1 1750 94 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 2 4622 24 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 3 6478 31 TOPICAL REVIEW: THE EMERGING FIELD OF EPIGENETICS: INFORMING MODELS OF PEDIATRIC TRAUMA AND PHYSICAL HEALTH. OBJECTIVE: TRAUMA EXPERIENCED DURING CHILDHOOD AND ADOLESCENCE HAS BEEN LINKED TO A NUMBER OF CHRONIC MEDICAL CONCERNS. WE HIGHLIGHT MAJOR FINDINGS FROM THE PEDIATRIC TRAUMA LITERATURE TO PROVIDE A MODEL FOR UNDERSTANDING THIS ASSOCIATION. METHODS: STUDIES EXAMINING THE EFFECTS OF TRAUMA WERE SYSTEMATICALLY REVIEWED AND SYNTHESIZED INTO A MODEL PROPOSING A CENTRAL ROLE FOR EPIGENETICS IN THE WAYS THAT CHILDHOOD EXPERIENCES CAN AFFECT HEALTH. RESULTS: EARLY HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS RESPONSE MAY IMPACT INITIAL TRAUMA EXPERIENCE, WITH DOWNSTREAM EFFECTS ON POSTTRAUMA ADJUSTMENT REFLECTED IN POSTTRAUMA NEUROBIOLOGY, PSYCHOLOGICAL HEALTH, AND PHYSICAL HEALTH. CONCLUSIONS: PROSPECTIVE RESEARCH WITH CHILDREN AND ADOLESCENTS EXPOSED TO TRAUMA IS NEEDED TO BETTER CHARACTERIZE THE GENETIC AND EPIGENETIC INFLUENCES ON THE COURSE OF HPA AND IMMUNE PROCESSES AS RELATED TO POSTTRAUMA PSYCHOLOGICAL AND PHYSICAL HEALTH OUTCOMES. 2016 4 248 39 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 5 5316 28 PSYCHOLOGICAL STRESS IN EARLY LIFE AS A PREDISPOSING FACTOR FOR THE DEVELOPMENT OF CHRONIC PAIN: CLINICAL AND PRECLINICAL EVIDENCE AND NEUROBIOLOGICAL MECHANISMS. A WEALTH OF RESEARCH OVER THE PAST 2 DECADES HAS EXPANDED OUR UNDERSTANDING OF THE IMPACT OF EARLY-LIFE ADVERSITY ON PHYSIOLOGICAL FUNCTION AND, CONSEQUENTLY, HEALTH AND WELLBEING IN LATER LIFE. EARLY-LIFE ADVERSITY INCREASES THE RISK OF DEVELOPING A NUMBER OF DISORDERS, SUCH AS CHRONIC PAIN, FIBROMYALGIA, AND IRRITABLE BOWEL SYNDROME. ALTHOUGH MUCH OF THE RESEARCH HAS EXAMINED THE IMPACT OF PHYSICAL MALTREATMENT, AN INCREASING NUMBER OF STUDIES HAVE BEEN PUBLISHED OVER THE PAST FEW YEARS EXAMINING THE EFFECT OF CHILDHOOD PSYCHOLOGICAL STRESS AND TRAUMA ON THE DEVELOPMENT OF VARIOUS TYPES OF CHRONIC PAIN CONDITIONS. WE REVIEW THE CLINICAL AND PRECLINICAL DATA EXAMINING THE LINK AMONG EARLY-LIFE PSYCHOLOGICAL STRESS, ALTERED NOCICEPTIVE BEHAVIOR, AND CHRONIC PAIN IN LATER LIFE. EVIDENCE SUPPORTING A ROLE FOR CERTAIN KEY NEUROBIOLOGICAL SUBSTRATES, INCLUDING THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS; MONOAMINERGIC, OPIOIDERGIC, ENDOCANNABINOID AND IMMUNE SYSTEMS; AND EPIGENETIC MECHANISMS IN THE ASSOCIATION BETWEEN EARLY-LIFE PSYCHOLOGICAL STRESS AND CHRONIC PAIN, IS PROVIDED. GREATER UNDERSTANDING OF THE IMPACT OF EARLY-LIFE STRESS MAY INFORM THE DEVELOPMENT OF PERSONALIZED TREATMENTS FOR CHRONIC PAIN IN