1 6626 102 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 2 6627 60 UNDERSTANDING RESILIENCE: NEW APPROACHES FOR PREVENTING AND TREATING PTSD. ALL INDIVIDUALS EXPERIENCE STRESSFUL LIFE EVENTS, AND UP TO 84% OF THE GENERAL POPULATION WILL EXPERIENCE AT LEAST ONE POTENTIALLY TRAUMATIC EVENT. IN SOME CASES, ACUTE OR CHRONIC STRESSORS LEAD TO THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD) OR OTHER PSYCHOPATHOLOGY; HOWEVER, THE MAJORITY OF PEOPLE ARE RESILIENT TO SUCH EFFECTS. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. A WEALTH OF RESEARCH HAS BEGUN TO IDENTIFY THE GENETIC, EPIGENETIC, NEURAL, AND ENVIRONMENTAL UNDERPINNINGS OF RESILIENCE, AND HAS INDICATED THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES ENCOMPASSING SEVERAL ENVIRONMENTAL FACTORS, NEURAL CIRCUITS, NUMEROUS NEUROTRANSMITTERS, AND MOLECULAR PATHWAYS. THE FIRST PART OF THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING THE GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS AS WELL AS NEURAL CIRCUITS AND MOLECULAR PATHWAYS THAT UNDERLIE THE DEVELOPMENT OF RESILIENCE. EMERGING AND EXCITING AREAS OF RESEARCH AND NOVEL METHODOLOGICAL APPROACHES, INCLUDING GENOME-WIDE GENE EXPRESSION STUDIES, IMMUNE, ENDOCANNABINOID, OXYTOCIN, AND GLUTAMATERGIC SYSTEMS, ARE EXPLORED TO HELP DELINEATE INNOVATIVE MECHANISMS THAT MAY CONTRIBUTE TO RESILIENCE. THE SECOND PART REVIEWS SEVERAL INTERVENTIONS AND PREVENTATIVE APPROACHES DESIGNED TO ENHANCE RESILIENCE IN BOTH DEVELOPMENTAL AND ADULT POPULATIONS. SPECIFICALLY, THE REVIEW WILL DELINEATE APPROACHES AIMED TO BOLSTER RESILIENCE IN INDIVIDUALS WITH PTSD. FURTHERMORE, WE DISCUSS NOVEL PHARMACOLOGIC APPROACHES, INCLUDING THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR KETAMINE AND NEUROPEPTIDE Y (NPY), AS EXCITING NEW PROSPECTS FOR NOT ONLY THE TREATMENT OF PTSD BUT AS NEW TARGETS TO ENHANCE RESILIENCE. OUR GROWING UNDERSTANDING OF RESILIENCE AND INTERVENTIONS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW STRATEGIES FOR NOT JUST TREATING PTSD BUT ALSO SCREENING AND EARLY IDENTIFICATION OF AT-RISK YOUTH AND ADULTS. TAKEN TOGETHER, EFFORTS AIMED AT DISSEMINATION AND IMPLEMENTATION OF NOVEL INTERVENTIONS TO ENHANCE RESILIENCE WILL HAVE TO KEEP PACE WITH THE GROWTH OF NEW PREVENTIVE AND TREATMENT STRATEGIES. 2016 3 5310 33 PSYCHOBIOLOGY AND MOLECULAR GENETICS OF RESILIENCE. EVERY INDIVIDUAL EXPERIENCES STRESSFUL LIFE EVENTS. IN SOME CASES ACUTE OR CHRONIC STRESS LEADS TO DEPRESSION AND OTHER PSYCHIATRIC DISORDERS, BUT MOST PEOPLE ARE RESILIENT TO SUCH EFFECTS. RECENT RESEARCH HAS BEGUN TO IDENTIFY THE ENVIRONMENTAL, GENETIC, EPIGENETIC AND NEURAL MECHANISMS THAT UNDERLIE RESILIENCE, AND HAS SHOWN THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES IN SEVERAL NEURAL CIRCUITS INVOLVING NUMEROUS NEUROTRANSMITTER AND MOLECULAR PATHWAYS. THESE CHANGES SHAPE THE FUNCTIONING OF THE NEURAL CIRCUITS THAT REGULATE REWARD, FEAR, EMOTION REACTIVITY AND SOCIAL BEHAVIOUR, WHICH TOGETHER ARE THOUGHT TO MEDIATE SUCCESSFUL COPING WITH STRESS. 