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Epigenetics of Stress and
Stress Disorders
Translational Epigenetics Series
Trygve Tollefsbol, Ph.D., D.O., Distinguished Professor - Series Editor
Professor of Biology, University of Alabama at Birmingham, and Senior Scientist, Comprehensive Cancer Center,
Comprehensive Center for Healthy, Birmingham, AL, United States
Aging, Comprehensive Diabetes Center and Nutrition Obesity Research Center, Birmingham, AL, United States
Director, Cell Senescence Culture Facility, Birmingham, AL, United States
Transgenerational Epigenetics Epigenetics in Human Disease, Second Edition

Edited by Trygve O. Tollefsbol, 2014 Edited by Trygve O. Tollefsbol, 2018
Personalized Epigenetics Epigenetics of Chronic Pain
Edited by Trygve O. Tollefsbol, 2015 Edited by Guang Bai and Ke Ren, 2018
Epigenetic Technological Applications Epigenetics of Cancer Prevention
Edited by Y. George Zheng, 2015 Edited by Anupam Bishayee and Deepak Bhatia, 2018
Epigenetic Cancer Therapy Computational Epigenetics and Diseases
Edited by Steven G. Gray, 2015 Edited by Loo Keat Wei, 2019
DNA Methylation and Complex Human Disease Pharmacoepigenetics
By Michel Neidhart, 2015 Edited by Ramón Cacabelos, 2019
Epigenomics in Health and Disease Epigenetics and Regeneration
Edited by Mario F. Fraga and Agustin F. F Fernández, 2015 Edited by Daniela Palacios, 2019
Epigenetic Gene Expression and Regulation Chromatin Signaling and Neurological Disorders
Edited by Suming Huang, Michael Litt and C. Ann Blakey, 2015 Edited by Olivier Binda, 2019
Epigenetic Biomarkers and Diagnostics Transgenerational Epigenetics, Second Edition
Edited by Jose Luis García-Giménez, 2015 Edited by Trygve Tollefsbol, 2019
Drug Discovery in Cancer Epigenetics Nutritional Epigenomics
Edited by Gerda Egger and Paola Barbara Arimondo, 2015 Edited by Bradley Ferguson, 2019
Medical Epigenetics Prognostic Epigenetics
Edited by Trygve O. Tollefsbol, 2016 Edited by Shilpy Sharma, 2019
Chromatin Signaling and Diseases Epigenetics of the Immune System
Edited by Olivier Binda and Martin Fernandez-Zapico, 2016 Edited by Dieter Kabelitz, 2020
Genome Stability Stem Cell Epigenetics
Edited by Igor Kovalchuk and Olga Kovalchuk, 2016 Edited by Eran Meshorer and Giuseppe Testa, 2020
Chromatin Regulation and Dynamics Epigenetics Methods
Edited by Anita Göndör, 2016 Edited by Trygve Tollefsbol, 2020
Neuropsychiatric Disorders and Epigenetics Histone Modifications in Therapy
Edited by Dag H. Yasui, Jacob Peedicayil and Dennis R. Grayson, Edited by Pedro Castelo-Branco and Carmen Jeronimo, 2020
2016 Environmental Epigenetics in Toxicology and Public Health
Polycomb Group Proteins Edited by Rebecca Fry, 2020
Edited by Vincenzo Pirrotta, 2016 Genome Stability
Epigenetics and Systems Biology Edited by Igor Kovalchuk and Olga Kovalchuk, 2021
Edited by Leonie Ringrose, 2017 Twin and Family Studies of Epigenetics
Cancer and Noncoding RNAs Edited by Shuai Li and John Hopper, 2021
Edited by Jayprokas Chakrabarti and Sanga Mitra, 2017 Epigenetics and Metabolomics
Nuclear Architecture and Dynamics Edited by Paban K. Agrawala and Poonam Rana, 2021
Edited by Christophe Lavelle and Jean-Marc Victor, 2017 Medical Epigenetics, Second Edition
Epigenetic Mechanisms in Cancer Edited by Trygve Tollefsbol, 2021
Edited by Sabita Saldanha, 2017 Epigenetics in Precision Medicine
Epigenetics of Aging and Longevity Edited by José Luis García-Giménez, 2022
Edited by Alexey Moskalev and Alexander M. Vaiserman, 2017
The Epigenetics of Autoimmunity
Edited by Rongxin Zhang, 2018
Translational Epigenetics
Epigenetics of Stress and

Stress Disorders
Volume 31
Edited by
Nagy A. Youssef, MD, PhD, Director of Clinical Research

Professor of Psychiatry, Department of Psychiatry & Behavioral Health,
The Ohio State University College of Medicine, Columbus, OH, United States
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Contents
Contributors......................................................................................................................................... xiii
Foreword..............................................................................................................................................xvii
Acknowledgments.................................................................................................................................xix
CHAPTER 1 The physiology of stress and the human body’s response to stress.....1
Richard S. Lee, PhD
Introduction...................................................................................................................1
Stress as an environmental factor.................................................................................2
The basics of the stress response..................................................................................2
Sympathetic and parasympathetic systems...................................................................3
Allostasis and allostatic load........................................................................................4
Allostatic load and disease burden................................................................................4
Allostatic load and the brain.........................................................................................5
Cortisol as the primary driver of the chronic stress response.......................................6
Glucocorticoids and the brain.......................................................................................6
Molecular mechanism of cortisol action.......................................................................7
Intracellular negative feedback and glucocorticoid resistance.....................................7
Epigenetics....................................................................................................................8
Effect of chronic stress on systemic cortisol dynamics..............................................10
Effect of chronic stress on neurotransmitter function and behavior...........................10
Conclusion..................................................................................................................10
Acknowledgments......................................................................................................11
References...................................................................................................................11
CHAPTER 2 Posttraumatic stress disorder: Diagnosis, measurement,
and assessment...........................................................................................19
Bhargav Patel, MD and Nagy A. Youssef, MD, PhD
Introduction to PTSD and stress-related disorders.....................................................19
Proper diagnosis according to DSM-5........................................................................20
Risk factors for PTSD.................................................................................................22
Comorbidities and complications of PTSD................................................................22
Differential diagnosis of PTSD...................................................................................23
PTSD vs acute stress disorder.....................................................................................23
Tools for diagnosis......................................................................................................24
Life events checklist for DSM 5 (LEC-5)..............................................................24
PTSD checklist for DSM-5 (PCL-5)......................................................................24
Clinician-administered PTSD scale 5 (CAPS-5)...................................................25
References...................................................................................................................25
v
vi Contents
CHAPTER 3 Nikola Tesla: An autobiographical case study of trauma and

resilience.....................................................................................................27
Safiye Bahar Ölmez, MD and Nagy A. Youssef, MD, PhD

Introduction.................................................................................................................27

Nikola Tesla’s mental symptoms and mental experiences..........................................28

References...................................................................................................................34
CHAPTER 4 Management of posttraumatic stress disorder.......................................37
Bhargav Patel, MD and Nagy A. Youssef, MD, PhD

Introduction.................................................................................................................37

Management algorithm...............................................................................................37

Treatment algorithm...................................................................................................38

Shared decision making..............................................................................................40

The role of PTSD checklist-5 (PCL-5) in management.............................................40

Trauma-focused psychotherapies...............................................................................41

Prolonged exposure therapy........................................................................................41

Cognitive processing therapy......................................................................................42

Eye movement desensitization and reprocessing........................................................42

Specific cognitive-behavioral therapies for PTSD......................................................43

Brief eclectic psychotherapy.......................................................................................43

Narrative exposure therapy.........................................................................................43

Written narrative exposure..........................................................................................43

Second-line therapies..................................................................................................44

Nontrauma-based psychotherapies.............................................................................44

Other psychotherapies................................................................................................44

First-line pharmacotherapies......................................................................................44

Second-line pharmacotherapies..................................................................................45

Medications to avoid in PTSD treatment....................................................................45

Complementary and alternative techniques................................................................45

Internet-based and tele-therapies................................................................................46

Management of PTSD comorbidities.........................................................................46

Summary.....................................................................................................................47

References...................................................................................................................47
CHAPTER 5 Depression and epigenetics: Epidemiology, pathophysiology,
diagnosis, and assessment.......................................................................51
Jeffrey O’Neill, MD, Parit Patel, MBChB, and Jayesh Kamath, MD, PhD
Epidemiology..............................................................................................................51
Neurobiology and pathophysiology............................................................................52
Genetic predisposition...........................................................................................53
Environmental factors and gene-environment interactions....................................53
Epigenetic mechanisms..........................................................................................54
Contents vii
Pathophysiology.........................................................................................................54
Monoamine dysfunction........................................................................................54
Glutamate dysfunction...........................................................................................54
Hypothalamic-pituitary-adrenal (HPA) axis dysfunction......................................54
Immune system dysregulation...............................................................................55
Dysfunction of neuroplasticity and neurogenesis..................................................56
Circadian rhythm dysregulation.............................................................................56
Dysregulation of opioid and endocannabinoid systems.........................................56
Diagnosis and assessment...........................................................................................56
Diagnostic criteria, classification, and symptomatology.......................................56
Major depressive disorder......................................................................................57
MDD subtypes and specifiers................................................................................58
Comorbidities.........................................................................................................59
Suicide risk.............................................................................................................60
Screening, diagnosis, and measurement-based care..............................................60
References...................................................................................................................61
CHAPTER 6 Depression management and pharmacoepigenetics.............................67
Sophia Walker, MD, Arthur Su, MD, and Jayesh Kamath, MD, PhD
Principles of depression management........................................................................67
General principles..................................................................................................67
Treatment phases....................................................................................................67
Measurement-based and evidence-informed care..................................................68
Stepped care and chronic disease management model..........................................69
Depression management strategies.............................................................................70
Suicide risk management.......................................................................................70
Treatment selection................................................................................................71
Pharmacotherapy........................................................................................................71
Antidepressant selection: Clinical factors..............................................................72
Antidepressant selection: Nonclinical factors........................................................73
Management of partial or lack of response............................................................73
Monitoring and management of adverse reactions................................................74
Psychotherapy.............................................................................................................76
Neurostimulation........................................................................................................77
Depression management in special populations.........................................................77
Pharmacoepigenetics..................................................................................................78
References...................................................................................................................79
CHAPTER 7 Psychotherapy for stress disorders: A military perspective................85
Demietrice Pittman, PhD

Overview of behavioral health in the military health system.....................................85