LATER LIFE AND STRATEGIES TO PREVENT ITS ONSET IN SUSCEPTIBLE INDIVIDUALS. (C) 2016 WILEY PERIODICALS, INC. 2017 6 2949 30 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 7 6626 32 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 8 1754 30 EARLY LIFE STRESS, THE DEVELOPMENT OF AGGRESSION AND NEUROENDOCRINE AND NEUROBIOLOGICAL CORRELATES: WHAT CAN WE LEARN FROM ANIMAL MODELS? EARLY LIFE STRESS (CHILD AND ADOLESCENT ABUSE, NEGLECT AND TRAUMA) INDUCES ROBUST ALTERATIONS IN EMOTIONAL AND SOCIAL FUNCTIONING RESULTING IN ENHANCED RISK FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS MOOD AND AGGRESSIVE DISORDERS. HERE, AN OVERVIEW IS GIVEN ON RECENT FINDINGS IN PRIMATE AND RODENT MODELS OF EARLY LIFE STRESS, DEMONSTRATING THAT CHRONIC DEPRIVATION OF EARLY MATERNAL CARE AS WELL AS CHRONIC DEPRIVATION OF EARLY PHYSICAL INTERACTIONS WITH PEERS ARE PROFOUND RISK FACTORS FOR THE DEVELOPMENT OF INAPPROPRIATE AGGRESSIVE BEHAVIORS. ALTERATIONS IN THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA), VASOPRESSIN AND SEROTONIN SYSTEMS AND THEIR RELEVANCE FOR THE REGULATION OF AGGRESSION ARE DISCUSSED. DATA SUGGEST THAT SOCIAL DEPRIVATION-INDUCED INAPPROPRIATE FORMS OF AGGRESSION ARE ASSOCIATED WITH HIGH OR LOW HPA AXIS (RE)ACTIVITY AND A GENERALLY LOWER FUNCTIONING OF THE SEROTONIN SYSTEM IN ADULTHOOD. MOREOVER, GENETIC AND EPIGENETIC MODIFICATIONS IN HPA AND SEROTONIN SYSTEMS INFLUENCE THE OUTCOME OF EARLY LIFE STRESS AND MAY EVEN MODERATE ADVERSE EFFECTS OF EARLY SOCIAL DEPRIVATION ON AGGRESSION. A MORE COMPREHENSIVE STUDY OF AGGRESSION, NEUROENDOCRINE, NEUROBIOLOGICAL AND (EPI)GENETIC CORRELATES OF EARLY LIFE STRESS USING ANIMAL MODELS IS NECESSARY TO PROVIDE A BETTER UNDERSTANDING OF THE INVASIVE AGGRESSIVE DEFICITS OBSERVED IN HUMANS EXPOSED TO CHILD MALTREATMENT. 2009 9 6278 25 THE PATHWAYS BETWEEN CORTISOL-RELATED REGULATION GENES AND PTSD PSYCHOTHERAPY. POST-TRAUMATIC STRESS DISORDER (PTSD) ONLY DEVELOPS AFTER EXPOSURE TO A TRAUMATIC EVENT IN SOME INDIVIDUALS. PTSD CAN BE CHRONIC AND DEBILITATING, AND IS ASSOCIATED WITH CO-MORBIDITIES SUCH AS DEPRESSION, SUBSTANCE USE, AND CARDIOMETABOLIC DISORDERS. ONE OF THE MOST IMPORTANT PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING THE DEVELOPMENT OF PTSD AND ITS SUBSEQUENT MAINTENANCE IS A DYSFUNCTIONAL HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE CORTICOTROPHIN-RELEASING HORMONE, CORTISOL, GLUCOCORTICOID RECEPTOR (GR), AND THEIR RESPECTIVE GENES ARE SOME OF THE MEDIATORS OF PTSD'S PATHOPHYSIOLOGY. SEVERAL TREATMENTS ARE AVAILABLE, INCLUDING MEDICATION AND PSYCHOTHERAPIES, ALTHOUGH THEIR SUCCESS RATE IS LIMITED. SOME PHARMACOLOGICAL THERAPIES BASED ON THE HPA AXIS