, allostasis, and allostatic load

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

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

Sex differences

Lessons of an ever-changing brain from gene expression

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

Individual differences and experiences throughout the life course

Early-life experiences

Intervention

Chapter 2. Cognitive and behavioral components of resilience to stress

Resilience: one of many possible responses to stress or trauma

Cognitive and behavioral components of the psychosocial factors associated with resilience

Cultivating psychosocial factors to promote resilience

Chapter 3. Resilience as a process instead of a trait

Introduction

Learning-to-cope training

Learning to cope inferred from hormones and behavior

Neurobiology of learning to cope

Limitations

Conclusions

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

The brain mineralocorticoid receptor

Mineralocorticoid receptor activation and neuronal activity

Mineralocorticoid receptors and cognitive function in rodents

Pharmacology, genetic variation, and vulnerability to psychopathology in humans

Concluding remarks

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

Introduction

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

Effects of GABAB receptor modulation on depression-like behaviors

The role of GABAB1 receptor subunit isoforms in stress resilience

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

Conclusions

Chapter 6. Sex differences in the programming of stress resilience

Introduction

Sex x life span interaction in producing resilience

Sex hormone x life span interaction in producing resilience

Sex chromosome x life span interaction in producing resilience

Conclusion

Chapter 7. Active resilience in response to traumatic stress

Resilience—a passive lack of effect or an active response?

Two isozymes of glutamic acid decarboxylase

GAD genes are regulated in response to fear and stress

GAD is required for resilience

GAD65 haplodeficiency conveys stress resilience

GAD65 and stress resilience—a complex picture

Summary

Chapter 8. Rhythms of stress resilience

Hypothalamic-pituitary-adrenal axis rhythms

Circadian rhythm and stress response

The importance of pulsatility for hormonal and behavioral response to stress

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

Cortisol rhythms and stress resilience in humans

Chapter 9. Mitochondrial function and stress resilience

Introduction

The mitochondrion

Mitochondria in neurotransmission and synaptic plasticity

Mitochondria and glucocorticoids

Mitochondrial dysfunction in stress-related disorders: human studies

Stress effects in mitochondrial function: animal studies

Promoting stress resilience through activation of mitochondrial function

Conclusions and future perspectives

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

Introduction

Definitions and measurement of resilience

Biological facets of resilience

Resilience as a multidimensional trait

Conclusion/summary

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

Introduction

Early-life stress—definition of the term

Early-life stress is a risk factor for psychiatric disorders

Early-life stress shapes adult phenotypes

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

Evidence for the match/mismatch theory in humans

Evidence for the match/mismatch theory in animal studies

Conclusions

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

Introduction

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

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

Conclusions

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

Stress responsivity physiology

Sympathetic nervous system

Glucocorticoid feedback regulation of stress responsivity

Epigenetics of stress responsivity

Stress responsivity neural circuits

Stress responsivity and inflammation

Stress responsivity and resilience

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

Treatment/implications/future

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

Introduction

Prenatal development

Infancy

Childhood

Adolescence

Adulthood

Conclusions

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

Introduction

DNA methylation

Chromatin modifications

MicroRNAs

Transcription factors

Immune-related processes

Neurotrophic factors

Circuit-related molecules

Genome-wide studies

Future directions

Summary

Chapter 16. The role of the CRF-urocortin system in stress resilience

Introduction to the corticotropin-releasing factor/urocortin system

The corticotropin-releasing factor/urocortin system as a critical mediator of the behavioral stress response

The corticotropin-releasing factor/urocortin system mediates stress vulnerability caused by chronic stress exposure

Corticotropin-releasing factor/urocortin system mechanisms influencing resilience

Conclusion

Chapter 17. Intergenerational transmission of stress vulnerability and resilience

Introduction

Foundational populations: studies of the Dutch hunger winter and holocaust survivor offspring

Maternal versus paternal transmission

Hypothesized mechanisms of transmission

Intergenerational transmission of resilience

Conclusions and future directions

Chapter 18. Stress and its effects across generations

What is epigenetic inheritance?

