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 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 3 248 41 ADVANCE IN STRESS FOR DEPRESSIVE DISORDER. STRESS IS AN ADAPTIVE RESPONSE TO ENVIRONMENT AVERSIVE STIMULI AND A COMMON LIFE EXPERIENCE OF ONE'S DAILY LIFE. CHRONIC OR EXCESSIVE STRESS ESPECIALLY THAT HAPPENED IN EARLY LIFE IS FOUND TO BE DELETERIOUS TO INDIVIDUAL'S PHYSICAL AND MENTAL HEALTH, WHICH IS HIGHLY RELATED TO DEPRESSIVE DISORDERS ONSET. STRESSFUL LIFE EVENTS ARE CONSISTENTLY CONSIDERED TO BE THE HIGH-RISK FACTORS OF ENVIRONMENT FOR PREDISPOSING DEPRESSIVE DISORDERS. IN LINKING STRESSFUL LIFE EVENTS WITH DEPRESSIVE DISORDER ONSET, DYSREGULATED HPA AXIS ACTIVITY IS SUPPOSED TO PLAY AN IMPORTANT ROLE IN MEDIATING AVERSIVE IMPACTS OF LIFE STRESS ON BRAIN STRUCTURE AND FUNCTION. INCREASING EVIDENCE HAVE INDICATED THE STRONG ASSOCIATION OF STRESS, ESPECIALLY THE CHRONIC STRESS AND EARLY LIFE STRESS, WITH DEPRESSIVE DISORDERS DEVELOPMENT, WHILE THE ASSOCIATION OF STRESS WITH DEPRESSION IS MODERATED BY GENETIC RISK FACTORS, INCLUDING POLYMORPHISM OF SERT, BDNF, GR, FKBP5, MR, AND CRHR1. MEANWHILE, STRESSFUL LIFE EXPERIENCE PARTICULARLY EARLY LIFE STRESS WILL EXERT EPIGENETIC MODIFICATION IN THESE RISK GENES VIA DNA METHYLATION AND MIRNA REGULATION TO GENERATE LONG-LASTING EFFECTS ON THESE GENES EXPRESSION, WHICH IN TURN CAUSE BRAIN STRUCTURAL AND FUNCTIONAL ALTERATION, AND FINALLY INCREASE THE VULNERABILITY TO DEPRESSIVE DISORDERS. THEREFORE, THE INTERACTION OF ENVIRONMENT WITH GENE, IN WHICH STRESSFUL LIFE EXPOSURE INTERPLAY WITH GENETIC RISK FACTORS AND EPIGENETIC MODIFICATION, IS ESSENTIAL IN PREDICTING DEPRESSIVE DISORDERS DEVELOPMENT. AS THE MEDIATOR OF ENVIRONMENTAL RISK FACTORS, STRESS WILL FUNCTION TOGETHER WITH GENETIC AND EPIGENETIC MECHANISM TO INFLUENCE BRAIN STRUCTURE AND FUNCTION, PHYSIOLOGY AND PSYCHOLOGY, AND FINALLY THE VULNERABILITY TO DEPRESSIVE DISORDERS. 2019 4 6329 43 THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. THIS REVIEW WILL DISCUSS THE ROLE OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS. RELEVANT STUDIES WERE IDENTIFIED VIA MEDLINE (PUBMED) AND PSYCINFO DATABASES PUBLISHED UP TO AND INCLUDING JULY 2015. THIS REVIEW CONTRIBUTES TO A NEW UNDERSTANDING OF THE NEGATIVE CONSEQUENCES OF EARLY LIFE STRESS, AS WELL AS SETTING CHILDHOOD TRAUMA IN A BIOLOGICAL CONTEXT OF SUSCEPTIBILITY AND DISCUSSING NOVEL LONG-TERM PATHOPHYSIOLOGICAL CONSEQUENCES IN BIPOLAR DISORDERS. CHILDHOOD TRAUMATIC EVENTS ARE RISK FACTORS FOR DEVELOPING BIPOLAR DISORDERS, IN ADDITION TO A MORE SEVERE CLINICAL