ARE CURRENTLY BEING TESTED IN CLINICAL TRIALS AND CHANGES IN HPA AXIS BIOMARKERS HAVE BEEN FOUND TO OCCUR IN RESPONSE NOT ONLY TO PHARMACOLOGICAL TREATMENTS, BUT ALSO TO PSYCHOTHERAPY-INCLUDING THE EPIGENETIC MODIFICATION OF THE GR GENE. PSYCHOTHERAPIES ARE CONSIDERED TO BE THE FIRST LINE TREATMENTS FOR PTSD IN SOME GUIDELINES, EVEN THOUGH THEY ARE EFFECTIVE FOR SOME, BUT NOT FOR ALL PATIENTS WITH PTSD. THIS REVIEW AIMS TO ADDRESS HOW KNOWLEDGE OF THE HPA AXIS-RELATED GENETIC MAKEUP CAN INFORM AND PREDICT THE OUTCOMES OF PSYCHOTHERAPEUTIC TREATMENTS. 2020 10 6853 65 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 11 2269 36 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 12 291 31 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 13 6627 38 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 14 1774 39 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY. 2018 15 632 30 BIOLOGICAL CORRELATES OF EARLY LIFE STRESSFUL EVENTS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS THE MOST COMMON PSYCHIATRIC DISORDER AND RESPONDS FOR IMPORTANT PSYCHOSOCIAL CONSEQUENCES. STRESSFUL LIFE EVENTS, ESPECIALLY EARLY LIFE STRESS (ELS), CONTRIBUTE TO AN INCREASED PROBABILITY TO DEVELOP MDD, LEADING IN PARTICULAR TO SEVERE AND CHRONIC MANIFESTATION AND UNFAVORABLE TREATMENT OUTCOME. THE ASSOCIATION BETWEEN ELS AND MDD SEEMS TO HAVE BIOLOGICAL BASES, CONSISTING IN DYSREGULATIONS OCCURRING AT DIFFERENT LEVELS. THE AIM OF THIS NARRATIVE REVIEW IS TO PROPOSE AN OVERVIEW OF THE LITERATURE RANGING FROM GENETIC, EPIGENETIC, EXPRESSION AND PROTEIN TO NEUROIMAGING CORRELATES UNDERLYING THIS RELATIONSHIP. A SEARCH ON PUBMED OF STUDIES ASSESSING BIOLOGICAL CORRELATES OF ELS IN MDD DEVELOPMENT, FOCUSING ON HUMAN STUDIES CONDUCTED IN BOTH PERIPHERAL AND BRAIN TISSUES, WAS PERFORMED. EVIDENCE INDICATED THAT THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND THE SEROTONERGIC, DOPAMINERGIC, NEUROTROPHIN AND OXYTOCIN SYSTEMS MIGHT PLAY A ROLE IN THE MEDIATION BETWEEN ELS AND MDD. THE MOST CONSISTENT RESULTS WERE FOUND FOR GENETIC AND EPIGENETIC STUDIES AND INDICATED A JOINT INVOLVEMENT OF THE SYSTEMS MENTIONED. EXPRESSION STUDIES ARE LESS NUMEROUS AND POINT TO AN INVOLVEMENT OF STRESS-RELATED SYSTEMS. CONCERNING PROTEIN STUDIES, THE MAIN MEDIATORS ARE MARKERS RELATED TO THE INFLAMMATORY AND IMMUNE SYSTEMS. NEUROIMAGING STUDIES AIMING AT EVALUATING BRAIN ALTERATIONS CONNECTING ELS AND MDD IN RELATION TO BIOMARKERS INDICATED THE HIPPOCAMPUS, THE AMYGDALA AND THE FRONTAL CORTEX AS IMPORTANT ANATOMICAL MEDIATORS. THESE FINDINGS CAN BUILD THE BASES FOR FUTURE RESEARCH AND CLINICAL INTERVENTIONS; INDEED, THE CLARIFICATION OF BIOLOGICAL MECHANISMS MEDIATING THE RELATIONSHIP BETWEEN ELS AND MDD CAN LEAD TO NEW AND INDIVIDUALIZED PREVENTIVE AND THERAPEUTIC POSSIBILITIES. 