1 2144 89 EPIGENETIC LANDSCAPE OF STRESS SURFEIT DISORDERS: KEY ROLE FOR DNA METHYLATION DYNAMICS. CHRONIC EXPOSURE TO STRESS THROUGHOUT LIFESPAN ALTERS BRAIN STRUCTURE AND FUNCTION, INDUCING A MALADAPTIVE RESPONSE TO ENVIRONMENTAL STIMULI, THAT CAN CONTRIBUTE TO THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE. STUDIES HAVE SHOWN THAT HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSFUNCTION IS ASSOCIATED WITH VARIOUS NEUROPSYCHIATRIC DISORDERS, INCLUDING MAJOR DEPRESSIVE, ALCOHOL USE AND POST-TRAUMATIC STRESS DISORDERS. DOWNSTREAM ACTORS OF THE HPA AXIS, GLUCOCORTICOIDS ARE CRITICAL MEDIATORS OF THE STRESS RESPONSE AND EXERT THEIR FUNCTION THROUGH SPECIFIC RECEPTORS, I.E., THE GLUCOCORTICOID RECEPTOR (GR), HIGHLY EXPRESSED IN STRESS/REWARD-INTEGRATIVE PATHWAYS. GRS ARE LIGAND-ACTIVATED TRANSCRIPTION FACTORS THAT RECRUIT EPIGENETIC ACTORS TO REGULATE GENE EXPRESSION VIA DNA METHYLATION, ALTERING CHROMATIN STRUCTURE AND THUS SHAPING THE RESPONSE TO STRESS. THE DYNAMIC INTERPLAY BETWEEN STRESS RESPONSE AND EPIGENETIC MODIFIERS SUGGEST DNA METHYLATION PLAYS A KEY ROLE IN THE DEVELOPMENT OF STRESS SURFEIT DISORDERS. 2021 2 3405 34 HOW STRESS GETS UNDER THE SKIN: EARLY LIFE ADVERSITY AND GLUCOCORTICOID RECEPTOR EPIGENETIC REGULATION. EARLY LIFE ADVERSITY IS ASSOCIATED WITH BOTH PERSISTENT DISRUPTIONS IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND PSYCHIATRIC SYMPTOMS. GLUCOCORTICOID RECEPTORS (GRS), WHICH ARE ENCODED BY THE NR3C1 GENE, BIND TO CORTISOL AND OTHER GLUCOCORTICOIDS TO CREATE A NEGATIVE FEEDBACK LOOP WITHIN THE HPA AXIS TO REGULATE THE BODY'S NEUROENDOCRINE RESPONSE TO STRESS. EXCESS METHYLATION OF A PROMOTER SEQUENCE WITHIN NR3C1 THAT ATTENUATES GR EXPRESSION, HOWEVER, HAS BEEN ASSOCIATED WITH BOTH EARLY LIFE ADVERSITY AND PSYCHOPATHOLOGY. AS CRITICAL REGULATORS WITHIN THE HPA AXIS, GRS AND THEIR EPIGENETIC REGULATION MAY MEDIATE THE LINK BETWEEN EARLY LIFE ADVERSITY AND THE ONSET OF PSYCHOPATHOLOGY. THE PRESENT REVIEW DISCUSSES THIS WORK AS ONE MECHANISM BY WHICH STRESS MAY GET UNDER THE SKIN TO DISRUPT HPA FUNCTIONING AT AN EPIGENETIC LEVEL AND CREATE LONG-LASTING VULNERABILITIES IN THE STRESS REGULATORY SYSTEM THAT SUBSEQUENTLY PREDISPOSE INDIVIDUALS TO PSYCHOPATHOLOGY. SPANNING PRENATAL INFLUENCES TO CRITICAL PERIODS OF EARLY LIFE AND ADOLESCENCE, WE DETAIL THE IMPACT THAT EARLY ADVERSITY HAS ON GR EXPRESSION, PHYSIOLOGICAL RESPONSES TO STRESS, AND THEIR IMPLICATIONS FOR LONG-TERM STRESS MANAGEMENT. WE NEXT PROPOSE A DUAL TRANSMISSION HYPOTHESIS REGARDING BOTH GENOMIC AND NON-GENOMIC MECHANISMS BY WHICH CHRONIC AND ACUTE STRESS PROPAGATE THROUGH NUMEROUS GENERATIONS. LASTLY, WE OUTLINE SEVERAL DIRECTIONS FOR FUTURE RESEARCH, INCLUDING POTENTIAL REVERSIBILITY OF METHYLATION PATTERNS AND ITS FUNCTIONAL IMPLICATIONS, VARIATION IN BEHAVIOR DETERMINED SOLELY BY NR3C1, AND CONSENSUS ON WHICH SPECIFIC PROMOTER REGIONS SHOULD BE STUDIED. 