PRESENTATION OVER TIME (PRIMARILY AN EARLIER AGE AT ONSET AND AN INCREASED RISK OF SUICIDE ATTEMPT AND SUBSTANCE MISUSE). CHILDHOOD TRAUMA LEADS TO ALTERATIONS OF AFFECT REGULATION, IMPULSE CONTROL, AND COGNITIVE FUNCTIONING THAT MIGHT DECREASE THE ABILITY TO COPE WITH LATER STRESSORS. CHILDHOOD TRAUMA INTERACTS WITH SEVERAL GENES BELONGING TO SEVERAL DIFFERENT BIOLOGICAL PATHWAYS [HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, SEROTONERGIC TRANSMISSION, NEUROPLASTICITY, IMMUNITY, CALCIUM SIGNALING, AND CIRCADIAN RHYTHMS] TO DECREASE THE AGE AT THE ONSET OF THE DISORDER OR INCREASE THE RISK OF SUICIDE. EPIGENETIC FACTORS MAY ALSO BE INVOLVED IN THE NEUROBIOLOGICAL CONSEQUENCES OF CHILDHOOD TRAUMA IN BIPOLAR DISORDER. BIOLOGICAL SEQUELAE SUCH AS CHRONIC INFLAMMATION, SLEEP DISTURBANCE, OR TELOMERE SHORTENING ARE POTENTIAL MEDIATORS OF THE NEGATIVE EFFECTS OF CHILDHOOD TRAUMA IN BIPOLAR DISORDERS, IN PARTICULAR WITH REGARD TO PHYSICAL HEALTH. THE MAIN CLINICAL IMPLICATION IS TO SYSTEMATICALLY ASSESS CHILDHOOD TRAUMA IN PATIENTS WITH BIPOLAR DISORDERS, OR AT LEAST IN THOSE WITH A SEVERE OR INSTABLE COURSE. THE CHALLENGE FOR THE NEXT YEARS WILL BE TO FILL THE GAP BETWEEN CLINICAL AND FUNDAMENTAL RESEARCH AND ROUTINE PRACTICE, SINCE RECOMMENDATIONS FOR MANAGING THIS SPECIFIC POPULATION ARE LACKING. IN PARTICULAR, LITTLE IS KNOWN ON WHICH PSYCHOTHERAPIES SHOULD BE PROVIDED OR WHICH TARGETS THERAPISTS SHOULD FOCUS ON, AS WELL AS HOW CHILDHOOD TRAUMA COULD EXPLAIN THE RESISTANCE TO MOOD STABILIZERS. 2016 5 2415 30 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS: STRESS AND DEPRESSION. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL DISORDERS INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS PLAY A ROLE IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION, ADDICTION, AND SCHIZOPHRENIA, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY POINT TO THE IMPORTANCE OF ADDITIONAL FACTORS. ENVIRONMENTAL FACTORS, SUCH AS STRESS, PLAY A MAJOR ROLE IN THE PSYCHIATRIC DISORDERS BY INDUCING STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR. INSULTS AT THE DEVELOPMENTAL STAGE AND IN ADULTHOOD APPEAR TO INDUCE DISTINCT MALADAPTATIONS. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND ASSOCIATED ABERRANT EPIGENETIC REGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. ASPECTS OF DEPRESSION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS, AND THESE STUDIES CAN PROVIDE A MORE GENERAL UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSYCHIATRIC DISORDERS. UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS IS PROVIDING NEW INSIGHTS INTO DISEASE MECHANISMS IN HUMANS. 