1 632 144 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 2 6228 34 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 3 5164 37 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 4 2021 33 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 5 1329 47 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 6 291 37 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 7 2231 38 EPIGENETIC MODIFICATIONS OF MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC DISEASE WHOSE NEUROLOGICAL BASIS AND PATHOPHYSIOLOGY REMAIN POORLY UNDERSTOOD. INITIALLY, IT WAS PROPOSED THAT GENETIC VARIATIONS WERE RESPONSIBLE FOR THE DEVELOPMENT OF THIS DISEASE. NEVERTHELESS, SEVERAL STUDIES WITHIN THE LAST DECADE HAVE PROVIDED EVIDENCE SUGGESTING THAT ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE IN MDD PATHOPHYSIOLOGY. ALTERATIONS IN EPIGENETICS MECHANISM, SUCH AS DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA EXPRESSION COULD FAVOR MDD ADVANCE IN RESPONSE TO STRESSFUL EXPERIENCES AND ENVIRONMENTAL FACTORS. THE AIM OF THIS REVIEW IS TO DESCRIBE GENETIC ALTERATIONS, AND PARTICULARLY ALTERED EPIGENETIC MECHANISMS, THAT COULD BE DETERMINANTS FOR MDD PROGRESS, AND HOW THESE ALTERATIONS MAY ARISE AS USEFUL SCREENING, DIAGNOSIS AND TREATMENT MONITORING BIOMARKERS OF DEPRESSIVE DISORDERS. 2016 8 2011 48 EPIGENETIC BASIS OF MENTAL ILLNESS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION AS WELL AS LIKELY ABNORMALITIES IN GLIAL CELLS. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF MOST MENTAL DISORDERS, THE RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS, PARTICULARLY FOR DEPRESSION AND OTHER STRESS-RELATED SYNDROMES, CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. EXPOSURE TO SUCH ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL VERSUS ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND THE ABERRANT EPIGENETIC REGULATION THAT UNDERLIES THIS DYSREGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. HERE, WE PROVIDE A PROGRESS REPORT OF EPIGENETIC STUDIES OF THE THREE MAJOR PSYCHIATRIC SYNDROMES, DEPRESSION, SCHIZOPHRENIA, AND BIPOLAR DISORDER. WE REVIEW THE LITERATURE DERIVED FROM ANIMAL MODELS OF THESE DISORDERS AS WELL AS FROM STUDIES OF POSTMORTEM BRAIN TISSUE FROM HUMAN PATIENTS. WHILE EPIGENETIC STUDIES OF MENTAL ILLNESS REMAIN AT EARLY STAGES, UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY WITHIN SPECIFIC BRAIN REGIONS TO CAUSE LASTING CHANGES IN DISEASE SUSCEPTIBILITY AND PATHOPHYSIOLOGY IS REVEALING NEW INSIGHT INTO THE ETIOLOGY AND TREATMENT OF THESE CONDITIONS. 2016 9 248 49 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 10 2572 37 EPIGENETICS OF DEPRESSION. MAJOR DEPRESSIVE DISORDER (MDD) IS A LEADING CAUSE OF DISABILITY WORLDWIDE AND IS ASSOCIATED WITH POOR PSYCHOLOGICAL, MEDICAL, AND SOCIOECONOMIC OUTCOMES. ALTHOUGH MUCH HAS BEEN LEARNED ABOUT THE ETIOLOGY AND TREATMENT OPTIONS OF MDD OVER THE PAST DECADE, THERE REMAIN UNANSWERED QUESTIONS THAT POSE CHALLENGES TO IMPROVING ACUTE AND CHRONIC OUTCOMES FOR THOSE WITH MDD. MDD IS A CLINICALLY HETEROGENEOUS DISORDER. GENETIC STUDIES TO DATE HAVE INDICATED A NUMBER OF GENES, INCLUDING TRANSPORTERS, NEUROTRANSMITTERS, NEUROTROPHINS, AND THEIR ASSOCIATED SIGNALING NETWORKS THAT MAY PREDISPOSE INDIVIDUALS TO MDD AND MAY ALSO PREDICT TREATMENT OUTCOMES. HOWEVER, TWIN