1 3151 150 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 2 2264 49 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 3 3092 43 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 4 2958 40 GENETIC AND EPIGENETIC INSIGHTS INTO FETAL ALCOHOL SPECTRUM DISORDERS. THE MAGNITUDE OF THE DETRIMENTAL EFFECTS FOLLOWING IN UTERO ALCOHOL EXPOSURE, INCLUDING FETAL ALCOHOL SYNDROME AND OTHER FETAL ALCOHOL SPECTRUM DISORDERS (FASD), IS GLOBALLY UNDERESTIMATED. THE EFFECTS INCLUDE IRREVERSIBLE COGNITIVE AND BEHAVIORAL DISABILITIES AS A RESULT OF ABNORMAL BRAIN DEVELOPMENT, PRE- AND POSTNATAL GROWTH RETARDATION AND FACIAL DYSMORPHISM. PARENTAL ALCOHOL EXPOSURE AND ITS EFFECT ON OFFSPRING HAS BEEN RECOGNIZED FOR CENTURIES, BUT ONLY RECENTLY HAVE WE BEGUN TO GAIN MOLECULAR INSIGHT INTO THE MECHANISMS INVOLVED IN ALCOHOL TERATOGENESIS. GENETIC ATTRIBUTES (SUSCEPTIBILITY AND PROTECTIVE ALLELES) OF THE MOTHER AND THE FETUS CONTRIBUTE TO THE RISK OF DEVELOPING FASD AND SPECIFIC ADDITIONAL ENVIRONMENTAL CONDITIONS, INCLUDING MALNUTRITION, HAVE AN IMPORTANT ROLE. THE SEVERITY OF FASD DEPENDS ON THE LEVEL OF ALCOHOL EXPOSURE, THE DEVELOPMENTAL STAGE AT WHICH EXPOSURE OCCURS AND THE NATURE OF THE EXPOSURE (CHRONIC OR ACUTE), AND ALTHOUGH THE MOST VULNERABLE PERIOD IS DURING THE FIRST TRIMESTER, DAMAGE CAN OCCUR THROUGHOUT GESTATION. PRECONCEPTION ALCOHOL EXPOSURE CAN ALSO HAVE A DETRIMENTAL EFFECT ON THE OFFSPRING. SEVERAL DEVELOPMENTAL PATHWAYS ARE AFFECTED IN FASD, INCLUDING NERVOUS SYSTEM DEVELOPMENT, GROWTH AND REMODELING OF TISSUES, AS WELL AS METABOLIC PATHWAYS THAT REGULATE GLUCOCORTICOID SIGNALING AND BALANCED LEVELS OF RETINOL, INSULIN AND NITRIC OXIDE. A BODY OF KNOWLEDGE HAS ACCUMULATED TO SUPPORT THE ROLE OF ENVIRONMENTALLY INDUCED EPIGENETIC REMODELING DURING GAMETOGENESIS AND AFTER CONCEPTION AS A KEY MECHANISM FOR THE TERATOGENIC EFFECTS OF FASD THAT PERSIST INTO ADULTHOOD. TRANSGENERATIONAL EFFECTS ARE LIKELY TO CONTRIBUTE TO THE GLOBAL BURDEN OF ALCOHOL-RELATED DISEASE. FASD RESULTS IN LIFELONG DISABILITY AND PREVENTATIVE PROGRAMS SHOULD INCLUDE BOTH MATERNAL ALCOHOL ABSTENTION AND PRECONCEPTION ALCOHOL AVOIDANCE. 