2014 6 5829 25 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 7 2386 28 EPIGENETIC REGULATORY MECHANISMS IN STRESS-INDUCED BEHAVIOR. STRESS RESPONSE IS CONSIDERED TO HAVE ADAPTIVE VALUE FOR ORGANISMS FACED WITH STRESSFUL CONDITION. CHRONIC STRESS HOWEVER ADVERSELY AFFECTS THE PHYSIOLOGY AND MAY LEAD TO NEUROPSYCHIATRIC DISORDERS. REPEATED STRESSFUL EVENTS IN ANIMAL MODELS HAVE BEEN SHOWN TO CAUSE LONG-LASTING CHANGES IN NEURAL CIRCUITRIES AT MOLECULAR, CELLULAR, AND PHYSIOLOGICAL LEVEL, LEADING TO DISORDERS OF MOOD AS WELL AS COGNITION. MOLECULAR STUDIES IN RECENT YEARS HAVE IMPLICATED DIVERSE EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, AND NONCODING RNAS, THAT UNDERLIE DYSREGULATION OF GENES IN THE AFFECTED NEURAL CIRCUITRIES IN CHRONIC STRESS-INDUCED PATHOPHYSIOLOGY. A REVIEW OF THE MYRIAD EPIGENETIC REGULATORY MECHANISMS ASSOCIATED WITH NEURAL AND BEHAVIORAL RESPONSES IN ANIMAL MODELS OF STRESS-INDUCED NEUROPSYCHIATRIC DISORDERS IS PRESENTED HERE. THE REVIEW ALSO DEALS WITH CLINICAL EVIDENCE OF THE EPIGENETIC DYSREGULATION OF GENES IN PSYCHIATRIC DISORDERS WHERE CHRONIC STRESS APPEARS TO UNDERLIE THE ETIOPATHOLOGY. 2014 8 1722 29 DYSREGULATION OF BRAIN DOPAMINE SYSTEMS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD OR DEPRESSION) IS A DEBILITATING NEUROPSYCHIATRIC SYNDROME WITH GENETIC, EPIGENETIC, AND ENVIRONMENTAL CONTRIBUTIONS. DEPRESSION IS ONE OF THE LARGEST CONTRIBUTORS TO CHRONIC DISEASE BURDEN; IT AFFECTS MORE THAN ONE IN SIX INDIVIDUALS IN THE UNITED STATES. A WIDE ARRAY OF CELLULAR AND MOLECULAR MODIFICATIONS DISTRIBUTED ACROSS A VARIETY OF NEURONAL PROCESSES AND CIRCUITS UNDERLIE THE PATHOPHYSIOLOGY OF DEPRESSION-NO ESTABLISHED MECHANISM CAN EXPLAIN ALL ASPECTS OF THE DISEASE. MDD SUFFERS FROM A VAST TREATMENT GAP WORLDWIDE, AND LARGE NUMBERS OF INDIVIDUALS WHO REQUIRE TREATMENT DO NOT RECEIVE ADEQUATE CARE. THIS MINI-REVIEW FOCUSES ON DYSREGULATION OF BRAIN DOPAMINE (DA) SYSTEMS IN THE PATHOPHYSIOLOGY OF MDD AND DESCRIBING NEW CELLULAR TARGETS FOR POTENTIAL MEDICATION DEVELOPMENT FOCUSED ON DA-MODULATED MICRO-CIRCUITS. WE ALSO EXPLORE HOW NEURODEVELOPMENTAL FACTORS MAY MODIFY RISK FOR LATER EMERGENCE OF MDD, POSSIBLY THROUGH DOPAMINERGIC SUBSTRATES IN THE BRAIN. 