Why epigenetic inheritance?

Germline versus non–germline transmission

Preclinical and clinical studies of inheritance of stress susceptibility

Relevance of studying inheritance of the effects of stress for society

Chapter 19. Corticolimbic stress regulatory circuits, hypothalamo–pituitary–adrenocortical adaptation, and resilience

Glucocorticoid signaling, stress, and reslience

Neural circuitry of stress regulation

Limbic regulation of hypothalamo–pituitary–adrenocortical axis stress responses: hippocampus, amygdala, and prefrontal cortex

Integration of hippocampal, prefrontal, and amygdala projections

Toward a neurocircuitry of stress resilience

Chapter 20. Biomarkers of resilience and susceptibility in rodent models of stress

Introduction

Experimental strategies

Potential additional biomarkers

Conclusion

Chapter 21. Maladaptive learning and the amygdala—prefrontal circuit

Modeling stress and anxiety disorders through behavioral paradigms of learning

Cognitive and physiological components of emotional learning

Associative learning in the amygdala: a preference for aversion

Associative learning in the medial prefrontal cortex: mixed selectivity encoding

The prelimbic and infralimbic subregions of the medial prefrontal cortex in associative learning

Overview of amygdala—prefrontal communication during aversive emotional learning

Directionality of amygdala–prefrontal communication during acquisition of stimulus discrimination

Amygdala–prefrontal communication during recall of learned associations

A unified view of mPFC–BLA circuit function in adaptive learning

Chapter 22. Endocannabinoid signaling and stress resilience

Impact of stress on endocannabinoid signaling

Endocannabinoid regulation of the stress response

Endocannabinoid signaling in the context of susceptibility and resilience to repeated stress

Conclusions

Index

Copyright

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Dedication

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 (1941–2012)

Contributors

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 Pediatrics, 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 Hospitalier Sainte-Anne, Paris, France

Jessica L. Bolton

Department of Anatomy/Neurobiology, University of California-Irvine, Irvine, CA, United States

Department of Pediatrics, 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 Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany

Olivia Engmann,     Laboratory of Neuroepigenetics, 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 – 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 Cincinnati, Cincinnati, OH, United States

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 Neuroscience 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 Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands

University of Groningen/University Medical Center Groningen, 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 Graduate 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, Stanford, 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 Neuroepigenetics, 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 Rockefeller 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 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

Iris Müller

Department of Genetics & Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Department of Psychological Sciences, 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, University 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 Anxiety, McLean Hospital; Department of Psychiatry, 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 Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

R. Angela Sarabdjitsingh,     Department of Translational 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 Pediatrics, 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: Translational 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 Neurobiology, University of Haifa, Haifa, Israel

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

A.P. Wingo,     Division of Depression and Anxiety, McLean Hospital; Department of Psychiatry, 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 Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States

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 Society—Weizmann 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 Weizmann 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 Professorial 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 aspects of the organism's stress response and actions that link specific stress-related genes, epigenetic mechanisms, and brain circuits with anxiety disorders, depression, eating disorders, 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 interventions 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.

Preface

It is not stress that kills us, it is our reaction to it.

Hans Selye (1907–1982)

Given that exposure to stressful life experiences is often unavoidable, understanding 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 understanding of resilience promoting factors and processes, as well as inter-individual differences in resilience is needed. Consequently, this understanding could pave the way for new clinical interventions for stress-related psychopathologies including anxiety, depression and post-traumatic stress disorder (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 traumatic stimuli; a continuum of adjustable physiological and behavioral changes that shows a large inter-individual variation and can change over time. World-leading scientists and psychiatrists, working in the newly emerging field of stress resilience, present and discuss the diverse biological and environmental 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 responses and precipitates the onset of psychiatric 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 organism's response to stressors is the maintenance 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 understood. Nevertheless, there is extensive evidence showing that inappropriate regulation, disproportional intensity, or chronic and/or irreversible activation of the stress response is linked to the etiology and pathophysiology 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 efficient 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 corticosterone/cortisol, are of obvious significance for understanding the mechanism of resilience. A proper balance in signaling cascades that regulate physiological responses and behavioral adaptation to a stressor is key in understanding the mechanisms of resilience. Thus, for optimal resilience, 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 resistance 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 assessments suggest that cognitive capabilities, personality, and neurobiological factors work alongside environmental factors to make certain individuals more or less resilient. Experiences that are emotionally stressful 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 processes that help buffer the effects of trauma.