2010 5 2269 46 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 6 5136 37 POTENTIAL MECHANISMS LINKING PSYCHOLOGICAL STRESS TO BONE HEALTH. CHRONIC PSYCHOLOGICAL STRESS AFFECTS MANY BODY SYSTEMS, INCLUDING THE SKELETON, THROUGH VARIOUS MECHANISMS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF THE FACTORS MEDIATING THE RELATIONSHIP BETWEEN PSYCHOLOGICAL STRESS AND BONE HEALTH. THESE FACTORS CAN BE DIVIDED INTO PHYSIOLOGICAL AND BEHAVIOURAL CHANGES INDUCED BY PSYCHOLOGICAL STRESS. THE PHYSIOLOGICAL FACTORS INVOLVE ENDOCRINOLOGICAL CHANGES, SUCH AS INCREASED GLUCOCORTICOIDS, PROLACTIN, LEPTIN AND PARATHYROID HORMONE LEVELS AND REDUCED GONADAL HORMONES. LOW-GRADE INFLAMMATION AND HYPERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM DURING PSYCHOLOGICAL STRESS ARE ALSO PHYSIOLOGICAL CHANGES DETRIMENTAL TO BONE HEALTH. THE BEHAVIOURAL CHANGES DURING MENTAL STRESS, SUCH AS ALTERED DIETARY PATTERN, CIGARETTE SMOKING, ALCOHOLISM AND PHYSICAL INACTIVITY, ALSO THREATEN THE SKELETAL SYSTEM. PSYCHOLOGICAL STRESS MAY BE PARTLY RESPONSIBLE FOR EPIGENETIC REGULATION OF SKELETAL DEVELOPMENT. IT MAY ALSO MEDIATE THE RELATIONSHIP BETWEEN SOCIOECONOMIC STATUS AND BONE HEALTH. HOWEVER, MORE DIRECT EVIDENCE IS REQUIRED TO PROVE THESE HYPOTHESES. IN CONCLUSION, CHRONIC PSYCHOLOGICAL STRESS SHOULD BE RECOGNISED AS A RISK FACTOR OF OSTEOPOROSIS AND STRESS-COPING METHODS SHOULD BE INCORPORATED AS PART OF THE COMPREHENSIVE OSTEOPOROSIS-PREVENTING STRATEGY. 2021 7 375 24 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018 8 6097 15 THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION IN THE BRAIN. STRESS LEADS TO DETRIMENTAL EFFECTS ON BRAIN FUNCTIONS AND RESULTS IN VARIOUS DISEASES. RECENT STUDIES HIGHLIGHT THE INVOLVEMENT OF GLUTAMATERGIC TRANSMISSION IN PATHOGENESIS OF DEPRESSIVE BEHAVIORS AND FEARS. ACUTE STRESS GENERATES DIFFERENT IMPACTS ON THE EXCITATORY TRANSMISSION COMPARED TO CHRONIC STRESS. DIFFERENT NEUROMODULATORS AND EPIGENETIC FACTORS ALSO PARTICIPATE IN THE ALTERATION OF SYNAPTIC TRANSMISSION AND THE REGULATION OF SYNAPTIC PLASTICITY. RESTORATION OF THE GLUTAMATERGIC TRANSMISSION IN STRESS-AFFECTED BRAIN AREAS THEREFORE PROVIDES NOVEL DIRECTIONS OF THERAPEUTIC INTERVENTIONS AGAINST STRESS. 2015 9 1981 33 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 10 235 32 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 11 4084 24 MATERNAL NUTRITION DURING PREGNANCY AND HEALTH OF THE OFFSPRING. THE ABILITY OF MOTHER TO PROVIDE NUTRIENTS AND OXYGEN FOR HER BABY IS A CRITICAL FACTOR FOR FETAL HEALTH AND ITS SURVIVAL. FAILURE IN SUPPLYING THE ADEQUATE AMOUNT OF NUTRIENTS TO MEET FETAL DEMAND CAN LEAD TO FETAL MALNUTRITION. THE FETUS RESPONDS AND ADAPTS TO UNDERNUTRITION BUT BY DOING SO IT PERMANENTLY ALTERS THE STRUCTURE AND FUNCTION OF THE BODY. MATERNAL OVERNUTRITION ALSO HAS