2021 9 4622 25 NEUROBIOLOGICAL DEVELOPMENT IN THE CONTEXT OF CHILDHOOD TRAUMA. NEUROBIOLOGICAL SYSTEMS MAY BE PARTICULARLY SUSCEPTIBLE TO DELETERIOUS IMPACT OF CHILDHOOD TRAUMA, AND THE IMPACT OF CHILDHOOD TRAUMA ON DEVELOPMENT AND SUBSEQUENT FUNCTIONAL OUTCOMES ACROSS THE LIFESPAN HAS BEEN WELL-DOCUMENTED. THE CURRENT REVIEW ADDRESSES THE NEUROBIOLOGICAL IMPACT OF EXPOSURE TO INTERPERSONAL TRAUMA IN CHILDHOOD IN THE CONTEXT OF EXECUTIVE FUNCTION, EMOTION REGULATION, AND DISSOCIATION/INTEROCEPTIVE AWARENESS. SUBSEQUENT RISK FOR PTSD AND DEPRESSION IS ALSO DISCUSSED. THE PATHWAY OF RISK FROM CHILDHOOD TRAUMA TO THESE COGNITIVE, EMOTIONAL, AND PSYCHIATRIC OUTCOMES IS ADDRESSED IN TERMS OF POTENTIAL STRUCTURAL AND FUNCTIONAL ALTERATIONS WITHIN THE HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA RESULTING FROM CHRONIC OR REPEATED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ITS INTERACTION WITH AND INFLUENCE ON GENETIC AND EPIGENETIC PROCESSES DURING SENSITIVE PERIODS OF DEVELOPMENT. IMPLICATIONS FOR PRACTICE ARE DISCUSSED. 2017 10 2949 29 GENETIC AND EPIGENETIC CONSEQUENCE OF EARLY-LIFE SOCIAL STRESS ON DEPRESSION: ROLE OF SEROTONIN-ASSOCIATED GENES. EARLY-LIFE ADVERSITY CAUSED BY POOR SOCIAL BONDING AND DEPRIVED MATERNAL CARE IS KNOWN TO AFFECT MENTAL WELLBEING AND PHYSICAL HEALTH. IT IS A FORM OF CHRONIC SOCIAL STRESS THAT PERSISTS BECAUSE OF A NEGATIVE ENVIRONMENT, AND THE CONSEQUENCES ARE LONG-LASTING ON MENTAL HEALTH. THE PRESENCE OF SOCIAL STRESS DURING EARLY LIFE CAN HAVE AN EPIGENETIC EFFECT ON THE BODY, POSSIBLY RESULTING IN MANY COMPLEX MENTAL DISORDERS, INCLUDING DEPRESSION IN LATER LIFE. HERE, WE REVIEW THE EVIDENCE FOR EARLY-LIFE SOCIAL STRESS-INDUCED EPIGENETIC CHANGES THAT MODULATE JUVENILE AND ADULT SOCIAL BEHAVIOR (DEPRESSION AND ANXIETY). THIS REVIEW HAS A PARTICULAR EMPHASIS ON THE INTERACTION BETWEEN EARLY-LIFE SOCIAL STRESS AND GENETIC VARIATION OF SEROTONIN ASSOCIATE GENES INCLUDING THE SEROTONIN TRANSPORTER GENE (5-HTT; ALSO KNOWN AS SLC6A4), WHICH ARE KEY MOLECULES INVOLVED IN DEPRESSION. 2020 11 235 22 ADDING FUEL TO THE FIRE: THE IMPACT OF STRESS ON THE AGEING BRAIN. BOTH AGEING AND CHRONIC STRESS ARE ASSOCIATED WITH ALTERED BRAIN PLASTICITY, DYSREGULATION OF THE IMMUNE SYSTEM, AND AN INCREASED RISK OF DEVELOPING BRAIN DISORDERS; ALL OF WHICH HAVE CONSEQUENCES FOR COGNITIVE AND EMOTIONAL PROCESSING. HERE WE EXAMINE THE SIMILARITIES BETWEEN BEHAVIOURAL CHANGES DURING AGEING AND STRESS ALTERED BEHAVIOURS (ANXIETY, DEPRESSIVE-LIKE BEHAVIOUR, COGNITION, AND SOCIABILITY) IN RODENTS AND HUMANS. THE MOLECULAR MECHANISMS HYPOTHESISED TO MEDIATE AGE-RELATED CHANGES IN BRAIN FUNCTION INCLUDING DYSFUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, DYSREGULATION OF NEUROTRANSMISSION AND NEUROTROPHIC FACTOR SIGNALLING, INCREASED INFLAMMATORY STATE, GENETIC AND EPIGENETIC CHANGES, OXIDATIVE STRESS, METABOLIC CHANGES, AND CHANGES IN THE MICROBIOTA-GUT-BRAIN AXIS ARE DISCUSSED. FINALLY, WE EXPLORE HOW THE ALREADY STRESSED AGED BRAIN PSYCHOLOGICALLY AND PHYSIOLOGICALLY RESPONDS TO EXTERNAL STRESSORS. 