2009 4 4914 27 PAIN VULNERABILITY: A NEUROBIOLOGICAL PERSPECTIVE. THERE ARE MANY KNOWN RISK FACTORS FOR CHRONIC PAIN CONDITIONS, YET THE BIOLOGICAL UNDERPINNINGS THAT LINK THESE FACTORS TO ABNORMAL PROCESSING OF PAINFUL SIGNALS ARE ONLY JUST BEGINNING TO BE EXPLORED. THIS REVIEW WILL DISCUSS THE POTENTIAL MECHANISMS THAT HAVE BEEN PROPOSED TO UNDERLIE VULNERABILITY AND RESILIENCE TOWARD DEVELOPING CHRONIC PAIN. PARTICULAR FOCUS WILL BE GIVEN TO GENETIC AND EPIGENETIC PROCESSES, PRIMING EFFECTS ON A CELLULAR LEVEL, AND ALTERATIONS IN BRAIN NETWORKS CONCERNED WITH REWARD, MOTIVATION/LEARNING AND DESCENDING MODULATORY CONTROL. ALTHOUGH RESEARCH IN THIS AREA IS STILL IN ITS INFANCY, A BETTER UNDERSTANDING OF HOW PAIN VULNERABILITY EMERGES HAS THE POTENTIAL TO HELP IDENTIFY INDIVIDUALS AT RISK AND MAY OPEN UP NEW THERAPEUTIC AVENUES. 2014 5 375 21 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 6 23 36 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015 7 225 41 ACUTE STRESS-INDUCED EPIGENETIC MODULATIONS AND THEIR POTENTIAL PROTECTIVE ROLE TOWARD DEPRESSION. PSYCHIATRIC DISORDERS ENTAIL MALADAPTIVE PROCESSES IMPAIRING INDIVIDUALS' ABILITY TO APPROPRIATELY INTERFACE WITH ENVIRONMENT. AMONG THEM, DEPRESSION IS CHARACTERIZED BY DIVERSE DEBILITATING SYMPTOMS INCLUDING HOPELESSNESS AND ANHEDONIA, DRAMATICALLY IMPACTING THE PROPENSITY TO LIVE A SOCIAL AND ACTIVE LIFE AND SERIOUSLY AFFECTING WORKING CAPABILITY. RELEVANTLY, BESIDES GENETIC PREDISPOSITION, FOREMOST RISK FACTORS ARE STRESS-RELATED, SUCH AS EXPERIENCING CHRONIC PSYCHOSOCIAL STRESS-INCLUDING BULLYING, MOBBING AND ABUSE-, AND UNDERGOING ECONOMIC CRISIS OR CHRONIC ILLNESSES. IN THE LAST FEW YEARS THE FIELD OF EPIGENETICS PROMISED TO UNDERSTAND CORE MECHANISMS OF GENE-ENVIRONMENT CROSSTALK, CONTRIBUTING TO GET INTO PATHOGENIC PROCESSES OF MANY DISORDERS HIGHLY INFLUENCED BY STRESSFUL LIFE CONDITIONS. HOWEVER, STILL VERY LITTLE IS KNOWN ABOUT MECHANISMS THAT TUNE GENE EXPRESSION TO ADAPT TO THE EXTERNAL MILIEU. IN THIS PERSPECTIVE ARTICLE, WE DISCUSS A SET OF PROTECTIVE, FUNCTIONALLY CONVERGENT EPIGENETIC PROCESSES INDUCED BY ACUTE STRESS IN THE RODENT HIPPOCAMPUS AND DEVOTED TO THE NEGATIVE MODULATION OF STRESS-INDUCED IMMEDIATE EARLY GENES (IEGS) TRANSCRIPTION, HINDERING STRESS-DRIVEN MORPHOSTRUCTURAL MODIFICATIONS OF CORTICOLIMBIC CIRCUITRY. WE ALSO SUGGEST THAT CHRONIC STRESS DAMAGING PROTECTIVE EPIGENETIC MECHANISMS, COULD BIAS THE FUNCTIONAL TRAJECTORY OF STRESS-INDUCED NEURONAL MORPHOSTRUCTURAL MODIFICATION FROM ADAPTIVE TO MALADAPTIVE, CONTRIBUTING TO THE ONSET OF DEPRESSION IN VULNERABLE INDIVIDUALS. A BETTER UNDERSTANDING OF THE EPIGENETIC RESPONSE TO STRESS WILL BE PIVOTAL TO NEW AVENUES OF THERAPEUTIC INTERVENTION TO TREAT DEPRESSION, ESPECIALLY IN LIGHT OF LIMITED EFFICACY OF AVAILABLE ANTIDEPRESSANT DRUGS. 2018 8 7 27 'BIOLOGIZING' PSYCHOPATHY: ETHICAL, LEGAL, AND RESEARCH IMPLICATIONS AT THE INTERFACE OF EPIGENETICS AND CHRONIC ANTISOCIAL CONDUCT. EPIGENETICS, A FIELD THAT LINKS GENETICS AND ENVIRONMENTAL INFLUENCES ON THE EXPRESSION OF PHENOTYPIC TRAITS, OFFERS TO INCREASE OUR UNDERSTANDING OF THE DEVELOPMENT AND TRAJECTORY OF DISEASE AND PSYCHOLOGICAL DISORDERS BEYOND THAT THOUGHT OF TRADITIONAL GENETIC RESEARCH AND BEHAVIOURAL MEASURES. BY EXTENSION, THIS NEW PERSPECTIVE HAS IMPLICATIONS FOR RISK AND RISK MANAGEMENT OF ANTISOCIAL BEHAVIOUR WHERE THERE IS A BIOLOGICAL COMPONENT, SUCH AS