The unique characteristics of resilient individuals have gained substantial interest in recent years, and growing efforts in animal models have attempted to unravel the molecular and cellular mechanisms that underlie this phenomenon. These animal studies have identified changes in several molecules, pathways and circuits, which involve multiple brain regions. While some molecular pathways identified in resilience overlap with those regulated in the opposite direction 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, transcriptional, cellular and circuit –based mechanisms playing important roles in mediating the behavioral and physiological response to stressful challenges.

In addition to the neurobiological factors associated with resilience, psychosocial factors 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 compass. Resilience promoting factors include having caring and supportive relationships, good communication and problem-solving skills, and the ability to manage strong feelings and impulses.

The mechanisms underlying resilience may be primed early on in life by the interplay 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 reduces 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 cognitive 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 adulthood. 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 behaviors. 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 developing brain towards susceptibility or resilience. 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 interactions in large longitudinal cohorts with repeated biological, neuroimaging, behavioral 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, protein, 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 molecular 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 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 evidence 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 potential mechanisms and treatment approaches 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 resilience, 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 molecular and cellular levels, which compensate for, bypass, or overcome the harmful effects of stressors. Delineating the complex interactions 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 continuum of physiological and behavioral modifications 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 factors that contribute to resilience versus other outcomes, including the emergence of psychiatric disorders. Understanding these factors 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 molecular and behavioral aspects of stress resilience.

Alon Chen,     Vera and John Schwartz Family Professorial Chair Weizmann Institute of Science, Rehovot, Israel,     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 reformatting the chapter figures. Finally, my thanks go to the team at Elsevier for bringing the book from a concept into print.

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

Abstract

The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor, which promote adaptation (allostasis) and also contribute to pathophysiology (allostatic load/overload) when overused and dysregulated. The adult, as well as developing brain, possesses a remarkable ability to show structural and functional plasticity in response to experiences, including neuronal replacement, dendritic remodeling, and synapse turnover. The hippocampus shows all three types of structural plasticity that have been recognized. The amygdala and prefrontal cortex show dendritic remodeling and spine synapse turnover. Acute stress and chronic stress cause an imbalance of neural activity that, in turn, affects systemic physiology. In the short term, these changes may be adaptive; however, if the danger passes and the behavioral state persists along with altered neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies.

Keywords

Adverse childhood experiences; Allostasis; Allostatic load/overload; Amygdala; Epigenetics; Excitatory amino acids; Glucocorticoids; Hippocampus; Life course; Neuroplasticity; Prefrontal cortex; Toxic stress

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 realization 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 circulating 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 allostatic 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.

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 mediators—for example, catecholamines that increase heart rate and blood pressure—and helps us cope with the situation; on the other hand, chronic elevation of these same mediators—for example, chronically increased heart rate and blood pressure—produces 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 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.

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, 171–179, with permission.

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/overload 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 catecholamines. Whereas catecholamines can increase proinflammatory cytokine production, glucocorticoids are known to inhibit this production. And yet, there are exceptions—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 the sympathetic nervous system and, for example, slows the heart and also has antiinflammatory 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 stress–induced immune enhancement is good for enhancing immunization, fighting an infection, or repairing 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 autoimmune 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 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).

Table 1.1

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 negative 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 resident—intruder 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 dendritic 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).

Table 1.2

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 remodeling 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 mechanisms 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 glucocorticoid 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).

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 hippocampus, 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. Hibernation 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 cytoskeleton, 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,