2015 12 1750 32 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD. 2020 13 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 14 380 31 AN EPIGENETIC PERSPECTIVE ON LIFESTYLE MEDICINE FOR DEPRESSION: IMPLICATIONS FOR PRIMARY CARE PRACTICE. DEPRESSION IS THE MOST COMMON PRESENTING MENTAL HEALTH DISORDER IN PRIMARY CARE. IT IS ALSO A MAJOR CONTRIBUTOR TO SOMATIC COMPLAINTS, WORSENING OF CHRONIC MEDICAL CONDITIONS, POOR QUALITY OF LIFE, AND SUICIDE. CURRENT PHARMACOLOGIC AND PSYCHOTHERAPEUTIC APPROACHES AVERT LESS THAN HALF OF DEPRESSION'S CUMULATIVE BURDEN ON SOCIETY. HOWEVER, THERE IS A GROWING BODY OF RESEARCH DESCRIBING BOTH HOW MALADAPTIVE LIFESTYLE CHOICES CONTRIBUTE TO THE DEVELOPMENT AND WORSENING OF DEPRESSION AND HOW LIFESTYLE-ORIENTED MEDICAL INTERVENTIONS CAN REDUCE THE INCIDENCE AND SEVERITY OF DEPRESSION. THIS RESEARCH, LARGELY DERIVED FROM AN EMERGING FIELD CALLED EPIGENETICS, ELUCIDATES THE INTERACTIONS BETWEEN OUR LIFESTYLE CHOICES AND THOSE EPIGENETIC FACTORS WHICH MEDIATE OUR TENDENCIES TOWARD EITHER HEALTH, OR THE ONSET, IF NOT WORSENING OF DISEASE. THE PRESENT REVIEW HIGHLIGHTS HOW LIFESTYLE CHOICES INVOLVING DIET, PHYSICAL ACTIVITY, SLEEP, SOCIAL RELATIONSHIPS, AND STRESS INFLUENCE EPIGENETIC PROCESSES POSITIVELY OR NEGATIVELY, AND THEREBY PLAY A SIGNIFICANT ROLE IN DETERMINING WHETHER ONE DOES OR DOES NOT SUFFER FROM DEPRESSION. THE AUTHORS PROPOSE THAT MEDICAL TRAINING PROGRAMS CONSIDER AND ADOPT LIFESTYLE MEDICINE ORIENTED INSTRUCTIONAL INITIATIVES THAT WILL ENABLE TOMORROW'S PRIMARY CARE PROVIDERS TO MORE EFFECTIVELY IDENTIFY AND THERAPEUTICALLY INTERVENE IN THE MALADAPTIVE CHOICES CONTRIBUTING TO THEIR PATIENTS' DEPRESSION. 2022 15 6184 33 THE IMPACT OF ENVIRONMENTAL FACTORS IN SEVERE PSYCHIATRIC DISORDERS. DURING THE LAST DECADES, SCHIZOPHRENIA HAS BEEN REGARDED AS A DEVELOPMENTAL DISORDER. THE NEURODEVELOPMENTAL HYPOTHESIS PROPOSES SCHIZOPHRENIA TO BE RELATED TO GENETIC AND ENVIRONMENTAL FACTORS LEADING TO ABNORMAL BRAIN DEVELOPMENT DURING THE PRE- OR POSTNATAL PERIOD. FIRST DISEASE SYMPTOMS APPEAR IN EARLY ADULTHOOD DURING THE SYNAPTIC PRUNING AND MYELINATION PROCESS. META-ANALYSES OF STRUCTURAL MRI STUDIES REVEALING HIPPOCAMPAL VOLUME DEFICITS IN FIRST-EPISODE PATIENTS AND IN THE LONGITUDINAL DISEASE COURSE CONFIRM THIS HYPOTHESIS. APART FROM THE INFLUENCE OF RISK GENES IN SEVERE PSYCHIATRIC