PSYCHOPATHY. PSYCHOPATHY IS A PERSONALITY DISORDER ASSOCIATED WITH REPEAT DISPLAYS OF ANTISOCIAL BEHAVIOUR, AND IS ASSOCIATED WITH THE DISPROPORTIONATE IMPOSITION OF HARM ON COMMUNITIES. DESPITE ADVANCES IN OUR KNOWLEDGE OF PSYCHOPATHIC INDIVIDUALS, THE CONSTRUCT REMAINS COMPLEX AND IS HAMPERED BY A LACK OF INTEGRATION ACROSS A RANGE OF FUNDAMENTAL DOMAINS. THE CLINICAL AND FORENSIC RESEARCH ON PSYCHOPATHY IS BROUGHT INTO CONVERSATION WITH THE EMERGING FIELD OF EPIGENETICS TO HIGHLIGHT CRITICAL ISSUES OF (1) CLINICAL DEFINITION AND DIAGNOSIS, (2) ASSESSMENT, (3) AETIOLOGY OF PSYCHOPATHIC PHENOTYPES, AND (4) TREATMENT AND REHABILITATION APPROACHES. BROADER ETHICAL AND LEGAL QUESTIONS OF THE ROLE OF EPIGENETIC MECHANISMS IN THE MANAGEMENT OF PSYCHOPATHY BEYOND THE CRIMINAL JUSTICE ARENA ARE ALSO OUTLINED. 2015 9 357 25 ALTERNATIVE MODELS FOR TRANSGENERATIONAL EPIGENETIC INHERITANCE: MOLECULAR PSYCHIATRY BEYOND MICE AND MAN. MENTAL ILLNESS REMAINS THE GREATEST CHRONIC HEALTH BURDEN GLOBALLY WITH FEW IN-ROADS HAVING BEEN MADE DESPITE SIGNIFICANT ADVANCES IN GENOMIC KNOWLEDGE IN RECENT DECADES. THE FIELD OF PSYCHIATRY IS CONSTANTLY CHALLENGED TO BRING NEW APPROACHES AND TOOLS TO ADDRESS AND TREAT THE NEEDS OF VULNERABLE INDIVIDUALS AND SUBPOPULATIONS, AND THAT HAS TO BE SUPPORTED BY A CONTINUOUS GROWTH IN KNOWLEDGE. THE MAJORITY OF NEUROPSYCHIATRIC SYMPTOMS REFLECT COMPLEX GENE-ENVIRONMENT INTERACTIONS, WITH EPIGENETICS BRIDGING THE GAP BETWEEN GENETIC SUSCEPTIBILITY AND ENVIRONMENTAL STRESSORS THAT TRIGGER DISEASE ONSET AND DRIVE THE ADVANCEMENT OF SYMPTOMS. IT HAS MORE RECENTLY BEEN DEMONSTRATED IN PRECLINICAL MODELS THAT EPIGENETICS UNDERPINS THE TRANSGENERATIONAL INHERITANCE OF STRESS-RELATED BEHAVIOURAL PHENOTYPES IN BOTH PATERNAL AND MATERNAL LINEAGES, PROVIDING FURTHER SUPPORTING EVIDENCE FOR HERITABILITY IN HUMANS. HOWEVER, UNBIASED PROSPECTIVE STUDIES OF THIS NATURE ARE PRACTICALLY IMPOSSIBLE TO CONDUCT IN HUMANS SO PRECLINICAL MODELS REMAIN OUR BEST OPTION FOR RESEARCHING THE MOLECULAR PATHOPHYSIOLOGIES UNDERLYING MANY NEUROPSYCHIATRIC CONDITIONS. WHILE RODENTS WILL REMAIN THE DOMINANT MODEL SYSTEM FOR PRECLINICAL STUDIES (ESPECIALLY FOR ADDRESSING COMPLEX BEHAVIOURAL PHENOTYPES), THERE IS SCOPE TO EXPAND CURRENT RESEARCH OF THE MOLECULAR AND EPIGENETIC PATHOLOGIES BY USING INVERTEBRATE MODELS. HERE, WE WILL DISCUSS THE UTILITY AND ADVANTAGES OF TWO ALTERNATIVE MODEL ORGANISMS-CAENORHABDITIS ELEGANS AND DROSOPHILA MELANOGASTER-AND SUMMARISE THE COMPELLING INSIGHTS OF THE EPIGENETIC REGULATION OF TRANSGENERATIONAL INHERITANCE THAT ARE POTENTIALLY RELEVANT TO HUMAN PSYCHIATRY. 2021 10 5812 43 STRESS AND ANXIETY: STRUCTURAL PLASTICITY AND EPIGENETIC REGULATION AS A CONSEQUENCE OF STRESS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT, AS WELL AS DEVELOPING BRAIN, POSSESS A REMARKABLE ABILITY TO SHOW REVERSIBLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. THIS IS PARTICULARLY EVIDENT IN THE HIPPOCAMPUS, WHERE ALL THREE TYPES OF STRUCTURAL PLASTICITY HAVE BEEN RECOGNIZED AND INVESTIGATED, USING A COMBINATION OF MORPHOLOGICAL, MOLECULAR, PHARMACOLOGICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL APPROACHES. THE AMYGDALA AND THE PREFRONTAL CORTEX, BRAIN