Posttraumatic stress disorder......................................................................................85
viii Contents
Pretraumatic factors...............................................................................................88
Peritraumatic factors..............................................................................................88
Posttraumatic factors..............................................................................................89
Treatment...............................................................................................................89
Depression..................................................................................................................92
Treatment...............................................................................................................92
Epigenetics and psychotherapy...................................................................................94
Conclusion..................................................................................................................95
References...................................................................................................................96
Further reading............................................................................................................98
CHAPTER 8 How stress affects gene expression through epigenetic
modifications...............................................................................................99
Charlotte Bainomugisa, MEpi and Divya Mehta, BSc, MSc, PhD
Introduction—Biology of stress.................................................................................99
Epigenetics................................................................................................................100
DNA methylation.................................................................................................100
Histone modification and noncoding RNA..........................................................101
Gene expression........................................................................................................102
Stress-induced epigenetic and gene expression changes in animal models.............102
Stress-induced epigenetic modifications and gene expression
changes in humans...............................................................................................103
DNA methylation and gene expression changes of candidate genes...................104
Genome-wide studies of DNA methylation and gene expression
changes.................................................................................................................105
Timing of stress is important—epigenetic modifications and gene expression
changes at different times during life...................................................................106
Epigenetic effects of stress in early life...............................................................106
Epigenetic effects of stress in childhood..............................................................106
Effects of stress in adulthood...............................................................................108
Transgenerational transmission of stress-induced epigenetic marks........................108
Limitations and future directions..............................................................................109
References.................................................................................................................111
CHAPTER 9 Proposed effect of epigenetic alterations on stress-related
disorders.................................................................................................... 119
Onur Yılmaz, MD
Introduction...............................................................................................................119
Genetic background and mechanisms of stress-related disorders............................120
Genetic background of depressive disorders.......................................................120
Genetic background of posttraumatic stress disorder..........................................121
From genetics to epigenetics................................................................................122
Epigenetic mechanisms in the process of stress-related disorders...........................122
Contents ix
The influences of psychosocial stress on an epigenetic level..............................123

Epigenetic correlates of stress-reducing interventions and psychotherapies.......125
Conclusion................................................................................................................128
References.................................................................................................................128
CHAPTER 10 PTSD and physiology: The long-term effects of PTSD
and relation to epigenetics, physical health, and
chronic diseases....................................................................................... 137
Kristina Reed, BA, Shiloh Cleveland, BA, Jordan Thomas, MA,
Aileen Hsu, BS, Annie Jeong, BA, Jessica Nguyen, BS, Aarti Patel, BA,
Sheila Zhang, BS, and Jennifer A. Sumner, PhD
Introduction...............................................................................................................137
PTSD and adverse physical health............................................................................138
Epigenetic studies of PTSD and implications for physical health............................139
EWAS of PTSD....................................................................................................139
Comparing EWAS study characteristics..............................................................139
PTSD and epigenetic aging..................................................................................149
Future directions.......................................................................................................154
Conclusions...............................................................................................................155
References.................................................................................................................155
CHAPTER 11 Epigenomic biomarkers of posttraumatic stress disorder.................. 163
Janitza L. Montalvo-Ortiz, PhD

Introduction...............................................................................................................163

Genetics of PTSD.....................................................................................................163

Epigenetics of PTSD.................................................................................................164

DNA methylation......................................................................................................165

Accelerated epigenetic aging and PTSD..................................................................168

Histone modifications...............................................................................................169

Noncoding RNAs......................................................................................................170

Toward the development of PTSD multiomics biomarkers......................................171

Gaps, challenges, and future directions....................................................................173

Acknowledgments....................................................................................................173

References.................................................................................................................173
CHAPTER 12 Adversity across time: Do sensitive periods across the life
span determine adversity-induced epigenetic changes?................... 179
Thorhildur Halldorsdottir, PhD, Heiddis B. Valdimarsdottir, PhD,
and Unnur A. Valdimarsdottir, PhD
Introduction...............................................................................................................179
Studies by timing of stress exposure........................................................................182
Prenatal................................................................................................................182
Postnatal to preadolescence (0–12 years old)......................................................183
x Contents
Adolescence (12–20 years old)............................................................................184

Adulthood (>20 years old)..................................................................................185
Intergenerational..................................................................................................186
Methodological considerations.................................................................................186
Summary and concluding remarks...........................................................................188
Funding.....................................................................................................................188
References.................................................................................................................188
CHAPTER 13 PTSD, telomeres, and aging.................................................................... 193
Laura Lockwood, DO, Sonia Dela Cruz, MD, and Nagy A. Youssef, MD, PhD

Introduction...............................................................................................................193

Methods....................................................................................................................194

Results.......................................................................................................................194

Discussion.................................................................................................................202

References.................................................................................................................204
CHAPTER 14 Accelerated aging in mood disorders.................................................... 207
Erika M. Salarda, BSc, Belinda U. Busogi, BSA,
and Gabriel R. Fries, BSc, MSc, PhD
Introduction...............................................................................................................207
Mood disorders.........................................................................................................208
Major depressive disorder....................................................................................208
Bipolar disorder...................................................................................................209
Clinical evidence of accelerated aging in mood disorders.......................................210
Pathophysiology of accelerated aging in mood disorders........................................212
Biological clock findings in mood disorders............................................................214
Antiaging effects of antidepressants and mood stabilizers..................................217
Conclusions...............................................................................................................218
References.................................................................................................................218
CHAPTER 15 Epigenetics, stress, and depression...................................................... 225
Laura Lockwood, DO, Shaoyong Su, PhD, and
Nagy A. Youssef, MD, PhD

Introduction...............................................................................................................225

Materials and methods..............................................................................................225

Results.......................................................................................................................226

Discussion.................................................................................................................236

References.................................................................................................................237
Contents xi
CHAPTER 16 Capturing the epigenome: Differences among blood, saliva,

and brain samples.................................................................................... 239
Shota Nishitani, PhD

Introduction...............................................................................................................239

Early days of research on neuropsychiatric epigenetics in animals and humans.....239

Comparison of DNA methylation among blood, saliva, and buccal samples...........241

Salivary DNA methylation analyses.........................................................................242

Salivary DNA methylation studies of PTSD and trauma.........................................244

Studies on correlations between brain and peripheral tissue DNA methylation
and its databases...................................................................................................244

Conclusion................................................................................................................250
References.................................................................................................................252
CHAPTER 17 Posttraumatic stress disorder, major depressive disorder,
and noncoding RNAs................................................................................ 257
Dušan Braný, PhD, Dana Dvorská, PhD, Laura Lockwood, DO,
Ján Strnádel, PhD, and Nagy A. Youssef, MD, PhD

Introduction...............................................................................................................257

Posttraumatic stress disorder....................................................................................258

Major depressive disorder.........................................................................................259

MicroRNAs...............................................................................................................260

Long noncoding RNAs.............................................................................................262

MicroRNA and posttraumatic stress disorder...........................................................264

MicroRNAs and major depressive disorder..............................................................266

Long noncoding RNAs and posttraumatic stress disorder........................................271

Long noncoding RNAs and major depressive disorder............................................272

Heritability of abnormal ncRNA and epigenetic profile after trauma......................274

Conclusion................................................................................................................274

Acknowledgments....................................................................................................275

References.................................................................................................................275
CHAPTER 18 MicroRNAs in posttraumatic stress disorder........................................ 285
Clara Snijders, PhD, Alana I.H. Escoto, MSc, Dewleen G. Baker, MD,
Richard L. Hauger, MD, Daniel van den Hove, PhD, Gunter Kenis, PhD,
Caroline M. Nievergelt, PhD, Marco P. Boks, MD, PhD, Eric Vermetten, MD, PhD,
Fred H. Gage, PhD, Bart P.F. Rutten, MD, PhD, and Laurence de Nijs, PhD
Introduction...............................................................................................................285
Posttraumatic stress disorder....................................................................................286
Epigenetics: The roles of microRNAs......................................................................286
Biogenesis and mode of action of microRNAs....................................................287
Circulating microRNAs.......................................................................................288
MicroRNAs in the central nervous system..........................................................288
xii Contents
MicroRNAs, stress, and PTSD.................................................................................289

Animal studies.....................................................................................................289
Human studies......................................................................................................295
Current challenges, pitfalls, and future perspectives................................................297
References.................................................................................................................299
CHAPTER 19 Potential transgenerational epigenetic effects of prolonged
stress and psychological trauma........................................................... 307
Nagy A. Youssef, MD, PhD, Laura Lockwood, DO, Shaoyong Su, PhD,
Guang Hao, MD, PhD, and Bart P.F. Rutten, MD, PhD

Introduction...............................................................................................................307

Studies on transgenerational effect of trauma and PTSD.........................................309

Transgenerational effects of trauma and stress and physical health.........................311

Discussion.................................................................................................................312

Acknowledgment......................................................................................................313

References.................................................................................................................313
CHAPTER 20 Targeting epigenetics as future treatments of trauma- and
stress-or-related disorders. Epidrugs and epinutraceuticals............ 317
Vinogran Naidoo, PhD, Olaia Martínez-Iglesias, PhD,
and Ramón Cacabelos, MD, PhD, DMSci
Introduction...............................................................................................................317
PTSD—Patterns of gene expression.........................................................................320
DNA methylation.................................................................................................321
Histone modifications in PTSD...........................................................................328
Regulatory RNAs and their relevance to PTSD...................................................329
Neurotransmitter systems and their epigenetic relationships with PTSD................331
Epigenetics of comorbid depression and anxiety in PTSD......................................334
The implications of epigenetics for the treatment of PTSD and stress-related
disorders...............................................................................................................336
Current drug-based treatments for PTSD and comorbid disorders......................337
Epigenetic-based drugs (epidrugs) for neuropsychiatric stress-related
disorders...............................................................................................................355
Epinutraceuticals with therapeutic potential for trauma- and stress-or-
related disorders...................................................................................................362
Conclusions and future perspectives.........................................................................366
References.................................................................................................................367
Further reading..........................................................................................................390
Index....................................................................................................................................................393
Contributors
Charlotte Bainomugisa, MEpi
Queensland University of Technology (QUT), Centre for Genomics and Personalised Health,
Faculty of Health, Kelvin Grove, QLD, Australia
Dewleen G. Baker, MD
Department of Psychiatry, University of California; VA Center of Excellence for Stress and Mental
Health; VA San Diego Healthcare System, San Diego, CA, United States
Marco P. Boks, MD, PhD
Psychiatry, Brain Center UMC Utrecht, Utrecht, The Netherlands
Dušan Braný, PhD
Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in
Bratislava, Martin, Slovakia
Belinda U. Busogi, BSA
Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The
University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
Ramón Cacabelos, MD, PhD, DMSci
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic
Medicine, Corunna, Spain
Shiloh Cleveland, BA
Department of Psychology, University of California, Los Angeles, CA, United States
Sonia Dela Cruz, MD
University of Central Florida/HCA Healthcare Graduate Medical Education Consortium Psychiatry
Residency Program of Greater Orlando, Orlando, FL, United States
Daniel van den Hove, PhD
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience
(MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre,
European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands; Laboratory
of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy,
University of Würzburg, Würzburg, Germany
Dana Dvorská, PhD
Alana I.H. Escoto, MSc
European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Gabriel R. Fries, BSc, MSc, PhD
xiii
xiv Contributors
Fred H. Gage, PhD

Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
Thorhildur Halldorsdottir, PhD
Department of Psychology, Reykjavik University; Center of Public Health Sciences, Faculty of
Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
Guang Hao, MD, PhD
Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, People’s Republic
of China
Richard L. Hauger, MD
Department of Psychiatry, University of California; VA Center of Excellence for Stress and Mental
Health; VA San Diego Healthcare System, San Diego, CA, United States
Aileen Hsu, BS
Annie Jeong, BA
Jayesh Kamath, MD, PhD
Director, Mood & Anxiety Program, Department of Psychiatry, University of Connecticut School of
Medicine, Farmington, CT, United States
Gunter Kenis, PhD
Richard S. Lee, PhD
Department of Psychiatry and Behavioral Sciences, Mood Disorders Center, Johns Hopkins
University School of Medicine, Baltimore, MD, United States
Laura Lockwood, DO
Family Service and Guidance Center, Topeka, KS, United States
Olaia Martínez-Iglesias, PhD
Divya Mehta, BSc, MSc, PhD
Queensland University of Technology (QUT), Centre for Genomics and Personalised Health,
Faculty of Health, Kelvin Grove, QLD, Australia
Janitza L. Montalvo-Ortiz, PhD
Department of Psychiatry, Yale University School of Medicine, VA Connecticut Healthcare System,
Errera Community Care Center, Orange, CT, United States
Vinogran Naidoo, PhD
Jessica Nguyen, BS
Contributors xv
Caroline M. Nievergelt, PhD