DISORDERS, ENVIRONMENTAL FACTORS MAY ALSO IMPACT BRAIN DEVELOPMENT DURING THE PERINATAL PERIOD. SEVERAL ENVIRONMENTAL FACTORS SUCH AS ANTENATAL MATERNAL VIRUS INFECTIONS, OBSTETRIC COMPLICATIONS ENTAILING HYPOXIA AS COMMON FACTOR OR STRESS DURING NEURODEVELOPMENT HAVE BEEN IDENTIFIED TO PLAY A ROLE IN SCHIZOPHRENIA AND BIPOLAR DISORDER, POSSIBLY CONTRIBUTING TO SMALLER HIPPOCAMPAL VOLUMES. IN MAJOR DEPRESSION, PSYCHOSOCIAL STRESS DURING THE PERINATAL PERIOD OR IN ADULTHOOD IS AN IMPORTANT TRIGGER. IN ANIMAL STUDIES, CHRONIC STRESS OR REPEATED ADMINISTRATION OF GLUCOCORTICOIDS HAVE BEEN SHOWN TO INDUCE DEGENERATION OF GLUCOCORTICOID-SENSITIVE HIPPOCAMPAL NEURONS AND MAY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF AFFECTIVE DISORDERS. EPIGENETIC MECHANISMS ALTERING THE CHROMATIN STRUCTURE SUCH AS HISTONE ACETYLATION AND DNA METHYLATION MAY MEDIATE EFFECTS OF ENVIRONMENTAL FACTORS TO TRANSCRIPTIONAL REGULATION OF SPECIFIC GENES AND BE A PROMINENT FACTOR IN GENE-ENVIRONMENTAL INTERACTION. IN ANIMAL MODELS, GENE-ENVIRONMENTAL INTERACTION SHOULD BE INVESTIGATED MORE INTENSELY TO UNRAVEL PATHOPHYSIOLOGICAL MECHANISMS. THESE FINDINGS MAY LEAD TO NEW THERAPEUTIC STRATEGIES INFLUENCING EPIGENETIC TARGETS IN SEVERE PSYCHIATRIC DISORDERS. 2014 16 4626 28 NEURODEVELOPMENTAL DISORDERS AND ENVIRONMENTAL TOXICANTS: EPIGENETICS AS AN UNDERLYING MECHANISM. THE INCREASING PREVALENCE OF NEURODEVELOPMENTAL DISORDERS, ESPECIALLY AUTISM SPECTRUM DISORDERS (ASD) AND ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD), CALLS FOR MORE RESEARCH INTO THE IDENTIFICATION OF ETIOLOGIC AND RISK FACTORS. THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE (DOHAD) HYPOTHESIZES THAT THE ENVIRONMENT DURING FETAL AND CHILDHOOD DEVELOPMENT AFFECTS THE RISK FOR MANY CHRONIC DISEASES IN LATER STAGES OF LIFE, INCLUDING NEURODEVELOPMENTAL DISORDERS. EPIGENETICS, A TERM DESCRIBING MECHANISMS THAT CAUSE CHANGES IN THE CHROMOSOME STATE WITHOUT AFFECTING DNA SEQUENCES, IS SUGGESTED TO BE THE UNDERLYING MECHANISM, ACCORDING TO THE DOHAD HYPOTHESIS. MOREOVER, MANY NEURODEVELOPMENTAL DISORDERS ARE ALSO RELATED TO EPIGENETIC ABNORMALITIES. EXPERIMENTAL AND EPIDEMIOLOGICAL STUDIES SUGGEST THAT EXPOSURE TO PRENATAL ENVIRONMENTAL TOXICANTS IS ASSOCIATED WITH NEURODEVELOPMENTAL DISORDERS. IN ADDITION, THERE IS ALSO EVIDENCE THAT ENVIRONMENTAL TOXICANTS CAN RESULT IN EPIGENETIC ALTERATIONS, NOTABLY DNA METHYLATION. IN THIS REVIEW, WE FIRST FOCUS ON THE RELATIONSHIP BETWEEN NEURODEVELOPMENTAL DISORDERS AND ENVIRONMENTAL TOXICANTS, IN PARTICULAR MATERNAL SMOKING, PLASTIC-DERIVED CHEMICALS (BISPHENOL A AND PHTHALATES), PERSISTENT ORGANIC POLLUTANTS, AND HEAVY METALS. WE THEN REVIEW STUDIES SHOWING THE EPIGENETIC EFFECTS OF THOSE ENVIRONMENTAL FACTORS IN HUMANS THAT MAY AFFECT NORMAL NEURODEVELOPMENT. 