2018 3 2269 40 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 4 110 33 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 5 997 28 CHRONIC STRESS-DRIVEN GLUCOCORTICOID RECEPTOR ACTIVATION PROGRAMS KEY CELL PHENOTYPES AND FUNCTIONAL EPIGENOMIC PATTERNS IN HUMAN FIBROBLASTS. CHRONIC ENVIRONMENTAL STRESS CAN PROFOUNDLY IMPACT CELL AND BODY FUNCTION. ALTHOUGH THE UNDERLYING MECHANISMS ARE POORLY UNDERSTOOD, EPIGENETICS HAS EMERGED AS A KEY LINK BETWEEN ENVIRONMENT AND HEALTH. THE GENOMIC EFFECTS OF STRESS ARE THOUGHT TO BE MEDIATED BY THE ACTION OF GLUCOCORTICOID STRESS HORMONES, PRIMARILY CORTISOL IN HUMANS, WHICH ACT VIA THE GLUCOCORTICOID RECEPTOR (GR). TO DISSECT HOW CHRONIC STRESS-DRIVEN GR ACTIVATION INFLUENCES EPIGENETIC AND CELL STATES, HUMAN FIBROBLASTS UNDERWENT PROLONGED EXPOSURE TO PHYSIOLOGICAL STRESS LEVELS OF CORTISOL AND/OR A SELECTIVE GR ANTAGONIST. CORTISOL WAS FOUND TO DRIVE ROBUST CHANGES IN CELL PROLIFERATION, MIGRATION, AND MORPHOLOGY, WHICH WERE ABROGATED BY CONCOMITANT GR BLOCKADE. THE GR-DRIVEN CELL PHENOTYPES WERE ACCOMPANIED BY WIDESPREAD, YET GENOMIC CONTEXT-DEPENDENT, CHANGES IN DNA METHYLATION AND MRNA EXPRESSION, INCLUDING GENE LOCI WITH KNOWN ROLES IN CELL PROLIFERATION AND MIGRATION. THESE FINDINGS PROVIDE INSIGHTS INTO HOW CHRONIC STRESS-DRIVEN FUNCTIONAL EPIGENOMIC PATTERNS BECOME ESTABLISHED TO SHAPE KEY CELL PHENOTYPES. 2022 6 6228 24 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 7 2520 27 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 8 291 28 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 9 1981 34 EPIGENETIC ALTERATIONS IN DNA AND HISTONE MODIFICATIONS CAUSED BY DEPRESSION AND ANTIDEPRESSANT DRUGS: LESSONS FROM THE RODENT MODELS. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN FOLDING AND FUNCTION. EPIGENETIC MECHANISMS REGULATE TRANSCRIPTION MEDIATING EFFECTS OF VARIOUS STIMULI ON GENE EXPRESSION. THESE MECHANISMS ARE INVOLVED IN TRANSCRIPTIONAL CONTROL IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS INCLUDING NEUROPSYCHIATRIC DISORDERS AND BEHAVIORAL ABNORMALITIES SUCH AS DEPRESSION. IN RODENTS, EXPOSURE TO CHRONIC SOCIAL STRESS WAS SHOWN TO INDUCE BEHAVIORAL IMPAIRMENTS AND MEMORY/LEARNING DEFICITS THAT RESEMBLE DEPRESSIVE-LIKE PHENOTYPE IN HUMANS. THE RODENT MODELS OF CHRONIC STRESS WERE WIDELY USED TO STUDY