STUDIES INDICATE THAT GENES ACCOUNT FOR ONLY A SMALL DEGREE OF THE VARIATION IN MDD. THUS, OTHER MECHANISMS, THROUGH EPIGENETIC MARKS, MAY ACT TO FORM A MOLECULAR MEMORY OF PREVIOUS GENE-TO-ENVIRONMENT INTERACTIONS AND TO ESTABLISH VULNERABILITIES (OR, CONVERSELY, RESISTANCE) TO MDD. CURRENT EVIDENCE SUPPORTS A ROLE FOR PRE-, PERI-, AND EARLY POSTNATAL ADVERSITIES AND STRESSFUL LIFE EVENTS INTO ADULTHOOD AFFECTING EPIGENETIC PATTERNS, PROVIDING A MECHANISTIC FOUNDATION TO DEVELOP EPIGENETIC MARKS AS BIOMARKERS FOR MDD. THIS REVIEW PRESENTS THE EVIDENCE SUPPORTING A ROLE FOR EPIGENETIC EFFECTS IN MDD AND IN TREATMENT RESPONSE. WE ALSO DISCUSS THE CONTROVERSY BEHIND MODULATING EPIGENETIC MECHANISMS IN LONG-TERM ANTIDEPRESSANT PHARMACOTHERAPY. 2014 11 2269 45 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 6184 41 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 13 6414 37 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 14 2917 31 GENE-ENVIRONMENT INTERACTIONS IN COMMON MENTAL DISORDERS: AN UPDATE AND STRATEGY FOR A GENOME-WIDE SEARCH. A DECADE OF RESEARCH HAS DEMONSTRATED THE EXPLANATORY POTENTIAL OF INTERPLAY BETWEEN GENETIC VARIANTS AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF COMMON MENTAL DISORDERS. INITIAL FINDINGS HAVE UNDERGONE TESTS OF REPLICABILITY AND SPECIFICITY. SOME GENE-ENVIRONMENT INTERACTIONS HAVE BEEN CONFIRMED, SOME HAVE NOT REPLICATED AND YET OTHER TURNED OUT TO BE MORE SPECIFIC THAN INITIALLY THOUGHT. SPECIFIC AND COMPLEMENTARY ROLES OF GENETIC FACTORS HAVE BEEN DELINEATED: A COMMON FUNCTIONAL LENGTH POLYMORPHISM IN THE SEROTONIN TRANSPORTER GENE (5-HTTLPR) MODERATED THE EFFECT OF CHILDHOOD MALTREATMENT ON CHRONIC DEPRESSION IN ADULTHOOD, BUT DID NOT SUBSTANTIALLY INFLUENCE THE EFFECTS OF ADULT STRESSFUL LIFE EVENTS ON THE ONSET OF NEW DEPRESSIVE EPISODES; IN CONTRAST, A COMMON FUNCTIONAL POLYMORPHISM IN THE BRAIN-DERIVED NEUROTROPHIC FACTOR GENE (BDNF) MODERATED THE EFFECT OF STRESSFUL LIFE EVENTS IN ADULTHOOD IN TRIGGERING NEW DEPRESSIVE EPISODES, BUT DID NOT INFLUENCE THE EFFECTS OF CHILDHOOD MALTREATMENT. MOLECULAR MECHANISMS UNDERLYING GENE-ENVIRONMENT INTERACTIONS ARE BEING UNCOVERED, INCLUDING DNA METHYLATION AND OTHER EPIGENETIC MODIFICATIONS. NEW GENE-ENVIRONMENT INTERACTIONS CONTINUE TO BE REPORTED, STILL LARGELY FROM HYPOTHESIS-DRIVEN RESEARCH. STATISTICAL AND BIOLOGICAL PRIORITIZATION STRATEGIES ARE PROPOSED TO FACILITATE A SYSTEMATIC DISCOVERY OF NOVEL GENE-ENVIRONMENT INTERACTIONS IN GENOME-WIDE ANALYSES. 2014 15 4642 44 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 16 110 36 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 17 2288 41 EPIGENETIC REGULATION IN MAJOR DEPRESSION AND OTHER STRESS-RELATED DISORDERS: MOLECULAR MECHANISMS, CLINICAL RELEVANCE AND THERAPEUTIC POTENTIAL. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC, GENERALLY EPISODIC AND DEBILITATING DISEASE THAT AFFECTS AN ESTIMATED 300 MILLION PEOPLE WORLDWIDE, BUT ITS PATHOGENESIS IS POORLY UNDERSTOOD. THE HERITABILITY ESTIMATE OF MDD IS 30-40%, SUGGESTING THAT GENETICS ALONE DO NOT ACCOUNT FOR MOST OF THE RISK OF MAJOR DEPRESSION. ANOTHER FACTOR KNOWN TO ASSOCIATE WITH MDD INVOLVES ENVIRONMENTAL STRESSORS SUCH AS CHILDHOOD ADVERSITY AND RECENT LIFE STRESS. RECENT STUDIES HAVE EMERGED TO SHOW THAT THE BIOLOGICAL IMPACT