Department of Psychiatry, University of California, San Diego, CA, United States
Laurence de Nijs, PhD
Shota Nishitani, PhD
Research Center for Child Mental Development, University of Fukui, Fukui; Division of
Developmental Higher Brain Functions, United Graduate School of Child Development, Osaka
University, Osaka, Japan
Jeffrey O’Neill, MD
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT,
United States
Safiye Bahar Ölmez, MD
Department of Psychiatry, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul,
Turkey
Aarti Patel, BA
Bhargav Patel, MD
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University,
Augusta, GA, United States
Parit Patel, MBChB
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT,
United States
Demietrice Pittman, PhD
US Army, Army Recruiting Command, Joint Base Fort Sam Houston, Houston, TX, United States
Kristina Reed, BA
Bart P.F. Rutten, MD, PhD
Erika M. Salarda, BSc
Clara Snijders, PhD
Ján Strnádel, PhD
xvi Contributors
Arthur Su, MD
University of Connecticut School of Medicine, Farmington, CT, United States
Shaoyong Su, PhD
Department of Medicine, Georgia Prevention Institute, Medical College of Georgia, Augusta
University, Augusta, GA, United States
Jennifer A. Sumner, PhD
Jordan Thomas, MA
Heiddis B. Valdimarsdottir, PhD
Department of Psychology, Reykjavik University, Reykjavik, Iceland; Icahn School of Medicine at
Mount Sinai, Population Health Science and Policy, New York City, NY, United States
Unnur A. Valdimarsdottir, PhD
Center of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of
Iceland, Reykjavik, Iceland; Department of Medical Epidemiology and Biostatistics, Karolinska
Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard TH Chan School of Public
Health, Boston, MA, United States
Eric Vermetten, MD, PhD
Brain Research & Innovation Centre, Ministry of Defence, Utrecht; Department of Psychiatry,
Leiden University Medical Center, Leiden, The Netherlands
Sophia Walker, MD
University of Connecticut School of Medicine, Farmington, CT, United States
Onur Yılmaz, MD
Doğuş University, Istanbul, Turkey
Nagy A. Youssef, MD, PhD
Department of Psychiatry & Behavioral Health, The Ohio State University College of Medicine,
Columbus, OH, United States
Sheila Zhang, BS
Foreword
I am proud to write the foreword of this groundbreaking book in a very important area of genomic
medicine focused on stress disorders that include posttraumatic stress disorder (PTSD) and depression
edited by Professor Youssef. The chapters in the textbook are authored by Dr. Youssef along with many
experts in the fields of genomics, neuroscience, pharmacology, and clinical sciences. As the Dean of
The Ohio State University College of Medicine, I work with Dr. Youssef and I am well aware of his
expertise and contributions to the literature and field.
Professor Youssef is a clinician-scientist and leading expert in the areas of genomics medicine
and neuromodulation. He studies treatment-resistant psychiatric disorders, especially mood disorders
and PTSD. He is Professor of Psychiatry and the Director of Clinical Research in the Department of
Psychiatry and Behavioral Health at The Ohio State University College of Medicine.
This book, Epigenetics of Stress and Stress Related Disorders, is important to both clinicians and
researchers as it presents both clinical care and translational research. It covers areas that impact both
our psychological and physical health by examining the epigenetic mechanisms that modify DNA
functioning or gene expression following prolonged stress and/or trauma. Beginning with the evalu-
ation of both the physiological and molecular impact of stress on the brain, brain function, and the
body, and how stress can eventually lead to disorders, the book also examines several other important
areas, including the long-term physical effects of PTSD on the health, the effect of stress disorders on
telomeres and aging, and the effect of adversity across time. The authors discuss whether there are
certain time-sensitive periods in the life span when people are more susceptible to adversity-induced
epigenetic changes, and explore the implications of different human samples (for example, blood ver-
sus saliva) on the examination of epigenetics and the epigenetic correlation of those samples to brain
epigenetics and pathology.
The textbook presents the important developments and studies in noncoding RNAs, including mi-
croRNAs, and concludes by examining two crucial and cutting-edge areas: the effects of trauma and
stress transgenerationality from an epigenetic perspective, as well as the potential for the development
of epigenetic therapeutics, or “epidrugs,” for stress-related disorders.
A very valuable resource for researchers and clinicians interested in stress and stress-related disor-
ders, the book is a must-read for those who would like to understand the cutting-edge genomic sciences
that underlie the interface between gene and environment and its functional genomic and phenomic
implications.
Carol R. Bradford, MD, MS, FACS
Dean, College of Medicine
Vice President for Health Sciences, Wexner Medical Center
Leslie H. and Abigail S. Wexner Dean’s Chair in Medicine
Professor of Otolaryngology–Head & Neck Surgery
xvii
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Acknowledgments
This book is dedicated to my family. I am very appreciative of my family and friends who endured
with me during the process of editing and writing this book. I also appreciate the support of my col-
leagues at the Department and Medical School. I appreciate the collaborative exchange of knowl-
edge, invigorating discussions, and collaborations with national and international colleagues at the
Psychiatric Genomics Consortium for PTSD and the workgroups.
This journey would have not been possible without the generosity of all the above individuals. I am
also greatly indebted to my patients and the research participants who volunteered for the advancement
of science, finding transformative treatments, and future cures.
xix
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CHAPTER
The physiology of stress and

the human body’s response
to stress
1
Richard S. Lee, PhD
Department of Psychiatry and Behavioral Sciences, Mood Disorders Center,
Johns Hopkins University School of Medicine, Baltimore, MD, United States
Introduction
The term “stress” was first coined by Hans Selye in 1936 when it was used to define “the non-specific
response of the body to any demand for change.”1 Stress encompassed what had been known as the
“fight-or-flight” response.2 Until our very recent history, the stress response was largely needed and
activated for brief bursts of energy for acts of survival of an organism such as evading predators, hunt-
ing prey, and securing mates, all of which are requisite survival traits for natural selection. However,
the Industrial Revolution in the 18th and 19th centuries changed the human stress experience, the
psychosocial remnants of which can still be observed in the very cities in which it started.3 What was
finely tuned over eons to enable organisms to exercise competition in nature has become a physiologi-
cal liability in the modern-day society. The system that had served our ancestors well in evading a lion
or engaging in brief skirmishes with other tribes now had to contend with worrying about mortgage or
spending hours in traffic; the stress response was not tuned for situations where the stressors became
chronic. As a result, humans exposed to chronic stressors began to exhibit a host of ailments driven in
part by stress and its associated hormones. Chronic stress exposure contributes to the burden of almost
all chronic diseases in the United States, such as heart disease, cancer, stroke, diabetes, and obesity.4
This chapter will begin by examining stress as an environmental factor and how it is unique from
other environmental factors such as exposures to infections or toxicants. The cascade of neuroendo-
crine responses to stress, starting from the experience of real or perceived stressors to the activation of
the sympathetic nervous system and hypothalamic-pituitary-adrenal axis (HPA axis) that culminates
in the release of the stress hormone cortisol, will be discussed. The chapter will also distinguish be-
tween acute and chronic stress response and the consequences of the latter on different organ systems
with special emphasis on the brain, psychiatric disorders, and behavior. A framework for how chronic
stress exposure impacts homeostatic cortisol levels will be proposed. Understanding such a framework
necessitates a brief introduction to the molecular mechanisms of how cortisol can affect gene expres-
sion changes in the cell, where genetic and epigenetic mechanisms become indispensable. However,
the molecular mechanisms of how stress exposure impacts gene function will be discussed in greater
detail in another chapter. Instead, it is hoped that the readers will gain a foundational knowledge on
stress response and some of the basic stress mechanisms to appreciate many of the detailed chapters
in this book.
Epigenetics of Stress and Stress Disorders. https://doi.org/10.1016/B978-0-12-823039-8.00017-4

Copyright © 2022 Elsevier Inc. All rights reserved.
1
2 Chapter 1 The physiology of stress and the human body’s response to stress
Stress as an environmental factor

Sometimes it may take an observer a moment of pause before considering stress as an environmental
factor. That is because triggering the stress response may not require that a person be directly exposed
to or ingest some physical substance. For instance, it is well established that environmental toxicants
such as lead wield a pernicious effect on neurodevelopment when exposed even at low quantities.5
Likewise, ionizing radiation, such as those emitted by X-ray machines or a nuclear power plant,
causes double stranded breaks in DNA.6 However, one can be sitting perfectly still in his car stuck in
traffic on the 495 Beltway in DC and yet, his stress hormone level is through the roof. Other than the
DC pollution seeping through the car’s ventilation system, no external chemical or physical factor has
entered the person to precipitate the stress response. The mere perception or thought of nonimmediate
events can trigger a stress response. Stress can also be highly subjective. For instance, the stressful
experience of solving mathematical problems in front of a group of people, such as those administered
during the Trier Social Stress Test,7 may not be challenging to calculus teachers who routinely per-
form these tasks in front of dozens of students. Even when a person is physically attacked, the stress
response is not due to the sustained physical damage, but rather the person’s awareness of the pos-
sibility of harm. Yet, the impact of stress can be just as detrimental to the body as many real, physical
environmental factors.
Stress is considered an environmental factor because stressors, which can be situational, mental, or
physical in nature, are external and can lead to powerful physiological responses in the human body
even without any physical contact. In other words, stressors, whether real or perceived, are a conse-
quence of our interactions with the environment even if they only manifest themselves as mere thoughts
in the minds of the “stressee.” In contrast, the response to these external stressors is almost always
internal and may require no direct, physical contribution from the environment.
The basics of the stress response

What happens when the stress response is provoked? Once stress has been perceived by the brain,
actions of the amygdala, the fear center of the brain, and the hypothalamus activate the sympathetic
nervous system that in a matter of seconds lead to the release of cortisol, adrenaline (epinephrine), and
noradrenaline (norepinephrine) from the adrenal glands. These actions then activate the HPA axis and
involve a cascade of neuroendocrine hormones that culminates in the additional release of the stress
hormone cortisol. First, the paraventricular nuclei or PVN, a small subpopulation of neurons in the
hypothalamus, release the corticotropin releasing hormone or factor (CRH or CRF), and the release
activity is dependent on the anticipation of the outcome.8 CRH released from the PVN travels down-
ward to the anterior pituitary via the hypophyseal transport system of capillaries that connect the two
structures.9 Activation of CRH receptors (CRHR1) on the anterior pituitary promotes the release of
adrenocorticotropic hormones (ACTH) that are released into the blood circulation.10 ACTH reaching
the adrenal glands binds and activates the melanocortin receptor type 2 (MC2R)11 that finally leads to
the release of cortisol into the bloodstream. Collectively, as mentioned, these three endocrine tissues
make up the HPA axis responsible for mounting the stress response and releasing cortisol. While sec-
ondary to the sympathetic nervous system in terms of time for activation (minutes vs seconds),12 the
HPA axis plays a more prominent role in chronic diseases due to the prolonged availability of cortisol
Sympathetic and parasympathetic systems 3
in the bloodstream, although there is evidence to suggest that both the sympathetic nervous system and
the HPA axis are interconnected and contribute to the impact of stress exposure on the body.13
There are additional factors that are released at the same time as cortisol and constitute a part of
the stress response. Additional factors that are integral to the stress response are pro-inflammatory cy-
tokines such as IL-1B and IL-6 that provoke the immune system14, 15 and hormones such as prolactin
and testosterone.16, 17 Release of these types of cytokines may seem counterintuitive given the immune-
suppressive nature of cortisol. However, chronic exposure to stress has a prolonged suppressing effect
on the immune system, as steroid medications or derivatives of cortisol such as dexamethasone or
prednisone are used to treat autoimmune diseases such as rheumatoid arthritis or asthma, or recently
the inflammatory “cytokine storm” associated with COVID-19.18
Sympathetic and parasympathetic systems