LONG-LASTING AND DETRIMENTAL EFFECTS ON THE HEALTH OF THE OFFSPRING. THERE IS GROWING EVIDENCE THAT MATERNAL NUTRITION CAN INDUCE EPIGENETIC MODIFICATIONS OF THE FETAL GENOME. ONLY RELATIVELY RECENTLY HAS EVIDENCE FROM EPIDEMIOLOGICAL AND ANIMAL STUDIES EMERGED SUGGESTING THAT FETAL RESPONSES TO THE INTRAUTERINE ENVIRONMENT MAY UNDERLIE THE PREVALENCE OF MANY CHRONIC DISEASES OF ADULTHOOD INCLUDING TYPE 2 (NON-INSULIN-DEPENDENT) DIABETES. IT IS NOW OF CRUCIAL IMPORTANCE TO GAIN THE UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THE RELATIONSHIP BETWEEN FETAL ALTERATIONS TO THE INTRA-UTERINE ENVIRONMENT AND THEIR LONG-TERM EFFECTS ON THE HEALTH OF AN INDIVIDUAL. 2006 12 5167 34 PRECONCEPTION PATERNAL MENTAL DISORDERS AND CHILD HEALTH: MECHANISMS AND INTERVENTIONS. MENTAL ILLNESS IS A SIGNIFICANT GLOBAL HEALTH ISSUE WITH A STEADY PREVALENCE. HIGH HERITABILITY IS SUSPECTED, BUT GENOME-WIDE ASSOCIATION STUDIES ONLY IDENTIFIED A SMALL NUMBER OF RISK GENES ASSOCIATED WITH MENTAL DISORDERS. THIS 'MISSING INHERITANCE' CAN BE PARTIALLY EXPLAINED BY EPIGENETIC HEREDITY. EVIDENCE FROM NUMEROUS ANIMAL MODELS AND HUMAN STUDIES SUPPORTS THE POSSIBILITY THAT PRECONCEPTION PATERNAL MENTAL HEALTH INFLUENCES THEIR OFFSPRING'S MENTAL HEALTH VIA NONGENETIC MEANS. HERE, WE REVIEW TWO POTENTIAL PATHWAYS, INCLUDING SPERM EPIGENETICS AND SEMINAL PLASMA COMPONENTS. THE CURRENT REVIEW HIGHLIGHTS THE ROLE OF SPERM EPIGENETICS AND EXPLORES EPIGENETIC MESSAGE ORIGINATION AND SUSCEPTIBILITY TO CHRONIC STRESS. MEANWHILE, POSSIBLE SPATIOTEMPORAL WINDOWS AND EVENTS THAT INDUCE SEXUALLY DIMORPHIC MODES AND EFFECTS OF PATERNAL STRESS TRANSMISSION ARE INFERRED IN THIS REVIEW. ADDITIONALLY, WE DISCUSS EMERGING INTERVENTIONS THAT COULD POTENTIALLY BLOCK THE INTERGENERATIONAL TRANSMISSION OF PATERNAL PSYCHIATRIC DISORDERS AND REDUCE THE INCIDENCE OF MENTAL ILLNESS. UNDERSTANDING THE UNDERLYING MECHANISMS BY WHICH PRECONCEPTION PATERNAL STRESS IMPACTS OFFSPRING HEALTH IS CRITICAL FOR IDENTIFYING STRATEGIES SUPPORTING HEALTHY DEVELOPMENT AND SUCCESSFULLY CONTROLLING THE PREVALENCE OF MENTAL ILLNESS. 2023 13 229 39 ADAPTATION OR PATHOLOGY? THE ROLE OF PRENATAL STRESSOR TYPE AND INTENSITY IN THE DEVELOPMENTAL PROGRAMING OF ADULT PHENOTYPE. THE MOTHER IS THE MAJOR INTERFACE BETWEEN THE OFFSPRING AND ITS PRENATAL ENVIRONMENT. PRENATAL TOXINS AND STRESS-INDUCING PHYSICAL AGENTS ARE IMPORTANT FACTORS PROGRAMMING THE DEVELOPMENTAL TRAJECTORY OF MAMMALS THAT LIKELY INVOLVE EPIGENETIC