REGIONS INVOLVED IN ANXIETY AND FEAR, MOOD, COGNITIVE FUNCTION AND BEHAVIORAL CONTROL, ALSO SHOW STRUCTURAL PLASTICITY. ACUTE AND CHRONIC STRESS CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. IN THE SHORT TERM, SUCH AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC OR MOOD ANXIETY DISORDERS. WE SHALL REVIEW CELLULAR AND MOLECULAR MECHANISMS, AS WELL AS RECENT WORK ON INDIVIDUAL DIFFERENCES IN ANXIETY-LIKE BEHAVIOR AND ALSO DEVELOPMENTAL INFLUENCES THAT BIAS HOW THE BRAIN RESPONDS TO STRESSORS. FINALLY, WE SUGGEST THAT SUCH AN APPROACH NEEDS TO BE EXTENDED TO OTHER BRAIN AREAS THAT ARE ALSO INVOLVED IN ANXIETY AND MOOD. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED 'ANXIETY AND DEPRESSION'. 2012 11 6414 33 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 12 4632 30 NEUROIMAGING GENETIC APPROACHES TO POSTTRAUMATIC STRESS DISORDER. NEUROIMAGING GENETIC STUDIES THAT ASSOCIATE GENETIC AND EPIGENETIC VARIATION WITH NEURAL ACTIVITY OR STRUCTURE PROVIDE AN OPPORTUNITY TO LINK GENES TO PSYCHIATRIC DISORDERS, OFTEN BEFORE PSYCHOPATHOLOGY IS DISCERNABLE IN BEHAVIOR. HERE WE REVIEW NEUROIMAGING GENETICS STUDIES WITH PARTICIPANTS WHO HAVE POSTTRAUMATIC STRESS DISORDER (PTSD). RESULTS SHOW THAT GENES RELATED TO THE PHYSIOLOGICAL STRESS RESPONSE (E.G., GLUCOCORTICOID RECEPTOR AND ACTIVITY, NEUROENDOCRINE RELEASE), LEARNING AND MEMORY (E.G., PLASTICITY), MOOD, AND PAIN PERCEPTION ARE TIED TO NEURAL INTERMEDIATE PHENOTYPES ASSOCIATED WITH PTSD. THESE GENES ARE ASSOCIATED WITH AND SOMETIMES PREDICT NEURAL STRUCTURE AND FUNCTION IN AREAS INVOLVED IN ATTENTION, EXECUTIVE FUNCTION, MEMORY, DECISION-MAKING, EMOTION REGULATION, SALIENCE OF POTENTIAL THREATS, AND PAIN PERCEPTION. EVIDENCE SUGGESTS THESE RISK POLYMORPHISMS AND NEURAL INTERMEDIATE PHENOTYPES ARE VULNERABILITIES TOWARD DEVELOPING PTSD IN THE AFTERMATH OF TRAUMA, OR VULNERABILITIES TOWARD PARTICULAR SYMPTOMS ONCE PTSD HAS DEVELOPED. WORK DISTINGUISHING BETWEEN THE RE-EXPERIENCING AND DISSOCIATIVE SUB-TYPES OF PTSD, AND EXAMINING OTHER PTSD SYMPTOM CLUSTERS IN ADDITION TO THE RE-EXPERIENCING AND HYPERAROUSAL SYMPTOMS, WILL FURTHER CLARIFY NEUROBIOLOGICAL MECHANISMS AND INCONSISTENT FINDINGS. FURTHERMORE, AN EXCITING POSSIBILITY IS THAT GENETIC ASSOCIATIONS WITH PTSD MAY EVENTUALLY BE UNDERSTOOD THROUGH DIFFERENTIAL INTERMEDIATE PHENOTYPES OF NEURAL CIRCUIT STRUCTURE AND FUNCTION, POSSIBLY UNDERLYING THE DIFFERENT SYMPTOM CLUSTERS SEEN WITHIN PTSD. 2016 13 4621 38 NEUROBIOLOGICAL AND SYSTEMIC EFFECTS OF CHRONIC STRESS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR, WHICH PROMOTE ADAPTATION ("ALLOSTASIS") BUT ALSO CONTRIBUTE TO PATHOPHYSIOLOGY ("ALLOSTATIC LOAD/OVERLOAD") WHEN OVERUSED AND DYSREGULATED. THE ADULT AS WELL AS DEVELOPING BRAIN POSSESSES A REMARKABLE ABILITY TO SHOW STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING AND SYNAPSE TURNOVER. STRESS CAN CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE THREAT PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION REQUIRES INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES. THERE ARE IMPORTANT SEX DIFFERENCES IN HOW THE BRAIN RESPONDS TO STRESSORS. MOREOVER, ADVERSE EARLY LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCES LASTING EFFECTS ON BRAIN AND BODY VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS KEY, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT UTILIZE BRAIN-BODY INTERACTIONS. POLICIES OF GOVERNMENT AND THE PRIVATE SECTOR ARE IMPORTANT TO PROMOTE HEALTH AND INCREASE "HEALTHSPAN." 