MOLECULAR MECHANISMS OF DEPRESSION. IN THESE MODELS, EARLY EXPOSURE TO CHRONIC STRESS SUCH AS PRENATAL OR POSTNATAL STRESS INDUCES LONG-TERM HYPERACTIVE STRESS RESPONSES, BEHAVIORAL ABNORMALITIES, AND FUNCTIONAL IMPAIRMENTS IN BRAIN FUNCTION THAT PERSIST IN ADULTHOOD. FURTHERMORE, THESE ALTERATIONS CAN BE TRANSMITTED TO OFFSPRING OF CHRONICALLY STRESSED ANIMALS ACROSS SEVERAL GENERATIONS. MOLECULAR STUDIES IN ANIMAL MODELS SHOWED THAT CHRONIC STRESS INDUCES STABLE EPIGENETIC CHANGES IN SPECIFIC BRAIN REGIONS, PRIMARILY IN THE LIMBIC SYSTEM. THESE CHANGES LEAD TO LONG-LASTING ABNORMALITIES IN BEHAVIOR THAT PERSIST IN ADULTHOOD AND CAN BE TRANSMITTED TO OFFSPRING. TREATMENT WITH EPIGENETICALLY ACTIVE ANTIDEPRESSANTS DISRUPTS THE ABNORMAL STRESS-INDUCED EPIGENETIC PROGRAMMING AND PROVIDES EPIGENETIC PATTERNS THAT RESEMBLE EPIGENETIC BACKGROUND OF STRESS RESILIENT INDIVIDUALS. 2017 10 3092 32 GENOMIC AND EPIGENOMIC MECHANISMS OF GLUCOCORTICOIDS IN THE BRAIN. FOLLOWING THE DISCOVERY OF GLUCOCORTICOID RECEPTORS IN THE HIPPOCAMPUS AND OTHER BRAIN REGIONS, RESEARCH HAS FOCUSED ON UNDERSTANDING THE EFFECTS OF GLUCOCORTICOIDS IN THE BRAIN AND THEIR ROLE IN REGULATING EMOTION AND COGNITION. GLUCOCORTICOIDS ARE ESSENTIAL FOR ADAPTATION TO STRESSORS (ALLOSTASIS) AND IN MALADAPTATION RESULTING FROM ALLOSTATIC LOAD AND OVERLOAD. ALLOSTATIC OVERLOAD, WHICH CAN OCCUR DURING CHRONIC STRESS, CAN RESHAPE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS THROUGH EPIGENETIC MODIFICATION OF GENES IN THE HIPPOCAMPUS, HYPOTHALAMUS AND OTHER STRESS-RESPONSIVE BRAIN REGIONS. GLUCOCORTICOIDS EXERT THEIR EFFECTS ON THE BRAIN THROUGH GENOMIC MECHANISMS THAT INVOLVE BOTH GLUCOCORTICOID RECEPTORS AND MINERALOCORTICOID RECEPTORS DIRECTLY BINDING TO DNA, AS WELL AS BY NON-GENOMIC MECHANISMS. FURTHERMORE, GLUCOCORTICOIDS SYNERGIZE BOTH GENOMICALLY AND NON-GENOMICALLY WITH NEUROTRANSMITTERS, NEUROTROPHIC FACTORS, SEX HORMONES AND OTHER STRESS MEDIATORS TO SHAPE AN ORGANISM'S PRESENT AND FUTURE RESPONSES TO A STRESSFUL ENVIRONMENT. HERE, WE DISCUSS THE MECHANISMS OF GLUCOCORTICOID ACTION IN THE BRAIN AND REVIEW HOW GLUCOCORTICOIDS INTERACT WITH STRESS MEDIATORS IN THE CONTEXT OF ALLOSTASIS, ALLOSTATIC LOAD AND STRESS-INDUCED NEUROPLASTICITY. 