1 235 83 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 2 291 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 3 2269 37 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 6228 32 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 5 3313 32 HIPPOCAMPAL BDNF IN PHYSIOLOGICAL CONDITIONS AND SOCIAL ISOLATION. EXPOSURE OF AN ORGANISM TO CHRONIC PSYCHOSOCIAL STRESS MAY AFFECT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION THAT HAS BEEN IMPLICATED IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS, SUCH AS DEPRESSION. GIVEN THAT DEPRESSION IN HUMANS HAS BEEN LINKED WITH SOCIAL STRESS, THE CHRONIC SOCIAL STRESS PARADIGMS FOR MODELING PSYCHIATRIC DISORDERS IN ANIMALS HAVE THUS BEEN DEVELOPED. CHRONIC SOCIAL ISOLATION IN ANIMAL MODELS GENERALLY CAUSES CHANGES IN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTIONING, ASSOCIATED WITH ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. ALSO, THIS CHRONIC STRESS CAUSES DOWNREGULATION OF BDNF PROTEIN AND MRNA IN THE HIPPOCAMPUS, A STRESS-SENSITIVE BRAIN REGION CLOSELY RELATED TO THE PATHOPHYSIOLOGY OF DEPRESSION. IN THIS REVIEW, WE DISCUSS THE CURRENT KNOWLEDGE REGARDING THE STRUCTURE, FUNCTION, INTRACELLULAR SIGNALING, INTER-INDIVIDUAL DIFFERENCES AND EPIGENETIC REGULATION OF BDNF IN BOTH PHYSIOLOGICAL CONDITIONS AND DEPRESSION AND CHANGES IN CORTICOSTERONE LEVELS, AS A MARKER OF STRESS RESPONSE. SINCE BDNF LEVELS ARE AGE DEPENDENT IN HUMANS AND RODENTS, THIS REVIEW WILL ALSO HIGHLIGHT THE EFFECTS OF ADOLESCENT AND ADULT CHRONIC SOCIAL ISOLATION MODELS OF BOTH GENDERS ON THE BDNF EXPRESSION. 2017 6 248 32 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 7 6729 30 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 8 1981 25 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 9 4622 25 NEUROBIOLOGICAL DEVELOPMENT IN THE CONTEXT OF CHILDHOOD TRAUMA. NEUROBIOLOGICAL SYSTEMS MAY BE PARTICULARLY SUSCEPTIBLE TO DELETERIOUS IMPACT OF CHILDHOOD TRAUMA, AND THE IMPACT OF CHILDHOOD TRAUMA ON DEVELOPMENT AND SUBSEQUENT FUNCTIONAL OUTCOMES ACROSS THE LIFESPAN HAS BEEN WELL-DOCUMENTED. THE CURRENT REVIEW ADDRESSES THE NEUROBIOLOGICAL IMPACT OF EXPOSURE TO INTERPERSONAL TRAUMA IN CHILDHOOD IN THE CONTEXT OF EXECUTIVE FUNCTION, EMOTION REGULATION, AND DISSOCIATION/INTEROCEPTIVE AWARENESS. SUBSEQUENT RISK FOR PTSD AND DEPRESSION IS ALSO DISCUSSED. THE PATHWAY OF RISK FROM CHILDHOOD TRAUMA TO THESE COGNITIVE, EMOTIONAL, AND PSYCHIATRIC OUTCOMES IS ADDRESSED IN TERMS OF POTENTIAL STRUCTURAL AND FUNCTIONAL ALTERATIONS WITHIN THE HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA RESULTING FROM CHRONIC OR REPEATED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ITS INTERACTION WITH AND INFLUENCE ON GENETIC AND EPIGENETIC PROCESSES DURING SENSITIVE PERIODS OF DEVELOPMENT. IMPLICATIONS FOR PRACTICE ARE DISCUSSED. 