2017 14 1748 34 EARLY LIFE EVENTS AND THEIR CONSEQUENCES FOR LATER DISEASE: A LIFE HISTORY AND EVOLUTIONARY PERSPECTIVE. BIOMEDICAL SCIENCE HAS LITTLE CONSIDERED THE RELEVANCE OF LIFE HISTORY THEORY AND EVOLUTIONARY AND ECOLOGICAL DEVELOPMENTAL BIOLOGY TO CLINICAL MEDICINE. HOWEVER, THE OBSERVATIONS THAT EARLY LIFE INFLUENCES CAN ALTER LATER DISEASE RISK--THE "DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE" (DOHAD) PARADIGM--HAVE LED TO A RECOGNITION THAT THESE PERSPECTIVES CAN INFORM OUR UNDERSTANDING OF HUMAN BIOLOGY. WE PROPOSE THAT THE DOHAD PHENOMENON CAN BE CONSIDERED AS A SUBSET OF THE BROADER PROCESSES OF DEVELOPMENTAL PLASTICITY BY WHICH ORGANISMS ADAPT TO THEIR ENVIRONMENT DURING THEIR LIFE COURSE. SUCH ADAPTIVE PROCESSES ALLOW GENOTYPIC VARIATION TO BE PRESERVED THROUGH TRANSIENT ENVIRONMENTAL CHANGES. CUES FOR PLASTICITY OPERATE PARTICULARLY DURING EARLY DEVELOPMENT; THEY MAY AFFECT A SINGLE ORGAN OR SYSTEM, BUT GENERALLY THEY INDUCE INTEGRATED ADJUSTMENTS IN THE MATURE PHENOTYPE, A PROCESS UNDERPINNED BY EPIGENETIC MECHANISMS AND INFLUENCED BY PREDICTION OF THE MATURE ENVIRONMENT. IN MAMMALS, AN ADVERSE INTRAUTERINE ENVIRONMENT RESULTS IN AN INTEGRATED SUITE OF RESPONSES, SUGGESTING THE INVOLVEMENT OF A FEW KEY REGULATORY GENES, THAT RESETS THE DEVELOPMENTAL TRAJECTORY IN EXPECTATION OF POOR POSTNATAL CONDITIONS. MISMATCH BETWEEN THE ANTICIPATED AND THE ACTUAL MATURE ENVIRONMENT EXPOSES THE ORGANISM TO RISK OF ADVERSE CONSEQUENCES-THE GREATER THE MISMATCH, THE GREATER THE RISK. FOR HUMANS, PREDICTION IS INACCURATE FOR MANY INDIVIDUALS BECAUSE OF CHANGES IN THE POSTNATAL ENVIRONMENT TOWARD ENERGY-DENSE NUTRITION AND LOW ENERGY EXPENDITURE, CONTRIBUTING TO THE EPIDEMIC OF CHRONIC NONCOMMUNICABLE DISEASE. THIS VIEW OF HUMAN DISEASE FROM THE PERSPECTIVES OF LIFE HISTORY BIOLOGY AND EVOLUTIONARY THEORY OFFERS NEW APPROACHES TO PREVENTION, DIAGNOSIS AND INTERVENTION. 2007 15 4067 27 MATERNAL AND PEDIATRIC HEALTH AND DISEASE: INTEGRATING BIOPSYCHOSOCIAL MODELS AND EPIGENETICS. THE CONCEPTS OF ALLOSTASIS (STABILITY THROUGH ADAPTATION) AND ACCUMULATED LIFE STRESS (MCEWEN'S ALLOSTATIC LOAD) AIM TO UNDERSTAND CHILDHOOD AND ADULT OUTCOMES. CHRONIC MALNUTRITION, CHANGES IN SOCIAL CONDITION, AND ADVERSE EARLY-LIFE EXPERIENCES MAY PROGRAM PHENOTYPES AND CONTRIBUTE TO LONG-LASTING DISEASE RISK. HOWEVER, INTEGRATION OF LIFE COURSE APPROACHES, SOCIAL AND ECONOMIC CONTEXTS, AND COMPARISON AMONG DIFFERENT BIOPSYCHOSOCIAL MODELS HAS NOT GENERALLY BEEN EXPLORED. THIS REVIEW CRITICALLY EXAMINES THE LITERATURE AND EVALUATES RECENT INSIGHTS INTO HOW ENVIRONMENTAL STRESS CAN ALTER LIFELONG HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IMMUNE SYSTEM RESPONSIVENESS AND INDUCE METABOLIC AND NEURODEVELOPMENTAL MALADAPTATION. MODELS OF BIOPSYCHOSOCIAL STRESS OVERLAP BUT MAY CONSIDER DIFFERENT CONDITIONS. CONCEPTS INCLUDE ALLOSTASIS, WHICH INCORPORATES HORMONAL RESPONSES TO PREDICTABLE