2017 11 4118 31 MECHANISMS OF BRAIN GLUCOCORTICOID RESISTANCE IN STRESS-INDUCED PSYCHOPATHOLOGIES. EXPOSURE TO STRESS ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND LEADS TO INCREASED LEVELS OF GLUCOCORTICOID (GC) HORMONES. PROLONGED ELEVATION OF GC LEVELS CAUSES NEURONAL DYSFUNCTION, DECREASES THE DENSITY OF SYNAPSES, AND IMPAIRS NEURONAL PLASTICITY. DECREASED SENSITIVITY TO GLUCOCORTICOIDS (GLUCOCORTICOID RESISTANCE) THAT DEVELOPS AS A RESULT OF CHRONIC STRESS IS ONE OF THE CHARACTERISTIC FEATURES OF STRESS-INDUCED PSYCHOPATHOLOGIES. IN THIS ARTICLE, WE REVIEWED THE PUBLISHED DATA ON PROPOSED MOLECULAR MECHANISMS THAT CONTRIBUTE TO THE DEVELOPMENT OF GLUCOCORTICOID RESISTANCE IN BRAIN, INCLUDING CHANGES IN THE EXPRESSION OF THE GLUCOCORTICOID RECEPTOR (GR) GENE, BIOSYNTHESIS OF GR ISOFORMS, AND GR POSTTRANSLATIONAL MODIFICATIONS. WE ALSO PRESENT DATA ON ALTERATIONS IN THE EXPRESSION OF THE FKBP5 GENE ENCODING THE MAIN COMPONENT OF CELL ULTRA-SHORT NEGATIVE FEEDBACK LOOP OF GC SIGNALING REGULATION. RECENT DISCOVERIES ON STRESS- AND GR-INDUCED CHANGES IN EPIGENETIC MODIFICATION PATTERNS AS WELL AS NORMALIZING ACTION OF ANTIDEPRESSANTS ARE DISCUSSED. GR AND FKBP5 GENE POLYMORPHISMS ASSOCIATED WITH STRESS-INDUCED PSYCHOPATHOLOGIES ARE DESCRIBED, AND THEIR ROLE IN GLUCOCORTICOID RESISTANCE IS DISCUSSED. 2017 12 2386 25 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 13 2264 35 EPIGENETIC PROGRAMMING BY STRESS AND GLUCOCORTICOIDS ALONG THE HUMAN LIFESPAN. PSYCHOSOCIAL STRESS TRIGGERS A SET OF BEHAVIORAL, NEURAL, HORMONAL, AND MOLECULAR RESPONSES THAT CAN BE A DRIVING FORCE FOR SURVIVAL WHEN ADAPTIVE AND TIME-LIMITED, BUT MAY ALSO CONTRIBUTE TO A HOST OF DISEASE STATES IF DYSREGULATED OR CHRONIC. THE BENEFICIAL OR DETRIMENTAL EFFECTS OF STRESS ARE LARGELY MEDIATED BY THE HYPOTHALAMIC-PITUITARY AXIS, A HIGHLY CONSERVED NEUROHORMONAL CASCADE THAT CULMINATES IN SYSTEMIC SECRETION OF GLUCOCORTICOIDS. GLUCOCORTICOIDS ACTIVATE THE GLUCOCORTICOID RECEPTOR, A UBIQUITOUS NUCLEAR RECEPTOR THAT NOT ONLY CAUSES WIDESPREAD CHANGES IN TRANSCRIPTIONAL PROGRAMS, BUT ALSO INDUCES LASTING EPIGENETIC MODIFICATIONS IN MANY TARGET TISSUES. WHILE THE EPIGENOME REMAINS SENSITIVE TO STRESSORS THROUGHOUT LIFE, WE PROPOSE TWO KEY PRINCIPLES THAT MAY GOVERN THE EPIGENETICS OF STRESS AND GLUCOCORTICOIDS ALONG THE LIFESPAN: FIRST, THE PRESENCE OF DISTINCT LIFE PERIODS, DURING WHICH THE EPIGENOME SHOWS HEIGHTENED PLASTICITY TO STRESS EXPOSURE, SUCH AS IN EARLY DEVELOPMENT AND AT ADVANCED AGE; AND, SECOND, THE POTENTIAL OF STRESS-INDUCED EPIGENETIC CHANGES TO ACCUMULATE THROUGHOUT LIFE BOTH IN SELECT CHROMATIN REGIONS AND AT THE GENOME-WIDE LEVEL. THESE PRINCIPLES HAVE IMPORTANT CLINICAL AND TRANSLATIONAL IMPLICATIONS, AND THEY SHOW STRIKING PARALLELS WITH THE EXISTENCE OF SENSITIVE DEVELOPMENTAL PERIODS AND THE CUMULATIVE IMPACT OF STRESSFUL EXPERIENCES ON THE DEVELOPMENT OF STRESS-RELATED PHENOTYPES. WE HOPE THAT THIS CONCEPTUAL MECHANISTIC FRAMEWORK WILL STIMULATE FRUITFUL RESEARCH THAT AIMS AT UNRAVELING THE MOLECULAR PATHWAYS THROUGH WHICH OUR LIFE STORIES SCULPT GENOMIC FUNCTION TO CONTRIBUTE TO COMPLEX BEHAVIORAL AND SOMATIC PHENOTYPES. 