Together, the endocrine factors elicit a specific set of physiological response in the human body. It
is entirely geared toward the expenditure of energy in the form of glucose for mounting the “fight or
flight” response. The activation of the stress response mediated by the sympathetic nervous system and
the HPA axis involves the immediate increase in heart rate, blood pressure, and glucose release aimed
toward providing energy to the muscles. Alertness and vigilance are also increased.19 In the animal
kingdom, the gazelle is able to outmaneuver the charging cheetah, or the male walrus bull is able to
overpower another challenger to his harem. A human equivalent may be giving a presentation at a board
meeting or running to catch a train. In all of these instances of stress response activation, the stressors
are acute for the most part and the body returns to its prestress, homeostatic baseline following the
resolution of the conflict.
It is important to note that the stress response that has evolved throughout evolution has been honed
mostly as a transient response. Mobilization of energy to tackle what for most of the animals is life-and-
death situations is relatively short in duration and comes at a great cost. During this period, activities
of several important bodily functions become marginalized in terms of priority. Processes involved
in storing away energy, fighting infections, digesting food, and engaging in reproductive transactions
come to a halt.20 These are reasonable short-term inconveniences given that a failure to mount an effec-
tive “fight or flight” response to survive predation renders these otherwise essential endeavors moot.
However, once the stressor has subsided, the system must return to normal for the animal to continue
its life. Therefore the body has also developed a rapid negative feedback system to quickly restore the
body to the baseline state. The parasympathetic nervous system is engaged to achieve homeostasis.21
Importantly, increased levels of cortisol in the bloodstream, in addition to its primary role of making
glucose available, initiate the suppression of CRH and ACTH release from their respective tissues, ulti-
mately causing the attenuation of additional cortisol release. The acute release of stress hormones and
the repertoire of coping behavior that they facilitate are ideally suited for the animal kingdom and many
instances in the human experience where the stressors are sporadic and brief in nature.
An argument could be made that acute stressors are beneficial for the most part, so long as the
organism does not sustain physical harm. For animals avoiding predation and competing for food and
mates, stressors provide the means by which their genetic fitness could be tested. Having succeeded
through the stressors meant not only the continued opportunities for propagation, but increased fit-
ness and probability to survive the next stressor. The increase in fitness included better physiological
response through stronger muscles and cardiovascular system as well as the increases in mental acuity
and learned response. In humans, similar adaptive response is also in play, as exposure to acute stress-
ors and transient activation of the sympathetic nervous system is beneficial to physical fitness and men-
tal acuity. One such example is vigorous physical exercise. Exercise can be seen as an acute stressor
that causes the release of cortisol and adrenaline for the purpose of predefined energy expenditure.22
Its benefits are many, from prevention of cardiovascular disease, diabetes, obesity, and others that are
associated, interestingly, with chronic stress exposure. In particular, regular intermittent exercise can
also prevent neurological disorders such as Alzheimer’s disease23, 24 and the amelioration of psychiatric
disorders such as anxiety and depression.25, 26 Unfortunately, as we will see, the development of the
modern society and the resulting social infrastructure has created an environment where the stressors
are long lasting and recurrent. Such an environment has led to a prolonged activation of the HPA axis
with detrimental physiological consequences, especially to the brain.
Allostasis and allostatic load

Prolonged HPA axis activation due to chronic stress exposure is not unique to humans but is an integral
part of the human experience in the 21st century. The workweek for some translates to more than 60 h/
week to meet deadlines. There is a family to support and mortgage and car payments to make. There are
many anxiogenic social events on a daily basis, whether they be from the supervisor, a spouse, or the
elected leadership. There is also a pandemic that has greatly diminished the (positive) physical social
interactions that are needed for wellbeing. In fact, prolonged social isolation is a potent stressor that
also activates the HPA axis and has been used in animals to study various symptoms of depression such
as anhedonia, learned helplessness, and cognitive deficits.27–31 All of these stressors contribute to the
overburdening of the HPA axis and cause deleterious symptoms in multiple organ systems.
Here, we introduce the term allostasis and allostatic load to describe the body’s maladaptive response
to chronic stress. Allostasis refers to the ability and desire of the body to return to homeostasis following
stress exposure.32 As mentioned before, the actions of the sympathetic nervous system, the HPA axis,
and their hormones cortisol and adrenaline to mount a stress response and the negative feedback system
involving cortisol and the parasympathetic nervous system altogether constitute an adaptive response
designed to reestablish homeostasis once the stressor has passed. Unfortunately, many man-made events
and circumstances have created environments where allostasis cannot be rapidly achieved. Repeated
and/or prolonged stressful events impact the HPA axis by flooding the bloodstream with cortisol and
adrenaline. The negative feedback system and the parasympathetic nervous system become impaired,
and hypercortisolemia continues to wreak havoc on different organ systems. The term allostatic load
was first coined by McEwen and Stellar in 1993 and refers to the degree to which the amount of “wear
and tear” or disease burden that chronic stress has exacted on the body.33 In instances of acute stress, al-
lostatic load is minimal. However, with allostasis being overburdened by chronic or repetitive stress, the
allostatic load becomes substantial and the overall stress response becomes maladaptive.
Allostatic load and disease burden

The sequelae of increased allostatic load are many and serve as a testament to the pernicious effects of
chronic stress. Many of the symptoms logically follow the long-term effects of the adaptive response in
Allostatic load and the brain 5
terms of energy utilization and marginalization of processes that are secondary to immediate survival.
For instance, increased risk to cardiovascular disease, hypertension, and diabetes makes intuitive sense,
since acute stressors cause increased heart rate, blood pressure, and hyperglycemia, respectively.34, 35
Also, impaired fertility, disruptions in GI function, and susceptibility to infections are likely to be
long-term manifestations of noncritical processes that have become marginalized during the “fight or
flight” response.36–38 In contrast, there are some that may be counterintuitive such as obesity, since
acute stressors favor energy utilization rather than storage.39 Regardless, it is important to note that
stress exposure plays such a significant role in the development of diseases that occupy such promi-
nent positions in terms of disease burden and prevalence in the United States.4 It would be of critical
importance to be able to empirically assess the extent to which chronic stress exposure contributes to
these diseases.
Great effort has been made to operationalize the concept of allostatic load in terms of physiologi-
cal parameters that can be measured. The MacArthur Successful Aging Study concluded that the ma-
jor determinants of allostatic load include systolic and diastolic blood pressure, waist hip ratio, LDL
cholesterol, HbA1C, DHEA-S, norepinephrine, epinephrine, and the glucocorticoid cortisol.40 Although
many of these measurements also have nonstress-related causes, they are nonetheless important assess-
ments for estimating the cumulative “wear and tear” on the body and can be recapitulated in a myriad
of animal models of stress that have excluded other contributing factors such as high-fat diet.41–44 The
contribution of chronic stress to any particular disease cannot be accurately assessed in humans due to
the difficulty of controlling for genetic diversity, food intake, environmental exposures, and behavior
as one can when using animal models. Instead, human studies must involve large swaths of the popula-
tion, and these confounding factors have to be controlled for by statistics.
The potential role for allostatic load in the human population can be best exemplified by the two
Whitehall studies of British civil servants. The first study examined 17,530 male civil servants and
observed that the grade of employment was a stronger predictor for coronary heart disease (CHD)
mortality than any other major coronary risk factors.45 The second Whitehall study was longitudinal
and prospective in design and examined 10,314 participants that included both male and female civil
servants.46 In addition to replicating the inverse correlation between grade level and CHD mortality of
the first study, the second study also focused on psychosocial factors such as stressful work environ-
ment, lack of social support, and financial difficulties, all of which were also inversely correlated with
the employment grade. While there is no universally accepted causal factor(s) for these relationships, it
is widely believed that chronic psychosocial stress (or “job strain”) likely played a prominent role given
its contribution to CHD and other metabolic diseases.47, 48
Allostatic load and the brain

One of the organs associated with chronic stress exposure not mentioned before (but of primary focus
in this book) is the brain. As mentioned previously, acute stress, for the most part, can be beneficial
to multiple organ systems, and the brain is no exception. Exposure to acute stress is associated with
enhanced short-term memory and memory consolidation.49, 50 These benefits are further supported by
increased neurogenesis and neuroprotection following exposure to acute stress.51–53 Interestingly, a
recent work using animal models of stress reported that acute stress inoculation can even increase re-
silience against future stressors.54 In contrast, chronic stress exposure generally has the opposite effect
and is associated with poor cognitive performance and memory.55, 56 In fact, one of the primary physi-
ological response of the brain to chronic stress has been a reduction in the volume of the hippocampus
that is associated with memory loss.57–59 Reduction of hippocampal volume is supported by animal
models of stress, in which prolonged exposure to chronic stress is associated with suppression of neu-
ronal proliferation, differentiation, and survival.60–62 In addition, chronic stress exposure is associated
with affective disorders such as depression and anxiety.63, 64 Another psychiatric disorder that arguably
can be included is posttraumatic stress disorder (PTSD). Although the term trauma often implies a
stressor of high magnitude and short duration, PTSD can be borne from stressful experiences that span
years, such as combat duty or child abuse.65, 66
Cortisol as the primary driver of the chronic stress response

Of the several endocrine factors and cytokines that mediate the chronic stress response, the primary
factor is cortisol. This is because adrenaline and noradrenaline are rapidly metabolized by the liver after
several minutes.67 On the other hand, cortisol has a longer half-life on the order of 1–2 h and as will be
discussed shortly, can have a long-lasting effect on gene function.68 Unlike adrenaline and noradrena-
line that are derived from the amino acid tyrosine, cortisol is derived from cholesterol.69 As such, it is
a hydrophobic compound that readily crosses the plasma membrane. While water-soluble ligands bind
to their corresponding receptors residing on the cell surface, receptors for cortisol reside in the cyto-
plasm. Two main receptors are the mineralocorticoid (MR) and glucocorticoid receptors (GR). Cortisol
is preferentially bound to the MR at low concentrations but shifts its preference for the GR at higher
concentrations.70 For the remainder half of the chapter, there will be much more focus on cortisol as the
primary hormone and the GR, as this receptor species mediates the intracellular signaling at elevated
cortisol concentrations.
Cortisol is also one of many steroid hormones (corticosteroids) classified under the umbrella term
glucocorticoids (GCs). Other glucocorticoids differ from cortisol from their route of administration,
bioavailability, and potency among many attributes. For instance, hydrocortisone is available as an
ointment for reducing swelling and inflammation on the skin, whereas prednisone is often prescribed
as an inhalant for asthma. Dexamethasone is a synthetic derivative of cortisol generally used for its
antiinflammatory and immunosuppressant properties that are up to 30 times more potent than the ac-
tions of cortisol.71
Glucocorticoids and the brain