ENVIRONMENTAL CHANGES, AND GERONIMUS'S "WEATHERING," WHICH AIMS TO EXPLAIN HOW SOCIALLY STRUCTURED, REPEATED STRESS CAN ACCUMULATE AND INCREASE DISEASE VULNERABILITY. WEATHERING EMPHASIZES ROLES OF INTERNALIZED/INTERPERSONAL RACISM IN OUTCOMES DISPARITIES. FOR MEXICAN IMMIGRANTS AND MEXICAN AMERICANS, THE "ACCULTURATION" FRAMEWORK HAS PROVEN ESPECIALLY USEFUL TO EXPLORE DISPARITIES, INCLUDING PRETERM BIRTH AND NEUROPSYCHIATRIC RISKS IN CHILDHOOD. COMPLEXITIES OF STRESS ASSESSMENTS AND RECENT RESEARCH INTO EPIGENETIC MECHANISMS MEDIATING EFFECTS OF PHYSICAL, NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL STRESS ARE REVIEWED. 2016 16 5466 32 RESILIENCE: SAFETY IN THE AFTERMATH OF TRAUMATIC STRESSOR EXPERIENCES. THE RELATIONSHIP BETWEEN ADVERSE EXPERIENCES AND THE EMERGENCE OF PATHOLOGY HAS OFTEN FOCUSED ON CHARACTERISTICS OF THE STRESSOR OR OF THE INDIVIDUAL (STRESSOR APPRAISALS, COPING STRATEGIES). THESE FEATURES ARE THOUGHT TO INFLUENCE MULTIPLE BIOLOGICAL PROCESSES THAT FAVOR THE DEVELOPMENT OF MENTAL AND PHYSICAL ILLNESSES. LESS OFTEN HAS ATTENTION FOCUSED ON THE AFTERMATH OF TRAUMATIC EXPERIENCES, AND THE IMPORTANCE OF SAFETY AND REASSURANCE THAT IS NECESSARY FOR LONGER-TERM WELL-BEING. IN SOME CASES (E.G., POST-TRAUMATIC STRESS DISORDER) THIS MAY BE REFLECTED BY A FAILURE OF FEAR EXTINCTION, WHEREAS IN OTHER INSTANCES (E.G., HISTORICAL TRAUMA), THE UNCERTAINTY ABOUT THE FUTURE MIGHT FOSTER CONTINUED ANXIETY. IN ESSENCE, THE QUESTION BECOMES ONE OF HOW INDIVIDUALS ATTAIN FEELINGS OF SAFETY WHEN IT IS FULLY UNDERSTOOD THAT THE WORLD IS NOT NECESSARILY A SAFE PLACE, UNCERTAINTIES ABOUND, AND FEELINGS OF AGENCY ARE OFTEN ILLUSORY. WE CONSIDER HOW INDIVIDUALS ACQUIRE RESILIENCE IN THE AFTERMATH OF TRAUMATIC AND CHRONIC STRESSORS. IN THIS RESPECT, WE REVIEW CHARACTERISTICS OF STRESSORS THAT MAY TRIGGER PARTICULAR BIOLOGICAL AND BEHAVIORAL COPING RESPONSES, AS WELL AS FACTORS THAT UNDERMINE THEIR EFFICACY. TO THIS END, WE EXPLORE STRESSOR DYNAMICS AND SOCIAL PROCESSES THAT FOSTER RESILIENCE IN RESPONSE TO SPECIFIC TRAUMATIC, CHRONIC, AND UNCONTROLLABLE STRESSOR CONTEXTS (INTIMATE PARTNER ABUSE; REFUGEE MIGRATION; COLLECTIVE HISTORICAL TRAUMA). WE POINT TO RESILIENCE FACTORS THAT MAY COMPRISE NEUROBIOLOGICAL CHANGES, SUCH AS THOSE RELATED TO VARIOUS STRESSOR-PROVOKED HORMONES, NEUROTROPHINS, INFLAMMATORY IMMUNE, MICROBIAL, AND EPIGENETIC PROCESSES. THESE BEHAVIORAL AND BIOLOGICAL STRESS RESPONSES MAY INFLUENCE, AND BE INFLUENCED BY, FEELINGS OF SAFETY THAT COME ABOUT THROUGH RELATIONSHIPS WITH OTHERS, SPIRITUAL AND PLACE-BASED CONNECTIONS. 2020 17 2724 33 EXPERIENCE-SENSITIVE EPIGENETIC MECHANISMS, DEVELOPMENTAL PLASTICITY, AND THE BIOLOGICAL EMBEDDING OF CHRONIC DISEASE RISK. A WIDE RANGE OF DEVELOPMENTAL, NUTRITIONAL, ENVIRONMENTAL, AND SOCIAL FACTORS AFFECT THE BIOLOGICAL ACTIVITIES OF EPIGENETIC MECHANISMS. THESE FACTORS CHANGE SPATIOTEMPORAL PATTERNS OF GENE EXPRESSION IN A VARIETY OF DIFFERENT WAYS AND BRING SIGNIFICANT IMPACTS TO BEAR ON DEVELOPMENT, PHYSIOLOGY, AND DISEASE RISK THROUGHOUT THE LIFE COURSE. ABUNDANT EVIDENCE DEMONSTRATES THAT BEHAVIORAL STRESSORS AND ADVERSE NUTRITIONAL CONDITIONS ARE PARTICULARLY POTENT INDUCERS OF EPIGENETIC CHANGES AND ENHANCERS OF