2017 10 2386 22 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 11 3092 26 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 12 2159 24 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 13 5164 28 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 14 4642 27 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 15 3405 32 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 16 4633 33 NEUROIMMUNE ACTIVATION DRIVES MULTIPLE BRAIN STATES. NEUROIMMUNE SIGNALING IS INCREASINGLY IDENTIFIED AS A CRITICAL COMPONENT OF NEURONAL PROCESSES UNDERLYING MEMORY, EMOTION AND COGNITION. THE INTERACTIONS OF MICROGLIA AND ASTROCYTES WITH NEURONS AND SYNAPSES, AND THE INDIVIDUAL CYTOKINES AND IMMUNE SIGNALING MOLECULES THAT MEDIATE THESE INTERACTIONS ARE A CURRENT FOCUS OF MUCH RESEARCH. HERE, WE DISCUSS NEUROIMMUNE ACTIVATION AS A MECHANISM TRIGGERING DIFFERENT STATES THAT MODULATE COGNITIVE AND AFFECTIVE PROCESSES TO ALLOW FOR APPROPRIATE BEHAVIOR DURING AND AFTER ILLNESS OR INJURY. WE PROPOSE THAT THESE STATES LIE ON A CONTINUUM FROM A NAIVE HOMEOSTATIC BASELINE STATE IN THE ABSENCE OF STIMULATION, TO ACUTE NEUROIMMUNE ACTIVITY AND CHRONIC ACTIVATION. IMPORTANTLY, CONSEQUENCES OF ILLNESS OR INJURY INCLUDING COGNITIVE DEFICITS AND MOOD IMPAIRMENTS CAN PERSIST LONG AFTER RESOLUTION OF IMMUNE SIGNALING. THIS SUGGESTS THAT NEUROIMMUNE ACTIVATION ALSO RESULTS IN AN ENDURING SHIFT IN THE HOMEOSTATIC BASELINE STATE WITH LONG LASTING CONSEQUENCES FOR NEURAL FUNCTION AND BEHAVIOR. SUCH DIFFERENT STATES CAN BE IDENTIFIED IN A MULTIDIMENSIONAL WAY, USING PATTERNS OF CYTOKINE AND GLIAL ACTIVATION, BEHAVIORAL AND COGNITIVE CHANGES, AND EPIGENETIC SIGNATURES. IDENTIFYING DISTINCT NEUROIMMUNE STATES AND THEIR CONSEQUENCES FOR NEURAL FUNCTION WILL PROVIDE A FRAMEWORK FOR PREDICTING VULNERABILITY TO DISORDERS OF MEMORY, COGNITION AND EMOTION BOTH DURING AND LONG AFTER RECOVERY FROM ILLNESS. 2018 17 3151 32 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 5812 39 STRESS AND ANXIETY: STRUCTURAL PLASTICITY AND EPIGENETIC REGULATION AS A CONSEQUENCE OF STRESS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT, AS WELL AS DEVELOPING BRAIN, POSSESS A REMARKABLE ABILITY TO SHOW REVERSIBLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. THIS IS PARTICULARLY EVIDENT IN THE HIPPOCAMPUS, WHERE ALL THREE TYPES OF STRUCTURAL PLASTICITY HAVE BEEN RECOGNIZED AND INVESTIGATED, USING A COMBINATION OF MORPHOLOGICAL, MOLECULAR, PHARMACOLOGICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL APPROACHES. THE AMYGDALA AND THE PREFRONTAL CORTEX, BRAIN REGIONS INVOLVED IN ANXIETY AND FEAR, MOOD, COGNITIVE FUNCTION AND BEHAVIORAL CONTROL, ALSO SHOW STRUCTURAL