The effect of GCs on the brain as part of its physiological response to chronic stress can be best ap-
preciated by several important studies that highlight cortisol’s impact on psychiatric symptoms. The
Whitehall Studies mentioned before reported significant association between depression and lower
employment grade (i.e., psychosocial stress).72 Clinical studies of Cushing’s disease in which ACTH-
secreting pituitary tumors cause the copious release of cortisol (hypercortisolemia) delineate a causal
role of cortisol on psychiatric disorders. Cushing’s patients have a high incidence of depression and
anxiety in 50%–80% of cases, both of which become alleviated following the resolution of hypercorti-
solemia with a surgical or biochemical cure.73–76 An even more powerful demonstration of the actions
of GCs can be seen in a large epidemiological study involving hundreds of thousands of participants,
Intracellular negative feedback and glucocorticoid resistance 7
in which significantly higher incidences (hazard ratios) of mania, depression, suicidal ideation, and
panic disorder were observed in patients administered corticosteroids over nonsteroidal antiinflamma-
tory drugs for nonpsychiatric, autoimmune-related diseases such as rheumatoid arthritis, lupus, and
asthma.77 These studies in humans are supported by hundreds of studies that have employed various
chronic stress regimen or GC exposure in rodents to provoke a stress response. These rodent studies
have not only examined stress-induced behavior under controlled conditions but have also investigated
molecular changes in the brain that can potentially account for behavior.78
Molecular mechanism of cortisol action

Up to this point, response to stress has been described in the context of neuroendocrine hormones and
their outcomes on physiology. A stress response at the cellular level of GC/cortisol signaling neces-
sarily follows a physiological response involving a systemic disruption of GC homeostasis. To better
understand how the maladaptive stress response unfolds in the tissues, especially the brain, a molecular
understanding of cortisol action on cells is needed. Since the granular detail of cortisol action will be
discussed elsewhere, only a summary will be provided to help the readers gain a glimpse of the overall
framework. In the chronically stressed state, cortisol has the capacity to reprogram cellular function by
genomic and nongenomic mechanisms in the cell.
The basic GC signaling involves the binding of cortisol to the GR and its dissociation from a com-
plex of chaperone proteins that aids in the proper folding of proteins under challenging conditions such
as elevated heat and oxidative stress.79, 80 Some of these proteins include heat shock proteins 70 and
90,81 as well as a protein called FKBP5 (or FK506-binding protein 5) that plays a crucial role in regulat-
ing GC signaling.82 Once dissociated from this complex, cortisol-bound GR homodimerizes with other
GR proteins and interacts with structural and motor proteins that facilitate its entry into the nucleus.83, 84
Once in the nucleus, the GR dimer acts as either a transcription factor or repressor where its DNA
binding domain binds DNA sequences called GC response elements (GREs) and facilitates either tran-
scription or suppression by recruiting appropriate cofactors to the gene promoter.85, 86 Interestingly, the
dual function of the GR as both receptor and transcription factor is a unique feature of nuclear receptor
hormone signaling that also extends to other sex steroid hormones such as estrogen, androgen, and pro-
gesterone.87 Genomic effects of GC signaling in the cell affects a common set of GC target genes across
all cell types as well as those specific to each tissue for exacting a well-defined physiological response
that likely contributes to the different organ diseases associated with chronic stress exposure.88 It is
also worthwhile to note that the activated glucocorticoid receptor has additional functions in the cell
that involves nongenomic effects such as protein modifications and protein interactions.89 However,
it is unclear how different stress conditions, i.e., chronic vs acute, affect protein interactions and lead
to chronic disease conditions. The differential response between chronic vs. acute stress exposure has
been better understood in the context of genomic effects of GC signaling that has an impact on systemic
cortisol dynamics and cell-specific function through epigenetic mechanisms.
Intracellular negative feedback and glucocorticoid resistance