2021 16 5171 26 PREDATOR-BASED PSYCHOSOCIAL STRESS ANIMAL MODEL OF PTSD: PRECLINICAL ASSESSMENT OF TRAUMATIC STRESS AT COGNITIVE, HORMONAL, PHARMACOLOGICAL, CARDIOVASCULAR AND EPIGENETIC LEVELS OF ANALYSIS. RESEARCH ON POST-TRAUMATIC STRESS DISORDER (PTSD) IS FACED WITH THE CHALLENGE OF UNDERSTANDING HOW A TRAUMATIC EXPERIENCE PRODUCES LONG-LASTING DETRIMENTAL EFFECTS ON BEHAVIOR AND BRAIN FUNCTIONING, AND MORE GLOBALLY, HOW STRESS EXACERBATES SOMATIC DISORDERS, INCLUDING CARDIOVASCULAR DISEASE. MOREOVER, THE DESIGN OF TRANSLATIONAL RESEARCH NEEDS TO LINK ANIMAL MODELS OF PTSD TO CLINICALLY RELEVANT RISK FACTORS WHICH ADDRESS WHY ONLY A SUBSET OF TRAUMATIZED INDIVIDUALS DEVELOP PERSISTENT PSYCHOPATHOLOGY. IN THIS REVIEW, WE HAVE SUMMARIZED OUR PSYCHOSOCIAL STRESS RODENT MODEL OF PTSD WHICH IS BASED ON WELL-DESCRIBED PTSD-INDUCING RISK FACTORS, INCLUDING A LIFE-THREATENING EXPERIENCE, A SENSE OF HORROR AND UNCONTROLLABILITY, AND INSUFFICIENT SOCIAL SUPPORT. SPECIFICALLY, OUR ANIMAL MODEL OF PTSD INTEGRATES ACUTE EPISODES OF INESCAPABLE EXPOSURE OF IMMOBILIZED RATS TO A PREDATOR WITH CHRONIC DAILY SOCIAL INSTABILITY. THIS STRESS REGIMEN PRODUCES PTSD-LIKE EFFECTS IN RATS AT BEHAVIORAL, COGNITIVE, PHYSIOLOGICAL, PHARMACOLOGICAL AND EPIGENETIC LEVELS OF ANALYSIS. WE HAVE DISCUSSED A RECENT EXTENSION OF OUR ANIMAL MODEL OF PTSD IN WHICH STRESS EXACERBATED CORONARY PATHOLOGY FOLLOWING AN ISCHEMIC EVENT, ASSESSED IN VITRO. IN ADDITION, WE HAVE REVIEWED OUR RESEARCH INVESTIGATING PHARMACOLOGICAL AND NON-PHARMACOLOGICAL THERAPEUTIC STRATEGIES WHICH MAY HAVE VALUE IN CLINICAL APPROACHES TOWARD THE TREATMENT OF TRAUMATIZED PEOPLE. OVERALL, OUR TRANSLATIONAL APPROACH BRIDGES THE GAP BETWEEN HUMAN AND ANIMAL PTSD RESEARCH TO CREATE A FRAMEWORK WITH WHICH TO ENHANCE OUR UNDERSTANDING OF THE BIOLOGICAL BASIS OF TRAUMA-INDUCED PATHOLOGY AND TO ASSESS THERAPEUTIC APPROACHES IN THE TREATMENT OF PSYCHOPATHOLOGY. 2016 17 2021 30 EPIGENETIC CHANGES ASSOCIATED WITH DIFFERENT TYPES OF STRESSORS AND SUICIDE. STRESS IS ASSOCIATED WITH VARIOUS EPIGENETIC CHANGES. SOME STRESS-INDUCED EPIGENETIC CHANGES ARE HIGHLY DYNAMIC, WHEREAS OTHERS ARE ASSOCIATED WITH LASTING MARKS ON THE EPIGENOME. IN OUR STUDY, A COMPREHENSIVE NARRATIVE REVIEW OF THE LITERATURE WAS PERFORMED BY INVESTIGATING THE EPIGENETIC CHANGES THAT OCCUR WITH ACUTE STRESS, CHRONIC STRESS, EARLY CHILDHOOD STRESS, AND TRAUMATIC STRESS EXPOSURES, ALONG WITH EXAMINING THOSE OBSERVED IN POST-MORTEM BRAINS OR BLOOD SAMPLES OF SUICIDE COMPLETERS AND ATTEMPTERS. IN ADDITION, THE TRANSGENERATIONAL