2017 17 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 18 225 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 19 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 20 6375 33 THE ROLE OF NEURO-IMMUNE INTERACTION IN CHRONIC PAIN CONDITIONS; FUNCTIONAL SOMATIC SYNDROME, NEUROGENIC INFLAMMATION, AND PERIPHERAL NEUROPATHY. FUNCTIONAL SOMATIC SYNDROMES ARE INCREASINGLY DIAGNOSED IN CHRONICALLY ILL PATIENTS PRESENTING WITH AN ARRAY OF SYMPTOMS NOT ATTRIBUTED TO PHYSICAL AILMENTS. CONDITIONS SUCH AS CHRONIC FATIGUE SYNDROME, FIBROMYALGIA SYNDROME, OR IRRITABLE BOWEL SYNDROME ARE COMMON DISORDERS THAT BELONG IN THIS BROAD CATEGORY. SUCH SYNDROMES ARE CHARACTERISED BY THE PRESENCE OF ONE OR MULTIPLE CHRONIC SYMPTOMS INCLUDING WIDESPREAD MUSCULOSKELETAL PAIN, FATIGUE, SLEEP DISORDERS, AND ABDOMINAL PAIN, AMONGST OTHER ISSUES. SYMPTOMS ARE BELIEVED TO RELATE TO A COMPLEX INTERACTION OF BIOLOGICAL AND PSYCHOSOCIAL FACTORS, WHERE A DEFINITE AETIOLOGY HAS NOT BEEN ESTABLISHED. THEORIES SUGGEST CAUSATIVE PATHWAYS BETWEEN THE IMMUNE AND NERVOUS SYSTEMS OF AFFECTED INDIVIDUALS WITH SEVERAL RISK FACTORS IDENTIFIED IN PATIENTS PRESENTING WITH ONE OR MORE FUNCTIONAL SYNDROMES. RISK FACTORS INCLUDING STRESS AND CHILDHOOD TRAUMA ARE NOW RECOGNISED AS IMPORTANT CONTRIBUTORS TO CHRONIC PAIN CONDITIONS. EMOTIONAL, PHYSICAL, AND SEXUAL ABUSE DURING CHILDHOOD IS CONSIDERED A SEVERE STRESSOR HAVING A HIGH PREVALENCE IN FUNCTIONAL SOMATIC SYNDROME SUFFERS. SUCH TRAUMA PERMANENTLY ALTERS THE BIOLOGICAL STRESS RESPONSE OF THE SUFFERS LEADING TO NEUROEXCITATORY AND OTHER NERVE ISSUES ASSOCIATED WITH CHRONIC PAIN IN ADULTS. TRAUMATIC AND CHRONIC STRESS RESULTS IN EPIGENETIC CHANGES IN STRESS RESPONSE GENES, WHICH ULTIMATELY LEADS TO DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY AXIS, THE AUTONOMIC NERVOUS SYSTEM, AND THE IMMUNE SYSTEM MANIFESTING IN A BROAD ARRAY OF SYMPTOMS. IMPORTANTLY, THESE SYSTEMS ARE KNOWN TO BE DYSREGULATED IN PATIENTS SUFFERING FROM FUNCTIONAL SOMATIC SYNDROME. FUNCTIONAL SOMATIC SYNDROMES ARE ALSO HIGHLY PREVALENT CO-MORBIDITIES OF PSYCHIATRIC CONDITIONS, MOOD DISORDERS, AND ANXIETY. CONSEQUENTLY, THIS REVIEW AIMS TO PROVIDE INSIGHT INTO THE ROLE OF THE NERVOUS SYSTEM AND IMMUNE SYSTEM IN CHRONIC PAIN DISORDERS ASSOCIATED WITH THE MUSCULOSKELETAL SYSTEM, AND CENTRAL AND PERIPHERAL NERVOUS SYSTEMS. 2022