In addition to the negative feedback system that exists at the HPA axis tissue level, there is also an ad-
ditional feedback control at the intracellular level. While the tissues of the HPA axis seek to attenuate
further cortisol release from the adrenal glands, proteins seek to limit intracellular signaling medi-
ated by chronically elevated cortisol. One of the target genes that are immediately transcribed by GC
signaling is the FKBP5 gene (gene: FKBP5 and protein: FKBP5).90 Other than its potential involve-
ment in the suppression of the immune system by cortisol,91 the FKBP5 protein functions to suppress
intracellular GC signaling by binding closely to the GR and preventing its activation by cortisol.84, 92
Consequently, the inability of the GR to utilize the available cortisol leads to a buildup of cortisol
outside of cells (hypercortisolemia) and a condition called glucocorticoid resistance, where the cells
become less sensitive to high levels of cortisol. In fact, cross-species molecular analysis of FKBP5
showed hypercortisolemia and glucocorticoid resistance observed in New World monkeys is due to the
overexpression of FKBP5 and the increased affinity of the monkey FKBP5 protein for the GR complex
compared to that of the human protein.93, 94
Another protein that can limit excess cortisol signaling is GR itself.95 In fact, studies have shown
that GC signaling via GR can suppress the NR3C1 gene (Nuclear Receptor Subfamily 3 Group C
Member 1 that encodes the GR) by binding “negative” GREs within an intron of NR3C1 and promoting
its suppression.96 This second negative feedback is a more obvious mechanism that directly limits the
level of the GR protein involved in binding cortisol and mediating its effects on transcription. The tran-
scriptional regulation of FKBP5 and NR3C1 occurs in both instances of acute and chronic stress expo-
sure. However, the development of GC resistance is specific to chronic stress exposure where dynamic
changes in gene function occur from prolonged cortisol action or in individuals with genetic variations
in NR3C1 that impair GC signaling.97–99 To gain an insight into how chronic stress exposure leads to
long-term changes in gene function, a basic understanding of epigenetic mechanisms is needed.
Epigenetics
A mechanistic insight of how GCs affect gene function through epigenetic modifications is integral to
our understanding of our body’s physiological response to stress. As the name suggests, epigenetics
refers to modifications on DNA, modifications on histones, or cylindrical proteins around which ge-
nomic DNA is “wrapped,” and noncoding RNA species that affect transcription or translation of target
genes. These epigenetic factors can influence gene function without involving any changes in the un-
derlying DNA sequence. Modifications on DNA and histones work by either structurally restricting or
facilitating the access of transcription factors to DNA. Noncoding RNAs can be small RNA species
such as microRNAs, which are ~ 22 nucleotides (nts) or bases long and impair translation of mRNAs
by sequence-specifically binding to their 3′-untranslated regions.100, 101 There are also long noncoding
RNAs defined as > 200 nts and can be as long as 17 kilobases in the case of the X-inactive specific
transcript (Xist) for silencing one of the two X chromosomes in females.102 Recent studies have identi-
fied yet a fourth candidate epigenetic mechanism in the form of covalent modifications on RNA that
influence its stability in an emerging field called epitranscriptomics.103, 104 Importantly, there is func-
tional crosstalk among the different epigenetic mechanisms to influence gene function. For example,
methylated DNA promotes the binding of transcriptional repressors such as MeCP2 that alters DNA
accessibility by recruiting histone-modifying enzymes.105, 106
There are many biological processes that depend on epigenetic mechanisms, such as cell differ-
entiation, X-inactivation, and genomic imprinting among many others.107–109 Epigenetic mechanisms
become especially relevant for understanding the physiological impact of environmental factors. Here,
Epigenetics 9
FIG. 1.1
Physiological response to chronic stress and glucocorticoid (GC) exposure. Top: Sources of cortisol or GC
exposure can be environmental or iatrogenic, such as through steroidal medications for the treatment of
asthma, rheumatoid arthritis, or lupus. Middle: Chronically elevated GC levels lead to several endocrine and
molecular consequences. One of these consequences is impaired negative feedback of the HPA axis and
altered systemic GC homeostasis. At the cellular level, excess GC signaling alters gene function through
interactions with genetic variations (genetic risk) and by epigenetic mechanisms. Nongenomic mechanisms
such as protein modifications may also be involved. Alterations in gene function can further influence
homeostatic GC levels and tissue-specific processes. Bottom: Disruption of normal tissue-specific processes
by GCs contributes to diseases and symptoms across multiple organ systems.
exposure to an environmental stressor, i.e., chronic exposure to psychosocial stress or GCs, leads to
elevated levels of cortisol (or GCs) inside the body that begins to alter the functions of genes, tissues,
and organs through, in part, epigenetic mechanisms (Fig. 1.1). In fact, epigenetic mechanisms have
been shown to play a role in modulating GC-induced changes in gene expression.110 They are impor-
tant in GC signaling, because they, along with altered GC homeostasis (see later), genetic risk, and
nongenomic protein modifications (e.g., protein kinase and phosphatase activity), provide the means to
transduce environmental exposure or stimuli into persistent changes in gene function. It is important to
note that acute stress or GC exposure generally does not cause persistent epigenetic changes on a given
genomic locus, since the degree of epigenetic change is dependent on dose (duration and/or magnitude)
of exposure.111, 112
One of the more widely studied epigenetic mechanisms in GC signaling is DNA methylation.
Studies have shown changes in DNA methylation in intronic regions of the FKBP5 and NR3C1 (both
of which are two primary drivers of GC signaling and resistance) that coincide with GREs.113, 114 In
other words, binding of GR to its response element (GRE) facilitates methylation changes to nearby
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The Old Buddha first called on all present to draw near to the
Throne; then, speaking with great vehemence, she declared that it
was impossible for her to brook these latest indignities put upon her
by the foreigners. Her Imperial dignity could not suffer it. Until
yesterday, until, in fact, she had read the dispatch addressed to the
Tsungli Yamên by the Diplomatic Body, it had been her intention to
suppress the Boxers; but in the face of their insolent proposal that
she should hand over the reins of government to the Emperor, who
had already proved himself quite unfitted to rule, she had been
brought to the conclusion that no peaceful solution of the situation
was possible. The insolence of the French Consul at Tientsin Tu
Shih-lan (Du Chaylard), in demanding the surrender of the Taku
Forts was bad enough, but not so grievous an affront as the
Ministers’ preposterous proposal to interfere with her personal
prerogatives as Sovereign. Her decision was now taken, her mind
resolved; not even Jung Lu, to whom she had always looked for wise
counsel, could turn her from this purpose. Then, addressing more
directly the Chinese present, she bade them all to remember that the
rule of her Manchu House had conferred many and great benefits
upon the nation for the past two hundred and fifty years, and that the
Throne had always held the balance fairly in the benevolent
consideration for all its subjects, north and south alike. The Dynasty
had scrupulously followed the teachings of the Sages in
administering the government; taxation had been lighter than under
any previous rulers. Had not the people been relieved, in time of
their distress, by grants from the Privy Purse? In her own reign, had
not rebellions been suppressed in such a manner as to earn the
lasting gratitude of the southern provinces? It was therefore now
their duty to rally to the support of the Throne, and to assist it in
putting an end, once and for all, to foreign aggression. It had lasted
too long. If only the nation were of one mind, it could not be difficult
to convince these barbarians that they had mistaken the leniency of
the past for weakness. That leniency had been great; in accordance
with the principle which prescribes the showing of kindness to
strangers from afar, the Imperial House had ever shown them the
greatest consideration. The Emperor K’ang Hsi had even allowed
them liberty to propagate their religion, an act of mistaken
benevolence which had been an increasing cause of regret to his
successors. In matters of vital principle, she said, these foreigners
ignore the sacred doctrines of the Sages; in matters of detail, they
insult the customs and cherished beliefs of the Chinese people. They
have trusted in the strength of their arms, but to-day China can rely
upon millions of her brave and patriotic volunteers. Are not even
striplings taking up arms for the defence of their country? She had
always been of the opinion that the allied armies had been permitted
to escape too easily in the tenth year of Hsien Feng (1860), and that
only a united effort was then necessary to have given China the
victory. To-day, at last, the opportunity for revenge had come.
Turning to the Emperor, she asked for his opinion. His Majesty,
after a long pause, and with evident hesitation, urged her to follow
Jung Lu’s advice, to refrain from attacking the Legations, and to
have the foreign Ministers escorted in safety to the coast. But, he
added, it must be for her to decide. He could not dare to assume any
responsibility in the matter.
The junior Chinese Member of the Council, Chao Shu-ch’iao then
spoke. He begged the Old Buddha to issue her orders for the
immediate extermination of every foreigner in the interior, so as to
avoid the danger of spies reporting on the nature and extent of the
patriotic movement. Her Majesty commanded the Grand Council to
consider this suggestion and to memorialise in due course for an
Edict.
After him, however, each in his turn, the Manchu Li-shan, and the
Chinese Hsü Ching-ch’eng and Yüan Ch’ang implored the Empress
not to declare war against the whole world. China, they said, could
not possibly escape defeat, and, even if the Empire should not be
partitioned, there must arise great danger of rebellion and anarchy
from within. Yüan Ch’ang even went so far as to say that he had
served as a Minister of the Tsungli Yamên for two years and that he
had found foreigners to be generally reasonable and just in their
dealings. He did not believe in the authenticity of the despatch
demanding the Empress’s abdication, which Prince Tuan professed
to have received from the Diplomatic Body; in his opinion, it was
impossible that the Ministers should have dared to suggest any such
interference with China’s internal affairs.
At this Prince Tuan arose and angrily asked the Empress whether
she proposed to listen to the words of a Chinese traitor? Her Majesty
rebuked him for his loud and violent manner of speaking, but ordered
Yüan Ch’ang to leave the Audience Hall. No one else dared to say
anything.
She then ordered the promulgation of the Decree, for immediate
communication to all parts of the Empire; at the same time
announcing her intention of sacrificing at the ancestral shrines before
the commencement of hostilities. Prince Chuang and Duke Lan were
appointed joint Commanders-in-Chief of the Boxers, but Tzŭ Hsi
gave them clearly to understand that if the foreign Ministers would
agree to take their departure from Peking this afternoon Jung Lu was
to do his best to protect them as far as Tientsin. Finally, the Empress
ordered the Grand Council to report themselves at mid-day for
further orders. All were then permitted to retire with the exception of
Prince Tuan and Duke Lan; these remained in special audience for
some time longer. Hsü T’ung was present at the general audience,
having made good his escape from the Legation quarter, and was
congratulated by Her Majesty on his safety.
They say that Duke Lan told the Empress of a vision in which, the
night before, he had seen Yü Huang, the Jade Emperor. To him, and
to his company of Boxers while drilling, the god had appeared, and
had expressed his satisfaction with them and their patriotic
movement. The Old Buddha observed that the Jade Emperor had
appeared in the same manner at the beginning of the reign of the
Empress Wu of the T’ang Dynasty (the most famous woman ruler in
Chinese history); the omen, she thought, showed clearly that the
gods are on the side of China and against the barbarians.
When, at the hour of the Sheep (1 p.m.) Kang Yi returned to the
Palace, he found Prince Ch’ing in the anteroom of the Grand
Council, greatly excited. It seems that En Hai,[77] a Manchu
sergeant, had just come to his residence and reported that he had
shot and killed two foreigners whom he had met, riding in sedan
chairs that morning, just opposite the Tsungpu Street. As orders had
been issued by Prince Tuan and Ch’i Hsiu to the troops that all
foreigners were to be shot wherever met, and as one of these two
was the German Minister, he hoped that Prince Ch’ing would
recommend him for special promotion. Prince Tuan had already
heard the news and was greatly pleased. Prince Ch’ing and Kang Yi
discussed the matter and decided to inform the Empress Dowager at
once. Kang Yi did not think that the death of one foreign devil, more
or less, could matter much, especially now that it had been decided
to wipe out the Legations entirely, but Prince Ch’ing thought
differently and reiterated his opinion that the killing of an accredited
Envoy is a serious matter. Until now, only missionaries and their
converts had been put to death, but the murder of a Minister could
not fail to arouse fierce indignation, even as it did in the case of the
British negotiator[78] who was captured by our troops in the 10th year
of Hsien-Feng (1860).
The Grand Council then entered the presence. Prince Li, as the
senior member of the Council, told the Old Buddha the news, but
added that the foreigners had brought it on themselves because they
had first fired on the people. Upon hearing this Her Majesty ordered
Jung Lu to be summoned in haste, but Kang Yi, being extremely
busy with his work of providing supplies for the Boxers, did not await
his arrival.
Now, even as I write, they tell me that bullets are whizzing and
whistling overhead; but I am too deaf to hear them. En Ch’u says
that already the Kansuh braves have begun the attack upon the
Legations and that Jung Lu’s endeavours to have the foreigners
escorted to a place of safety have completely failed.
Liu Shun has just come in and asked for leave to go home for a
week. People are leaving the city in all directions and in great
numbers.
24th Day of the 5th Moon: the Hour of the Dog, 7-9 p.m. (June
20th, 1900).—En Ming has just come in to inform me that a foreign
devil[79] has been captured by Tung Fu-hsiang’s troops. They were
taking him, wounded, to Prince Chuang’s Palace, prodding at him
with their bayonets; and he was babbling in his foreign tongue. He
will be decapitated, and his captors will receive good rewards (Prince
Ch’ing has just been given command of the gendarmerie). “The rut in
which the cart was overturned is just ahead.” Let this be a warning to
those puny barbarian ruffians, the soldiery encamped at the very
gates of the Palace. (This alludes to the proximity of the Legations to
the Palace enclosure.) Jung Lu was all ready to escort the foreigners
to Tientsin; he had with him over 2,000 Manchu troops. Doubtless he
means well, but the Old Buddha now says that she will not prevent
the Kansuh braves from destroying the Legations. If the foreigners
choose to leave with Jung Lu, let them do so, and they will not be
attacked; but if they insist upon remaining, then their punishment be
upon their own heads, and “let them not say they were not
forewarned.”
Duke Lan sent over to invite me to breakfast with him to-morrow;
he is sore pressed with business cares just now; nevertheless, he
and his brothers always treat their old teacher with politeness and
respect. Though bellicose by nature, he is singularly gentle and
refined. Chi Pin[80] sent over to ask whether we would like to move
to his house in the north of the city, because the noise of the firing is
very great in our quarter, but I am so deaf that I hear not a sound of it
all.[81]
Chi Pin is writing to his father-in-law, Yü Hsien, about the audience
in the Palace.
Duke Lan writes to tell me that this evening ⸺ informed Prince
Tuan and Chi Hsiu that, by the orders of that rascally Chinaman,
Yüan Ch’ang, the corpse of the foreign devil had been coffined. ⸺
wanted Prince Tuan to have the corpse decapitated and the head
exhibited over the Tung An Gate. Yüan Ch’ang defends his action,
saying that he knew the German Minister personally at the Tsung Li
Yamên, and he cannot bear the idea of leaving his body uncoffined.
Mencius says, “It is common to all men to feel pity. No one can see a
child fall into a well without a shudder of commiseration and horror.”
But these Chinese traitors of ours are compassionate to the enemies
of our glorious Kingdom, and the foes of our ancient race. It is
passing strange!
25th Day of the 5th Moon: the Hour of the Monkey, 3-5 p.m. (June
21st).—My chair-bearers have fled from the city, so to-day I had to
use my cart to go to Duke Lan’s residence. Prince Tuan and the
Grand Secretary, Kang Yi, were there; also Chung Li, lately
Commandant of the gendarmerie, and the “Beileh” Tsai Lien. Prince
Tuan had seen the Old Buddha this morning; their Majesties have
moved from the Palace by the lake into the Forbidden City. As the
Empress Dowager was crossing the road which runs between the
Gate of the Hsi Yüan (Western Park) and the Hsi Hua Gate of the
Forbidden City she saw that a number of Boxers had lined up on
each side of the street as a Guard of Honour for the “Sacred
Chariot.” She presented them with 2,000 taels, congratulating their
commander, Prince Chuang, on their stalwart appearance. Said the
Old Buddha to Prince Tuan, “The foreigners are like fish in the stew-
pan. For forty years have I lain on brushwood and eaten bitterness
because of them, nursing my revenge like Prince Kou Chien of the
Yüeh State (5th Century b.c.). Never have I treated the foreigners
otherwise than generously; have I not invited their womenfolk to visit
the Lake Palace? But now, if only the country will stand together,
their defeat is certain.”
I think Prince Tuan hopes that the Old Buddha will now have the
Ta-A-Ko proclaimed Emperor; but unfortunately the Nanking Viceroy,
Liu K’un-yi, has much influence over her in this matter. When he was
in Peking this spring, in the second moon, he solemnly warned her
against the Boxers and ventured even to remonstrate at the Ta-A-Ko
being made Heir Apparent. Were it not for Liu K’un Yi, he would have
been Emperor long since; therefore Prince Tuan has a very bitter
hatred against him. Liu told the Old Buddha at his second audience
that if H.M. Kuang Hsü were deposed, the people of his province
would assuredly rise in rebellion. What concern is it of theirs who
reigns in the Capital? His present Majesty’s reign has brought many
misfortunes to the nation; it is high time that it came to an end. Why
does not Prince Tuan enter the Palace and proclaim his son
Emperor? Tung Fu-hsiang’s Kansuh braves and the Prince’s own
Manchu soldiery would surely rally round him. But if Jung Lu
opposed them the Old Buddha would side with him. His wife[82] is for
ever in the Palace.
26th Day of the 5th Moon (June 22nd).—I went this morning to
Prince Li’s palace in the western quarter of the city. I had to go in my
small cart, because my chair-bearers have either run away to their
homes in the country or had joined the Boxers. My two sons, En
Ch’u and En Ming, have been making arrangements to quarter one
hundred Boxers in our outer courtyard, and it seems that we shall
have to supply them with food. Although it cannot be denied that
everyone should join in this noble work of exterminating the
barbarians, I grudge, nevertheless, spending money in these hard
times even for the Boxers, for rice is now become as dear as pearls,
and firewood more precious than cassia buds. It may be that, in my
old age, I am becoming like that Hsiao Lung, brother to the founder
of the Liang Dynasty, who was so miserly that he stored up his
money in heaps. On every heap of a million cash he would place a
yellow label, while a purple label marked each hoard of ten millions.
It is recorded of him, that his relatives abused him for this habit; as
for me, my sons would like to get at my money, but they cannot.
I find Prince Li much depressed in his mind; his treasure vaults
contain vast wealth; as senior member of the Grand Council,
moreover, he feels a weight of responsibility that is too much for him.
His abilities are certainly small, and I have never yet understood why
the Old Buddha appointed him to succeed Prince Kung as senior
Councillor. He tells me of a stormy meeting at the Grand Council this
morning; it seems that Her Majesty is greatly annoyed with Liu K’un-
yi for sending in a telegram strongly denouncing the Boxers. He has
also telegraphed privately to Jung Lu, imploring him to check their
rebellion, but no one knows what answer Jung Lu has made.
In his telegram to the Empress Dowager, which came forward by
express couriers from Pao-ting-fu, the Viceroy declares that he
would be more than ready to march north with all his troops if it were
to repel a foreign invasion, but he firmly declines to lend his forces
for the purpose of massacring a few helpless foreigners.
Commenting on this, the Empress Dowager quoted the words of the
Classic Historical Commentary (Tso Chüan): “The upper and lower
jaws mutually assist each other; if the lips shrivel, then must the
teeth catch cold.” Thereby she meant to imply that even such, in its
close interdependence, is the relation between the northern and
southern parts of our Empire, and no one should know this better
than Liu K’un-yi, after his experiences at the time of the Taiping
Rebellion.
The Old Buddha has directed Prince Chuang, as head of the city
gendarmerie, to issue a proclamation offering Tls. 50 for every head
of a male barbarian brought in, Tls. 40 for that of a woman, and Tls.
30 for that of a child.
While I was still talking with Prince Li, Jung Lu came over in his
sedan chair to visit his kinsman. He looks very tired, and walks with
a limp. He was loud in denouncing the Boxers, who, he says, are
quite incapable of doing any good. They had even now dared to
shout abuse at him while passing the “Houmen,” calling him a
Chinese traitor. I could not help thinking that Jung Lu deserved the
name, but I did not say so. He is a strong man, the strongest of all
the Manchus, and I greatly fear that his influence may yet be able to
wreck all our hopes.
Returning to my house, I heard that the Princes Tuan and Chuang
were sending troops to surround the French Cathedral, which is
defended by a few foreign soldiers only, and which should, therefore,
be easily captured. Prince Li’s palace is within a stone’s throw of the
cathedral, and to enter the Forbidden City he has to pass just south
of it, through the “Hsi-Hua” gate. Although greatly disturbed by the
impending hostilities in his neighbourhood, he fears to move to a
quieter locality, lest, in his absence, his treasure vaults should be
plundered. No doubt the cathedral will fall in a few days.
My courtyard is now full of Boxers and Kansuh soldiery; I can no
longer call my house my own. How I loathe these cursed foreigners
for causing all this disturbance!
The same Day: at the Hour of the Dog (7-9 p.m.).—I learn that
Jung Lu has just sent off a courier with a telegram, which Yüan Shih-
k’ai is to send on to the Viceroys of Canton, Nanking and Wucha’ng.
Prince Li has sent me a copy, which I am to keep secret; it reads as
follows:—
“With all respect I have received your telegrams. Where