2017 14 6414 40 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 15 235 24 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 16 5833 41 STRESS-INDUCED MECHANISMS IN MENTAL ILLNESS: A ROLE FOR GLUCOCORTICOID SIGNALLING. STRESS REPRESENTS THE MAIN ENVIRONMENTAL RISK FACTOR FOR MENTAL ILLNESS. EXPOSURE TO STRESSFUL EVENTS, PARTICULARLY EARLY IN LIFE, HAS BEEN ASSOCIATED WITH INCREASED INCIDENCE AND SUSCEPTIBILITY OF MAJOR DEPRESSIVE DISORDERS AS WELL AS OF OTHER PSYCHIATRIC ILLNESSES. AMONG THE KEY PLAYERS IN THESE EVENTS ARE GLUCOCORTICOID RECEPTORS. DYSFUNCTIONAL GLUCOCORTICOID SIGNALLING MAY INDEED CONTRIBUTE TO PSYCHOPATHOLOGY THROUGH A NUMBER OF MECHANISMS THAT REGULATE THE RESPONSE TO ACUTE OR CHRONIC STRESS AND THAT AFFECT THE FUNCTION OF GENES AND SYSTEMS KNOWN TO BE RELEVANT FOR MOOD DISORDERS. INDEED, EXPOSURE TO CHRONIC STRESS EARLY IN LIFE AS WELL AS IN ADULTHOOD HAS BEEN SHOWN TO REDUCE THE EXPRESSION OF GLUCOCORTICOID RECEPTORS (GR), ALSO THROUGH EPIGENETIC MECHANISMS, AND TO UP-REGULATE THE EXPRESSION OF THE CO-CHAPERONE GENE FKBP5, WHICH RESTRAINS GR ACTIVITY BY LIMITING THE TRANSLOCATION OF THE RECEPTOR COMPLEX TO THE NUCLEUS. ANOTHER MECHANISM THAT CONTRIBUTES TO CHANGES IN GR RESPONSIVENESS IS THE STATE OF RECEPTOR PHOSPHORYLATION THAT CONTROLS ACTIVATION, SUBCELLULAR LOCALIZATION AS WELL AS ITS TRANSCRIPTIONAL ACTIVITY. MOREOVER, GR PHOSPHORYLATION MAY REPRESENT AN IMPORTANT MECHANISM FOR THE CROSS TALK BETWEEN NEUROTROPHIC SIGNALLING AND GR-DEPENDENT TRANSCRIPTION, BRIDGING TWO IMPORTANT PLAYERS FOR MOOD DISORDERS. ONE GENE THAT LIES DOWNSTREAM FROM GR AND MAY CONTRIBUTE TO STRESS-RELATED CHANGES IS SERUM GLUCOCORTICOID KINASE-1 (SGK1). WE HAVE DEMONSTRATED THAT THE EXPRESSION OF SGK1 IS SIGNIFICANTLY INCREASED AFTER EXPOSURE TO CHRONIC STRESS IN RODENTS AS WELL AS IN THE BLOOD OF DRUG-FREE DEPRESSED PATIENTS. WE HAVE ALSO SHOWN THAT SGK1 UP-REGULATION MAY ULTIMATELY REDUCE HIPPOCAMPAL NEUROGENESIS AND CONTRIBUTE TO THE STRUCTURAL ABNORMALITIES THAT HAVE BEEN REPORTED TO OCCUR IN DEPRESSED PATIENTS. IN SUMMARY, GR SIGNALLING MAY REPRESENT A POINT OF CONVERGENCE AS WELL AS OF DIVERGENCE FOR DEFECTS ASSOCIATED WITH PATHOLOGIC CONDITIONS CHARACTERIZED BY HEIGHTENED VULNERABILITY TO STRESS. THE CHARACTERIZATION OF THESE ABNORMALITIES IS CRUCIAL TO IDENTIFY NOVEL TARGETS FOR THERAPEUTIC INTERVENTION THAT MAY COUNTERACT MORE EFFECTIVELY STRESS-INDUCED NEUROBIOLOGICAL ABNORMALITIES. 