OF ENVIRONMENTAL FACTORS IN MDD AND OTHER STRESS-RELATED DISORDERS IS MEDIATED BY A VARIETY OF EPIGENETIC MODIFICATIONS. THESE EPIGENETIC MODIFICATION ALTERATIONS CONTRIBUTE TO ABNORMAL NEUROENDOCRINE RESPONSES, NEUROPLASTICITY IMPAIRMENT, NEUROTRANSMISSION AND NEUROGLIA DYSFUNCTION, WHICH ARE INVOLVED IN THE PATHOPHYSIOLOGY OF MDD. FURTHERMORE, EPIGENETIC MARKS HAVE BEEN ASSOCIATED WITH THE DIAGNOSIS AND TREATMENT OF MDD. THE EVALUATION OF EPIGENETIC MODIFICATIONS HOLDS PROMISE FOR FURTHER UNDERSTANDING OF THE HETEROGENEOUS ETIOLOGY AND COMPLEX PHENOTYPES OF MDD, AND MAY IDENTIFY NEW THERAPEUTIC TARGETS. HERE, WE REVIEW PRECLINICAL AND CLINICAL EPIGENETIC FINDINGS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNA, RNA MODIFICATION, AND CHROMATIN REMODELING FACTOR IN MDD. IN ADDITION, WE ELABORATE ON THE CONTRIBUTION OF THESE EPIGENETIC MECHANISMS TO THE PATHOLOGICAL TRAIT VARIABILITY IN DEPRESSION AND DISCUSS HOW SUCH MECHANISMS CAN BE EXPLOITED FOR THERAPEUTIC PURPOSES. 2023 18 6729 40 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 19 2520 38 EPIGENETICS AND THE GLUCOCORTICOID RECEPTOR: A REVIEW OF THE IMPLICATIONS IN DEPRESSION. DEPRESSION IS A SERIOUS PSYCHIATRIC DISORDER THAT EFFECTS AT LEAST 350 MILLION PEOPLE WORLDWIDE TODAY. DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPAA) IS A ROBUST FINDING IN THE PATHOPHYSIOLOGY OF DEPRESSION. THIS DYSREGULATION IS HYPOTHESIZED TO RESULT FROM ALTERED CENTRAL GLUCOCORTICOID RECEPTOR (GR) LEVELS AND/OR FUNCTION AS A CONSEQUENCE OF CHRONIC GLUCOCORTICOID (GC) RELEASE, LEADING TO RECEPTOR RESISTANCE. PIVOTAL ANIMAL AND HUMAN RESEARCH TO DATE HAS IDENTIFIED THAT EARLY LIFE EXPOSURE TO PROLONGED LEVELS OF GCS, STRESS AND/OR DEPRESSION, CAN INDUCE EPIGENETIC MODIFICATIONS AT KEY REGIONS ON THE GR GENE THAT LEAD TO ALTERATIONS IN GR EXPRESSION AND FUNCTION. EPIGENETICS PROVIDES AN ATTRACTIVE MECHANISM TO EXPLAIN HOW ONES' GENES AND ENVIRONMENT CAN INTERACT TO PRODUCE DIFFERENT DISEASE PHENOTYPES. THIS REVIEW AIMS TO COMPILE THE INFORMATION THAT HAS BEEN COLLECTED TO DATE AND TO IDENTIFY KEY AREAS FOR FURTHER INVESTIGATION. 2016 20 2159 30 EPIGENETIC MECHANISMS IMPACTED BY CHRONIC STRESS ACROSS THE RODENT LIFESPAN. EXPOSURES TO STRESS AT ALL STAGES OF DEVELOPMENT CAN LEAD TO LONG-TERM BEHAVIOURAL EFFECTS, IN PART THROUGH CHANGES IN THE EPIGENOME. THIS REVIEW DESCRIBES RODENT RESEARCH SUGGESTING THAT STRESS IN PRENATAL, POSTNATAL, ADOLESCENT AND ADULT STAGES LEADS TO LONG-TERM CHANGES IN EPIGENETIC REGULATION IN THE BRAIN WHICH HAVE CAUSAL IMPACTS ON RODENT BEHAVIOUR. WE FOCUS ON STRESS-INDUCED EPIGENETIC CHANGES THAT HAVE BEEN LINKED TO BEHAVIOURAL DEFICITS INCLUDING POOR LEARNING AND MEMORY, AND INCREASED ANXIETY-LIKE AND DEPRESSIVE-LIKE BEHAVIOURS. INTERESTINGLY, ASPECTS OF THESE STRESS-INDUCED BEHAVIOURAL CHANGES CAN BE TRANSMITTED TO OFFSPRING ACROSS SEVERAL GENERATIONS, A PHENOMENON THAT HAS BEEN PROPOSED TO RESULT VIA EPIGENETIC MECHANISMS IN THE GERMLINE. HERE, WE ALSO DISCUSS EVIDENCE FOR THE DIFFERENTIAL IMPACT OF STRESS ON THE EPIGENOME IN MALES AND FEMALES, CONSCIOUS OF THE FACT THAT THE MAJORITY OF PUBLISHED STUDIES HAVE ONLY INVESTIGATED MALES. THIS HAS LED TO A LIMITED PICTURE OF THE EPIGENETIC IMPACT OF STRESS, HIGHLIGHTING THE NEED FOR FUTURE STUDIES TO INVESTIGATE FEMALES AS WELL AS MALES. 2022