one weak people dares to oppose ten or more powerful
nations, the inevitable result can only be complete ruin. It has
always been maintained as a fixed principle with civilised
nations, that, in the event of war between any two Powers,
their respective Envoys should be treated with respect. Can it
now be that this our great inheritance, founded by our remote
ancestors at so great a cost of toil and danger, is to be
endangered, and suddenly brought to ruin, by these false
workers of magic? Shall the fate of the Dynasty be staked on
a single throw? It requires no peculiar sagacity to see that
these Boxers’ hopes of success are nothing but the shadow
of a dream. It is true and undeniable, that, from their
Majesties on the Throne down to the very lowest of our
people, all have suffered from the constant aggression of
foreigners and their unceasing insults. For this reason these
patriotic train-bands have been organised, claiming a divine
mission of retaliation; but the present crisis is all-serious, and
although I have used every effort to explain its dangers, I
have laboured in vain. I am sick and suffering from lameness,
but since I obtained leave of absence I have already
submitted seven separate memorials denouncing these
Boxers. Seeing that they produced no result, I have now left
my sick bed, in order, if possible, to explain the situation
clearly to their Majesties; and this also has been in vain.
“All the Princes and Ministers of State who surround the
Throne now cry out against me with one voice, as your
Excellencies can readily believe. I dare not quote in this place
the words of Her Majesty, but I may say that the whole of the
Imperial family have joined the Boxers, and at least two-thirds
of our troops, both Manchu and Chinese, are with them. They
swarm in the streets of our capital like a plague of locusts,
and it will be extremely difficult to disperse them.
“Even the divine wisdom of Her Majesty is not sufficient to
stand against the will of the majority. If Heaven is not on our
side, how can I oppose its will? For several days past I have
been pondering night and day on some way out of our
difficulties, some forlorn hope of escape. Therefore yesterday
morning (June 20th) I arranged for a meeting with the foreign
Ministers at the Tsung Li Yamên, with a view to providing a
safe conduct for the entire foreign community, with my own
troops, to Tientsin. This course appeared to me to hold out
some reasonable chances of success, but Prince Tuan’s
soldiery slew the German Minister, and since then the
situation continues to develop from hour to hour with such
extraordinary rapidity that words fail me to describe it. On my
side, in the discussions of the Grand Council and the
Chamberlains of the Presence, are Prince Ch’ing and Wang
Wen-shao, but the former, following his usual practice, has
applied for leave, and Her Majesty will have nothing to do with
him; so that these two are of no real assistance to me. I have
no fear of death, but I grieve at the thought of the guilt which
will be recorded against me in history; Heaven knows that I
am overwhelmed with grief and shame. I have received great
favours at the hands of the Throne, and can only now pray to
the spirits of the Dynastic ancestors to protect our Empire.
The situation here is well-nigh lost, but it remains for your
Excellencies to take all possible steps for the protection of
your respective provinces. Let each do his utmost, and let
proper secrecy be maintained.” Signed “Jung Lu, with tears in
his eyes.”
It is reported from the Grand Council that Chang Chih-tung has

telegraphed to Her Majesty, assuring her of his devotion and loyalty,
and asking whether he should come north with his troops to help in
the work of destroying the barbarians. Chang is a time-server, and
loves not the Emperor;[83] we have not forgotten how he approved
the Decree appointing an Heir Apparent, and how he would have
been a party to His Majesty’s removal from the Throne, justifying
himself on quibbling grounds of legality and precedents as to the
lawful succession. He trims his sails according to the wind of the
moment, and has no courage of fixed principles, like Liu K’un-yi. I
despise the latter’s views in opposing the Boxers, but no one can
help admiring his upright character.
(At this point the diarist proceeds to give a full account of the rise
and spread of the Boxer movement, describing in detail their magic
rites, their incantations, and their ceremonies of initiation. The facts
have nearly all been published before, so that most of this portion of
the Diary is here omitted. It is chiefly interesting as showing to what
heights of superstition even the most educated of the Manchus,
including the Empress Dowager, could go. We give one example
only of the farrago of gibberish which, believed in high quarters,
nearly brought about the end of the Dynasty.)
The Boxers also possess a secret Talisman, consisting of a small
piece of yellow paper, which they carry on their persons when going
into battle. On it is drawn, in vermilion paint, a figure which is neither
that of man nor devil, demon nor saint. It has a head, but no feet; its
face is sharp-pointed, with eyes and eyebrows, and four halos. From
the monster’s heart to its lower extremities runs a mystic inscription,
which reads: “I am Buddha of the cold cloud; before me lies the
black deity of fire; behind is Laotzu himself.” On the creature’s body
are also borne the characters for Buddha, Tiger, and Dragon. On the
top left-hand corner are the words “invoke first the Guardian of
Heaven,” and on the right-hand corner, “invoke next the black gods
of pestilence.” The Empress Dowager has learned this incantation by
heart, and repeats it seventy times daily, and every time that she
repeats it the chief eunuch (Li Lien-ying) shouts: “There goes one
more foreign devil.” The Boxers determine the fate of their victims by
a curious test, which consists of burning a ball of paper, and seeing
whether the ashes ascend or remain upon the ground. They may
believe that it is the spirits who decide, but, as a matter of fact, these
balls of paper are sometimes made of thinner material, which
naturally leave a lighter ash that is easily caught up in the air;
whereas, when they use thick paper, the ashes seldom rise. Some of
the balls are also more tightly rolled than others, and it is quite
evident that the ashes of the loose ones have a much better chance
of blowing away than those which are tightly rolled. Similarly, when
they set fire to any place, they profess to be guided by their gods,
and they say that fire leaps forth at the point of their swords in any
quarter which the spirits desire to have destroyed. As a matter of
fact, however, there is deception practised in this also, for when they
wish to burn any place for purposes of plunder they have it sprinkled
in advance with kerosene oil, and if no oil is available, they even pile
up brushwood around it, upon which they drop a lighted match
secreted upon their persons.
27th Day of the 5th Moon (June 23rd).—The foreign barbarian of
whom I have written[84] was executed this morning at the hour of the
Hare (6 a.m.) and his head is now exhibited in a cage, hanging from
the main beam of the “Tung-An” gate. It had to be put in a cage, as
there was no queue to hang it by. The face has a most horrible
expression, but it is a fine thing, all the same, to see a foreigner’s
head hung up at our palace gates. It brings back to memory the
heads that I saw outside the Board of Punishments in the tenth year
of Hsien-Feng (1860), but there were black devils among those.
Jung Lu tried to save the barbarian’s life, and even intended to
rescue him by force, but the Princes Tuan and Chuang had
determined upon his death, and they had him executed before Jung
Lu knew it, so that, when his men arrived upon the scene, the
foreigner’s head had already parted company from his body. The
Princes had him kneeling before them yesterday for several hours on
a chain, and all the time he kept on imploring them to spare his life;
his groans were most painful to hear. The Old Buddha has been
informed of his death, and she gave orders that Tls. 500 be
distributed to the soldiers who had captured him, i.e. a reward ten
times greater than that which was promised in the proclamations.
The Ta-A-Ko, Son of Prince Tuan, the Boxer Leader.
Appointed Heir-Apparent in January, 1900. Appointment rescinded November,