EFFECTS OF THESE CHANGES ARE REPORTED. FOR ALL TYPES OF STRESS STUDIES EXAMINED, THE GENES NR3C1, OXTR, SLC6A4, AND BDNF REPRODUCIBLY SHOWED EPIGENETIC CHANGES, WITH SOME MODIFICATIONS OBSERVED TO BE PASSED DOWN TO SUBSEQUENT GENERATIONS FOLLOWING STRESS EXPOSURES. THE AFOREMENTIONED GENES ARE KNOWN TO BE INVOLVED IN NEURONAL DEVELOPMENT AND HORMONAL REGULATION AND ARE ALL ASSOCIATED WITH SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS INCLUDING DEPRESSION, ANXIETY, PERSONALITY DISORDERS, AND PTSD (POST-TRAUMATIC STRESS DISORDER). FURTHER RESEARCH IS WARRANTED IN ORDER TO DETERMINE THE SCOPE OF EPIGENETIC ACTIONABLE TARGETS IN INDIVIDUALS SUFFERING FROM THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES. 2023 18 5164 31 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 19 6729 38 VULNERABILITY TO STROKE: IMPLICATIONS OF PERINATAL PROGRAMMING OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. CHRONIC STRESS IS CAPABLE OF EXACERBATING EACH MAJOR, MODIFIABLE, ENDOGENOUS RISK FACTOR FOR CEREBROVASCULAR AND CARDIOVASCULAR DISEASE. INDEED, EXPOSURE TO STRESS CAN INCREASE BOTH THE INCIDENCE AND SEVERITY OF STROKE, PRESUMABLY THROUGH ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. NOW THAT CHARACTERIZATION OF THE MECHANISMS UNDERLYING EPIGENETIC PROGRAMMING OF THE HPA AXIS IS WELL UNDERWAY, THERE HAS BEEN RENEWED INTEREST IN EXAMINING THE ROLE OF EARLY ENVIRONMENT ON THE EVOLUTION OF HEALTH CONDITIONS ACROSS THE ENTIRE LIFESPAN. INDEED, NEONATAL MANIPULATIONS IN RODENTS THAT REDUCE STRESS RESPONSIVITY, AND SUBSEQUENT LIFE-TIME EXPOSURE TO GLUCOCORTICOIDS, ARE ASSOCIATED WITH A REDUCTION IN THE DEVELOPMENT OF NEUROENDOCRINE, NEUROANATOMICAL, AND COGNITIVE DYSFUNCTIONS THAT TYPICALLY PROGRESS WITH AGE. ALTHOUGH IMPROVED DAY TO DAY REGULATION OF THE HPA AXIS ALSO MAY BE ACCOMPANIED BY A DECREASE IN STROKE RISK, EVIDENCE FROM RODENT STUDIES SUGGEST THAT AN ASSOCIATED COST COULD BE INCREASED SUSCEPTIBILITY TO INFLAMMATION AND NEURONAL DEATH IN THE EVENT THAT A STROKE DOES OCCUR AND THE INDIVIDUAL IS EXPOSED TO PERSISTENTLY ELEVATED CORTICOSTEROIDS. GIVEN ITS IMPORTANCE IN REGULATION OF HEALTH AND DISEASE STATES, ANY LONG-TERM MODULATION OF THE HPA AXIS IS LIKELY TO BE ASSOCIATED WITH BOTH BENEFITS AND POTENTIAL RISKS. THE GOALS OF THIS REVIEW ARTICLE ARE TO EXAMINE (1) THE CLINICAL AND EXPERIMENTAL DATA SUGGESTING THAT NEONATAL EXPERIENCES CAN SHAPE HPA AXIS REGULATION, (2) THE INFLUENCE OF STRESS AND THE HPA AXIS ON STROKE INCIDENCE AND SEVERITY, AND (3) THE POTENTIAL FOR NEONATAL PROGRAMMING OF THE HPA AXIS TO IMPACT ADULT CEREBROVASCULAR HEALTH. 2009 20 6228 25 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016