2016 17 3151 30 GLUCOCORTICOIDS, EPIGENETIC CONTROL AND STRESS RESILIENCE. GLUCOCORTICOID HORMONES PLAY A PIVOTAL ROLE IN THE RESPONSE TO STRESSFUL CHALLENGES. THE SURGE IN GLUCOCORTICOID HORMONE SECRETION AFTER STRESS NEEDS TO BE TIGHTLY CONTROLLED WITH CHARACTERISTICS LIKE PEAK HEIGHT, CURVATURE AND DURATION DEPENDING ON THE NATURE AND SEVERITY OF THE CHALLENGE. THIS IS IMPORTANT AS CHRONIC HYPER- OR HYPO-RESPONSES ARE DETRIMENTAL TO HEALTH DUE TO INCREASING THE RISK FOR DEVELOPING A STRESS-RELATED MENTAL DISORDER. PROPER GLUCOCORTICOID RESPONSES TO STRESS ARE CRITICAL FOR ADAPTATION. THEREFORE, THE TIGHT CONTROL OF BASELINE AND STRESS-EVOKED GLUCOCORTICOID SECRETION ARE IMPORTANT CONSTITUENTS OF AN ORGANISM'S RESILIENCE. HERE, WE ADDRESS A NUMBER OF MECHANISMS THAT ILLUSTRATE THE MULTITUDE AND COMPLEXITY OF MEASURES SAFEGUARDING THE CONTROL OF GLUCOCORTICOID FUNCTION. THESE MECHANISMS INCLUDE THE CONTROL OF MINERALOCORTICOID (MR) AND GLUCOCORTICOID RECEPTOR (GR) OCCUPANCY AND CONCENTRATION, THE DYNAMIC CONTROL OF FREE GLUCOCORTICOID HORMONE AVAILABILITY BY CORTICOSTEROID-BINDING GLOBULIN (CBG), AND THE CONTROL EXERTED BY GLUCOCORTICOIDS AT THE SIGNALING, EPIGENETIC AND GENOMIC LEVEL ON GENE TRANSCRIPTIONAL RESPONSES TO STRESS. WE REVIEW THE BENEFICIAL EFFECTS OF REGULAR EXERCISE ON HPA AXIS AND SLEEP PHYSIOLOGY, AND COGNITIVE AND ANXIETY-RELATED BEHAVIOR. FURTHERMORE, WE DESCRIBE THAT, POSSIBLY THROUGH CHANGES IN THE GABAERGIC SYSTEM, EXERCISE REDUCES THE IMPACT OF STRESS ON A SIGNALING PATHWAY SPECIFICALLY IN THE DENTATE GYRUS THAT IS STRONGLY IMPLICATED IN THE BEHAVIORAL RESPONSE TO THAT STRESSOR. THESE OBSERVATIONS UNDERLINE THE IMPACT OF LIFE STYLE ON STRESS RESILIENCE. FINALLY, WE ADDRESS HOW SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AFFECTING GLUCOCORTICOID ACTION CAN COMPROMISE STRESS RESILIENCE, WHICH BECOMES MOST APPARENT UNDER CONDITIONS OF CHILDHOOD ABUSE. 2015 18 2414 35 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION AND ADDICTION, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS OR PRIOR DRUG EXPOSURE ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. SUCH EXPOSURE TO ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL AND ADULT EXPOSURES. 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 AND ADDICTION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS (E.G., CHRONIC STRESS, DRUG ADMINISTRATION). UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS REVEALS NEW INSIGHT INTO DISEASE MECHANISMS IN HUMANS. 2014 19 6729 32 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 2415 35 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