1901.
The Boxers who occupy my courtyard tried to take away my cigars

from me, but subsequently relented and allowed me to keep them
because of my extreme old age. Nothing of foreign origin, not even
matches, may be used nowadays, and these Boxer chiefs, Chang
Te-ch’eng and Han Yi-li, both of whom are common and uneducated
men, are treated with the greatest respect even by Princes of the
blood: a curious state of affairs indeed!
Duke Tsai Lan came to see me this afternoon. He tells me an
extraordinary story how that the Heir Apparent called the Emperor a
“Devil’s pupil” this morning, and, when rebuked for it, actually boxed
His Majesty’s ears. The Emperor then reported the facts in a
memorial to Her Majesty, who flew into a towering rage, and gave
orders to the eunuch Ts’ui to administer twenty sharp strokes of the
whip on the Heir Apparent’s person. Prince Tuan is much enraged at
this, but he is horribly afraid of Her Majesty, and, when she speaks to
him, “he is on tenter-hooks, as if thorns pricked him, and the sweat
runs down his face.”
T’ung Fu-hsiang told the Empress Dowager yesterday that the
Legations have come to the end of their tether. From a rockery on
some high ground in the Forbidden City gardens, the Old Buddha
could see the flames bursting from the Legation quarter, and was
more than once assured that final destruction had come upon the
foreigners at last. But later in the afternoon, Hsü Ching-ch’eng was
received in audience, when he presented a memorial which he and
Yüan Chang had drawn up, denouncing the Boxers; he told Her
Majesty that it was not the Legations, but the Han Lin Academy, that
was in flames, the Kansuh soldiery having set fire to it in the hope
that the conflagration might spread and thus enable them to force a
way into the Legation. Her Majesty was greatly disappointed and
displeased, severely blaming Tung Fu-hsiang, and she sent for Jung
Lu and talked with him in private for a long while.
Good news has come in to-day of victorious fighting at Tientsin; Yü
Lu reports that many foreigners were slain in their attack on the Taku
forts, and several of their warships sunk. Practically the whole of the
foreign community of Tientsin had been annihilated, he says.
Many hundreds of Chinese Christians were put to death to-day
just outside Prince Chuang’s palace. The judges who convicted them
were Prince Chuang, Yi Ku, Fen Che, and Kuei Ch’un. There was no
mercy shown, and a large number of innocent people perished with
the guilty. The Empress is essentially a kind-hearted woman, and
she was greatly shocked to hear of this wholesale massacre. She
was heard to say that if the Catholics would only recant and reform,
a way of escape might very well be provided for them.
29th Day of the 5th Moon (June 25th).—To-day about sixty of the
Boxers, led by the Princes Tuan and Chuang, and the “Beilehs” Tsai
Lien and Tsai Ying, marched to the Palace at 6 o’clock in the
morning to search there for converts. Coming to the gate of the
Palace of Peaceful Longevity, where their Majesties were still abed,
they noisily clamoured for the Emperor to come out, denouncing him
as a friend of foreigners. Prince Tuan was their spokesman. I heard
of the incident from Wen Lien, Comptroller of the Household, who
was on duty this morning; he was amazed at the foolhardy effrontery
of Prince Tuan, and thought that he had probably been drinking. On
hearing the noise outside and the shouts of the Boxers clamouring to
kill all “Devil’s pupils,” the Old Buddha, who was taking her early tea,
came out swiftly and stood at the head of the steps, while the
Princes and the Boxer leaders swarmed in the court-yard below her.
She asked Prince Tuan whether he had come to look upon himself
as the Emperor; if not, how dared he behave in this reckless and
insolent manner? She would have him know that she, and she alone,
had power to create or depose the Sovereign, and she would have
him remember that the power which had made his son Heir Apparent
could also wipe him out in a moment. If he and his fellow Princes
thought that because the State was at a crisis of confusion they
could follow their own inclinations in matters of this kind, they would
find themselves very seriously mistaken. She bade them depart, and
refrain from ever again entering the palace precincts, except when
summoned to her presence on duty. But they would first prostrate
themselves and ask His Majesty’s pardon for their insolent
behaviour. As a slight punishment for their offences, she further
commanded that the Princes be mulcted of a year’s allowances. As
to the Boxer chiefs, who had dared to create this uproar in her
hearing, they should be decapitated upon the spot, and Jung Lu’s
guards, who were on duty at the outer gates, were ordered to carry
this sentence into immediate effect. Her Majesty is so greatly
incensed against the Boxers at this moment that everyone thinks
that Jung Lu will now be able to put a stop to the attacks on the
Legations. The Emperor was much alarmed at this incident, and
when it was over humbly thanked Her Majesty for so benevolently
protecting him.
Later; 9 p.m.—The Old Buddha has suddenly determined, in her
rage against Prince Tuan and his followers, to put a stop to the
fighting in Peking, and she now agrees that Jung Lu shall proceed to
the Legations to discuss terms of peace. At 6 p.m. to-day all firing
stopped, and Jung Lu, at the head of his troops, proceeded to the
bridge which lies on the north of the Legation quarter. The foreigners
came out from their hiding-places and commenced to parley; they
were shown a board, and on it the words written: “Orders have now
been received from the Empress Dowager to afford due protection to
the Legations.” Jung Lu hoped to be able to induce the foreign
Ministers to confer with him for the purpose of restoring order. For
three hours not a shot has been fired; but En Ming has just come in
to tell me that the situation has again changed, and that the Old
Buddha has heard such good accounts of the defeat of the foreign
relief force on its way to Peking that she is once more determined to
give the Boxers their head and “to eat the flesh and sleep on the
skins” of the foreign devils.
4th Day of the 6th Moon: at the Hour of the Dog, 7 p.m. (June 30,
1900).—Kang Yi called to-day, and remained with me for the evening
meal. He tells me that Tung Fu-hsiang called in person this morning
on Jung Lu at his residence, and asked him for the loan of the heavy
artillery which is under his orders. Jung Lu is said to have ample
armaments in stock in the city, the property of the Wu Wei-chün
(Military Defence Corps) sufficient to knock every foreign building to
pieces in a few hours.
Tung was kept waiting at Jung Lu’s door for over an hour; when
finally admitted, he began to bluster, whereupon Jung Lu feigned
sleep. “He gave no consent, but leant on his seat and
slumbered.”[85] Tung then expostulated with Jung Lu for his
rudeness, but the Commander-in-chief only smiled, and brought the
interview to an end by remarking that Tung’s only way to get the
guns would be to persuade the Old Buddha to give him Jung Lu’s
head with them. “Apply for an audience at once,” he said. “She
believes you to be a brave man and will certainly comply with any
request you may make.”
Tung Fu-hsiang left in a towering rage, and made straight for the
Forbidden City, although the hour for audiences was long since past.
At the gate of the Hall of Imperial Supremacy (Huang Chi-tien) he
made a loud disturbance, bidding the eunuchs inform Her Majesty
that the Kansuh Commander-in-chief was without, desiring audience.
It so happened that the Old Buddha was engaged in painting a
design of bamboos on silk, and she was highly displeased at being
thus disturbed. Tung was ushered in, however, and fell on his knees.
“Well,” said Her Majesty, “I suppose that you have come to report the
complete destruction of the Legations? This will be the tenth time
since the end of last Moon.” “I have come,” replied Tung Fu-hsiang,
“to ask Your Majesty’s permission to impeach the Grand Secretary
Jung Lu as a traitor and the friend of barbarians. He has the guns
which my army needs; with their aid not a stone would be left
standing in the whole of the Legation quarter. But he has sworn
never to lend these guns, even though Your Majesty should
command it.” Angrily the Old Buddha replied, “Be silent. You were
nothing but a brigand to begin with, and if I allowed you to enter my
army it was only to give you an opportunity of atoning for your former
misdeeds. Even now you are behaving like a brigand, forgetting the
majesty of the Imperial Presence. Of a truth, your tail is becoming
too heavy to wag. Leave the Palace forthwith, and do not let me find
you here again unless summoned to audience.”
Reproduction of Picture painted on Silk, by Her Majesty Tzŭ Hsi.
Kang Yi declares that we shall never take the Legations so long as

Jung Lu continues to exercise his present great influence at Court. Li
Shan, who is also a great favourite of the Empress Dowager, is now
on the side of those who would make peace with the foreigners, and
has been impeached for it by Na T’ung.
The following proclamation is now placarded all over the city, in
accordance with the Empress Dowager’s orders issued to Prince
Chuang. They say that she means to pay the rewards from her own
privy purse:
“Rewards.
“Now that all foreign churches and chapels have been
razed to the ground, and that no place of refuge or
concealment is left for the foreigners, they must unavoidably
scatter, flying in every direction. Be it therefore known and
announced to all men, scholars and volunteers, that any
person found guilty of harbouring foreigners will incur the
penalty of decapitation. For every male foreigner taken alive a
reward of 50 taels will be given; for every female 40 taels, and
for every child 30 taels; but it is to be clearly understood that
they shall be taken alive, and that they shall be genuine
foreigners. Once this fact has been duly authenticated, the
reward will be paid without delay. A special proclamation,
requiring reverent obedience.”
Much larger rewards than these were paid in the tenth year of
Hsieng-Feng (1860) for the heads of barbarians, but of course in
those days they were comparatively rare, whereas now, alas, they
have become as common as bees!
This morning an important trial took place outside the gate of
Prince Chuang’s palace; Yi Ku, Fen Che, and Kuei Ch’un presided.
Over nine hundred people were summarily executed by the Boxers,
in some cases before any proofs whatsoever had been substantiated
in regard to their alleged connection with foreigners. Helpless babes
even were amongst the slain. Fen Che is nothing more than a
butcher and the Old Buddha remonstrated with Prince Chuang for
not keeping the Boxers in better order.
8th Day of the 6th Moon, 11 a.m. (July 4th).—Yü Hsien’s son-in-
law, Chi Shou-ch’eng, came and talked with me for a long while. The
bombardment of the city was going on all the time he was here, and
to the south of my house, close to the Imperial City Wall, the troops
of Li Ping-heng were mounting cannon on an elevated platform.
They are all still very wroth with Jung Lu, who refuses to lend his
guns, and his troops are so faithful to him that it is impossible to
bribe them to disobey him. Jung Lu’s courage is really extraordinary;
he said of himself lately, that “in the days of the wicked Ruler
(meaning Prince Tuan) he bided his time on the shores of the bleak
North Sea, awaiting the purification of the Empire.”[86] I am told that
Prince Tuan has taken possession of one of the Imperial Seals, so
as to be able to proclaim his son Emperor at the first favourable
opportunity; but if the Old Buddha finds this out, as most probably
she will, there is trouble ahead for Prince Tuan.
Chi Shou-ch’eng tells me that Yü Hsien has sent in a memorial to
the Empress Dowager with reference to the missionaries in Shansi.
Ten days ago she had sent him a secret Decree, saying, “Slay all
foreigners wheresoever you find them; even though they be
prepared to leave your province, yet must they be slain.” It seems
that the Old Buddha ordered that this Decree should be sent to every
high provincial official in the Empire, but it is now reported that Tuan
Fang, the acting governor of Shensi, and Yü Chang, governor of
Honan, together with the high officials in Mongolia, received the
Edict in a very different form, for the word “slay” had been changed
to “protect.” It is feared that some treacherous minister is responsible
for this, but no one dares inform Her Majesty. To Yü Hsien’s latest
memorial, she has made the following reply, which has been sent by
the fastest express riders to T’ai-Yüan fu:—“I command that all
foreigners—men, women, and children, old and young—be
summarily executed. Let not one escape, so that my Empire may be
purged of this noisome source of corruption, and that peace may be
restored to my loyal subjects.” Chi Shou-ch’eng tells me that Yü
Hsien’s bitterness against foreigners is inspired by his wife, of whom
he is greatly afraid. He himself has earned golden opinions in T’ai-
Yüan during his short administration, and has a high reputation for
even-handed justice. He says also that this last Decree gave
pleasure to Prince Chuang; Jung Lu tried to stop it, asking the Old
Buddha what glory could China expect to gain by the slaughter of
women and children. “We should become the laughing-stock of the
world,” he said, “and the Old Buddha’s widespread fame and
reputation for benevolence would be grievously injured.” “Yes,”
replied the Empress Dowager, “but these foreigners of yours wish to
see me deposed, and I am only paying off old scores. Ever since the
days of Tao-Kuang this uproarious guest within our borders has been
maltreating his hosts, and it is time that all should know who is the
real master of the house.”
Yesterday afternoon the Empress Dowager crossed over to the
Lake Palace for a water picnic, attended by several ladies of the
Court. The continuous bombardment of the French cathedral
eventually made her head ache, so she despatched a chamberlain

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