CHRONIC DISEASE RISKS. RECENT INSIGHTS FROM BOTH HUMAN CLINICAL STUDIES AND RESEARCH WITH MODEL ORGANISMS FURTHER INDICATE THAT SUCH EXPERIENCE-DEPENDENT CHANGES TO THE EPIGENOME CAN BE TRANSMITTED THROUGH THE GERMLINE ACROSS MULTIPLE GENERATIONS, WITH IMPORTANT CONSEQUENCES FOR THE HERITABILITY OF BOTH ADAPTIVE AND MALADAPTIVE PHENOTYPES. EPIGENETICS RESEARCH THUS OFFERS MANY POSSIBILITIES FOR DEVELOPING INFORMATIVE BIOMARKERS OF ACQUIRED CHRONIC DISEASE RISK AND DETERMINING THE EFFECTIVENESS OF PREVENTIVE AND THERAPEUTIC INTERVENTIONS. MOREOVER, THE EXPERIENCE-SENSITIVE NATURE OF THESE DISEASE RISKS RAISES IMPORTANT QUESTIONS ABOUT SOCIETAL AND INDIVIDUAL RESPONSIBILITIES FOR THE PREVENTION OF ILL-HEALTH AND THE PROMOTION OF WELL-BEING DURING DEVELOPMENT, ACROSS THE LIFE COURSE AND BETWEEN GENERATIONS. BETTER UNDERSTANDING OF HOW EPIGENETIC MECHANISMS REGULATE DEVELOPMENTAL PLASTICITY AND MEDIATE THE BIOLOGICAL EMBEDDING OF CHRONIC DISEASE RISKS IS THEREFORE LIKELY TO SHED IMPORTANT NEW LIGHT ON THE NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS LINKING SOCIAL AND HEALTH INEQUALITIES, AND WILL HELP TO INFORM PUBLIC POLICY INITIATIVES IN THIS AREA. CONFLICT OF INTEREST: THE AUTHOR HAS DECLARED NO CONFLICTS OF INTEREST FOR THIS ARTICLE. 2015 18 4985 34 PATHWAYS TO AGING: THE MITOCHONDRION AT THE INTERSECTION OF BIOLOGICAL AND PSYCHOSOCIAL SCIENCES. COMPELLING EVIDENCE SUGGESTS THAT BOTH BIOLOGICAL AND PSYCHOSOCIAL FACTORS IMPACT THE PROCESS OF AGING. HOWEVER, OUR UNDERSTANDING OF THE DYNAMIC INTERPLAY AMONG BIOLOGICAL AND PSYCHOSOCIAL FACTORS ACROSS THE LIFE COURSE IS STILL FRAGMENTARY. FOR EXAMPLE, IT NEEDS TO BE ESTABLISHED HOW THE INTERACTION OF INDIVIDUAL FACTORS (E.G., GENETIC AND EPIGENETIC ENDOWMENT AND PERSONALITY), BEHAVIORAL FACTORS (E.G., PHYSICAL ACTIVITY, DIET, AND STRESS MANAGEMENT), AND PSYCHOSOCIAL EXPERIENCES (E.G., SOCIAL SUPPORT, WELL-BEING, SOCIOECONOMIC STATUS, AND MARRIAGE) IN PERINATAL, CHILDHOOD, AND ADULTHOOD INFLUENCE HEALTH ACROSS THE AGING CONTINUUM. THIS PAPER AIMS TO OUTLINE POTENTIAL INTERSECTION POINTS SERVING AS AN INTERFACE BETWEEN BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WITH AN EMPHASIS ON THE MITOCHONDRION. MITOCHONDRIA ARE CELLULAR ORGANELLES WHICH PLAY A CRITICAL ROLE IN CELLULAR SENESCENCE. BOTH CHRONIC EXPOSURE TO PSYCHOSOCIAL STRESS AND GENETIC-BASED MITOCHONDRIAL DYSFUNCTION HAVE STRIKINGLY SIMILAR BIOLOGICAL CONSEQUENCES; BOTH PREDISPOSE INDIVIDUALS TO ADVERSE AGE-RELATED HEALTH DISORDERS AND EARLY MORTALITY. EXPLORING THE INTERACTIVE NATURE OF THE FACTORS RESULTING IN PATHWAYS TO NORMAL HEALTHY AGING, AS WELL AS THOSE LEADING TO MORBIDITY AND EARLY MORTALITY, WILL CONTINUE TO ENHANCE OUR ABILITY TO TRANSLATE RESEARCH INTO EFFECTIVE PRACTICES THAT CAN BE IMPLEMENTED THROUGHOUT THE LIFE COURSE TO OPTIMISE THE AGING PROCESS. 