PLASTICITY. ACUTE AND CHRONIC STRESS CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. IN THE SHORT TERM, SUCH AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC OR MOOD ANXIETY DISORDERS. WE SHALL REVIEW CELLULAR AND MOLECULAR MECHANISMS, AS WELL AS RECENT WORK ON INDIVIDUAL DIFFERENCES IN ANXIETY-LIKE BEHAVIOR AND ALSO DEVELOPMENTAL INFLUENCES THAT BIAS HOW THE BRAIN RESPONDS TO STRESSORS. FINALLY, WE SUGGEST THAT SUCH AN APPROACH NEEDS TO BE EXTENDED TO OTHER BRAIN AREAS THAT ARE ALSO INVOLVED IN ANXIETY AND MOOD. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED 'ANXIETY AND DEPRESSION'. 2012 19 678 31 BRAIN DEVELOPMENT UNDER STRESS: HYPOTHESES OF GLUCOCORTICOID ACTIONS REVISITED. ONE OF THE CONUNDRUMS IN TODAY'S STRESS RESEARCH IS WHY SOME INDIVIDUALS FLOURISH AND OTHERS PERISH UNDER SIMILAR STRESSFUL CONDITIONS. IT IS RECOGNIZED THAT THIS INDIVIDUAL VARIABILITY IN ADAPTATION TO STRESS DEPENDS ON THE OUTCOME OF THE INTERACTION OF GENETIC AND COGNITIVE/EMOTIONAL INPUTS IN WHICH GLUCOCORTICOID HORMONES AND RECEPTORS PLAY A CRUCIAL ROLE. HENCE ONE APPROACH TOWARDS UNDERSTANDING INDIVIDUAL VARIATION IN STRESS COPING IS HOW GLUCOCORTICOID ACTIONS CAN CHANGE FROM PROTECTIVE TO HARMFUL. TO ADDRESS THIS QUESTION WE FOCUS ON FOUR HYPOTHESES THAT ARE CONNECTED AND NOT MUTUAL EXCLUSIVE. FIRST, THE CLASSICAL GLUCOCORTICOID CASCADE HYPOTHESIS, IN WHICH THE INABILITY TO COPE WITH CHRONIC STRESS CAUSES A VICIOUS CYCLE OF EXCESS GLUCOCORTICOID AND DOWNREGULATION OF GLUCOCORTICOID RECEPTORS (GR) IN THE HIPPOCAMPUS TRIGGERING A FEED-FORWARD CASCADE OF DEGENERATION AND DISEASE. SECOND, THE BALANCE HYPOTHESIS, WHICH TAKES ALSO THE LIMBIC MINERALOCORTICOID RECEPTORS (MR) INTO ACCOUNT AND PROPOSES THAT AN INTEGRAL LIMBIC MR:GR IMBALANCE IS CAUSAL TO ALTERED PROCESSING OF INFORMATION IN CIRCUITS UNDERLYING FEAR, REWARD, SOCIAL BEHAVIOUR AND RESILIENCE, DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND IMPAIRMENT OF BEHAVIOURAL ADAPTATION. THE MR:GR BALANCE IS ALTERED BY GENE VARIANTS OF THESE RECEPTOR COMPLEXES AND EXPERIENCE-RELATED FACTORS, WHICH CAN INDUCE LASTING EPIGENETIC CHANGES IN THE EXPRESSION OF THESE RECEPTORS. A PARTICULAR POTENT EPIGENETIC STIMULUS IS THE MATERNAL ENVIRONMENT WHICH IS FUNDAMENTAL FOR THE MATERNAL MEDIATION HYPOTHESIS. THE OUTCOME OF PERINATAL GENE X ENVIRONMENT INTERACTION, AND THUS OF MR:GR-MEDIATED FUNCTIONS DEPENDS HOWEVER, ON THE DEGREE OF 'MATCHING' WITH ENVIRONMENTAL DEMANDS IN LATER LIFE. THE PREDICTIVE ADAPTATION HYPOTHESIS THEREFORE PRESENTS A CONCEPTUAL FRAMEWORK TO EXAMINE THE ROLE OF GLUCOCORTICOIDS IN UNDERSTANDING INDIVIDUAL PHENOTYPIC DIFFERENCES IN STRESS-RELATED BEHAVIOURS OVER THE LIFESPAN. 2010 20 679 26 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021