2011 19 2269 39 EPIGENETIC PROGRAMMING OF THE NEUROENDOCRINE STRESS RESPONSE BY ADULT LIFE STRESS. THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IS CRITICALLY INVOLVED IN THE NEUROENDOCRINE REGULATION OF STRESS ADAPTATION, AND THE RESTORATION OF HOMEOSTASIS FOLLOWING STRESS EXPOSURE. DYSREGULATION OF THIS AXIS IS ASSOCIATED WITH STRESS-RELATED PATHOLOGIES LIKE MAJOR DEPRESSIVE DISORDER, POST-TRAUMATIC STRESS DISORDER, PANIC DISORDER AND CHRONIC ANXIETY. IT HAS LONG BEEN UNDERSTOOD THAT STRESS DURING EARLY LIFE CAN HAVE A SIGNIFICANT LASTING INFLUENCE ON THE DEVELOPMENT OF THE NEUROENDOCRINE SYSTEM AND ITS NEURAL REGULATORS, PARTIALLY BY MODIFYING EPIGENETIC REGULATION OF GENE EXPRESSION, WITH IMPLICATIONS FOR HEALTH AND WELL-BEING IN LATER LIFE. EVIDENCE IS ACCUMULATING THAT EPIGENETIC PLASTICITY ALSO EXTENDS TO ADULTHOOD, PROPOSING IT AS A MECHANISM BY WHICH PSYCHOLOGICAL TRAUMA LATER IN LIFE CAN LONG-LASTINGLY AFFECT HPA AXIS FUNCTION, BRAIN PLASTICITY, NEURONAL FUNCTION AND BEHAVIOURAL ADAPTATION TO NEUROPSYCHOLOGICAL STRESS. FURTHER CORROBORATING THIS CLAIM IS THE PHENOMENON THAT THESE EPIGENETIC CHANGES CORRELATE WITH THE BEHAVIOURAL CONSEQUENCES OF TRAUMA EXPOSURE. THEREBY, EPIGENETIC MODIFICATIONS PROVIDE A PUTATIVE MOLECULAR MECHANISM BY WHICH THE BEHAVIOURAL PHENOTYPE AND TRANSCRIPTIONAL/TRANSLATIONAL POTENTIAL OF GENES INVOLVED IN HPA AXIS REGULATION CAN CHANGE DRASTICALLY IN RESPONSE TO ENVIRONMENTAL CHALLENGES, AND APPEAR AN IMPORTANT TARGET FOR TREATMENT OF STRESS-RELATED DISORDERS. HOWEVER, IMPROVED INSIGHT IS REQUIRED TO INCREASE THEIR THERAPEUTIC (DRUG) POTENTIAL. HERE, WE PROVIDE AN OVERVIEW OF THE GROWING BODY OF LITERATURE DESCRIBING THE EPIGENETIC MODULATION OF THE (PRIMARILY NEUROENDOCRINE) STRESS RESPONSE AS A CONSEQUENCE OF ADULT LIFE STRESS AND INTERPRET THE IMPLICATIONS FOR, AND THE CHALLENGES INVOLVED IN APPLYING THIS KNOWLEDGE TO, THE IDENTIFICATION AND TREATMENT OF STRESS-RELATED PSYCHIATRIC DISORDERS. 2017 20 682 41 BRAIN ON STRESS: HOW THE SOCIAL ENVIRONMENT GETS UNDER THE SKIN. STRESS IS A STATE OF THE MIND, INVOLVING BOTH BRAIN AND BODY AS WELL AS THEIR INTERACTIONS; IT DIFFERS AMONG INDIVIDUALS AND REFLECTS NOT ONLY MAJOR LIFE EVENTS BUT ALSO THE CONFLICTS AND PRESSURES OF DAILY LIFE THAT ALTER PHYSIOLOGICAL SYSTEMS TO PRODUCE A CHRONIC STRESS BURDEN THAT, IN TURN, IS A FACTOR IN THE EXPRESSION OF DISEASE. THIS BURDEN REFLECTS THE IMPACT OF NOT ONLY LIFE EXPERIENCES BUT ALSO GENETIC VARIATIONS AND INDIVIDUAL HEALTH BEHAVIORS SUCH AS DIET, PHYSICAL ACTIVITY, SLEEP, AND SUBSTANCE ABUSE; IT ALSO REFLECTS STABLE EPIGENETIC MODIFICATIONS IN DEVELOPMENT THAT SET LIFELONG PATTERNS OF PHYSIOLOGICAL REACTIVITY AND BEHAVIOR THROUGH BIOLOGICAL EMBEDDING OF EARLY ENVIRONMENTS INTERACTING WITH CUMULATIVE CHANGE FROM EXPERIENCES OVER THE LIFESPAN. HORMONES ASSOCIATED WITH THE CHRONIC STRESS BURDEN PROTECT THE BODY IN THE SHORT RUN AND PROMOTE ADAPTATION (ALLOSTASIS), BUT IN THE LONG RUN, THE BURDEN OF CHRONIC STRESS CAUSES CHANGES IN THE BRAIN AND BODY THAT CAN LEAD TO DISEASE (ALLOSTATIC LOAD AND OVERLOAD). BRAIN CIRCUITS ARE PLASTIC AND REMODELED BY STRESS TO CHANGE THE BALANCE BETWEEN ANXIETY, MOOD CONTROL, MEMORY, AND DECISION MAKING. SUCH CHANGES MAY HAVE ADAPTIVE VALUE IN PARTICULAR CONTEXTS, BUT THEIR PERSISTENCE AND LACK OF REVERSIBILITY CAN BE MALADAPTIVE. HOWEVER, THE CAPACITY OF BRAIN PLASTICITY TO EFFECTS OF STRESSFUL EXPERIENCES IN ADULT LIFE HAS ONLY BEGUN TO BE EXPLORED ALONG WITH THE EFFICACY OF TOP-DOWN STRATEGIES FOR HELPING THE BRAIN CHANGE ITSELF, SOMETIMES AIDED BY PHARMACEUTICAL AGENTS AND OTHER TREATMENTS. 2012