MODIFICATIONS. HOWEVER, PRENATAL STRESSORS COMMONLY-USED IN THE LABORATORY (E.G. PRENATAL RESTRAINT STRESS AND PRENATAL CHRONIC VARIABLE STRESS) ARE TYPICALLY ADMINISTERED AT HIGH INTENSITIES. THESE EXPOSURES TYPICALLY LEAD TO PATHOLOGICAL PHENOTYPES SUPPORTING THE DEVELOPMENT ORIGIN OF HEALTH AND DISEASE HYPOTHESIS. IN THIS REVIEW, WE COMPARE THE PHENOTYPIC OUTCOMES OF THESE COMMONLY-USED PRENATAL STRESSORS TO AN ECOLOGICALLY-RELEVANT, PSYCHOGENIC STRESSOR THAT HAS BEEN PRESENT OVER EVOLUTIONARY TIMES, PREDATOR OR PREDATOR CUES PRESENCE. PRENATAL STRESS BY PREDATOR THREAT RESULTS IN BEHAVIORAL, PHYSIOLOGICAL, ENDOCRINE, TRANSCRIPT ABUNDANCE AND EPIGENETIC (DNA METHYLATION) MODIFICATIONS. THESE PHENOTYPIC MODIFICATIONS ARE CONSISTENT WITH DEVELOPMENTAL FORECASTING ACCORDING TO THE PREDICTIVE ADAPTIVE RESPONSE HYPOTHESIS, YIELDING ADAPTIVE RESPONSES IN ENVIRONMENTS WHERE SUCH PREDATION STRESS IS PRESENT. THE EVIDENCE DESCRIBED IN THIS REVIEW SUGGESTS THAT THE TYPE OF PRENATAL STRESS AGENT AND ITS INTENSITY MODIFIES THE PHENOTYPE EXPRESSED, WHICH CAN RANGE FROM ADAPTIVE TO PATHOLOGICAL. PRENATAL BISPHENOL A EXPOSURE STUDIES ARE PRESENTED AS AN EXAMPLE WHERE GRADED INTENSITIES (CONCENTRATIONS) OF PRENATAL TOXIN EXPOSURE CAN BE COMPARED DIRECTLY. FINALLY, WE EMPHASIZE THE IMPORTANCE OF STUDYING BOTH SEXES IN THESE STUDIES, AS SEX DIFFERENCES APPEAR TO BE A COMMON FEATURE OF THE RESPONSE TO PRENATAL STRESS. 2018 14 4798 39 NUTRITIONALLY MEDIATED PROGRAMMING OF THE DEVELOPING IMMUNE SYSTEM. A GROWING BODY OF EVIDENCE HIGHLIGHTS THE IMPORTANCE OF A MOTHER'S NUTRITION FROM PRECONCEPTION THROUGH LACTATION IN PROGRAMMING THE EMERGING ORGAN SYSTEMS AND HOMEOSTATIC PATHWAYS OF HER OFFSPRING. THE DEVELOPING IMMUNE SYSTEM MAY BE PARTICULARLY VULNERABLE. INDEED, EXAMPLES OF NUTRITION-MEDIATED IMMUNE PROGRAMMING CAN BE FOUND IN THE LITERATURE ON INTRA-UTERINE GROWTH RETARDATION, MATERNAL MICRONUTRIENT DEFICIENCIES, AND INFANT FEEDING. CURRENT MODELS OF IMMUNE ONTOGENY DEPICT A "LAYERED" EXPANSION OF INCREASINGLY COMPLEX DEFENSES, WHICH MAY BE PERMANENTLY ALTERED BY MATERNAL MALNUTRITION. ONE PROGRAMMING MECHANISM INVOLVES ACTIVATION OF THE MATERNAL HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN RESPONSE TO NUTRITIONAL STRESS. FETAL OR NEONATAL EXPOSURE TO ELEVATED STRESS HORMONES IS LINKED IN ANIMAL STUDIES TO PERMANENT CHANGES IN NEUROENDOCRINE-IMMUNE INTERACTIONS, WITH DIVERSE MANIFESTATIONS SUCH AS AN ATTENUATED INFLAMMATORY RESPONSE OR REDUCED RESISTANCE TO TUMOR COLONIZATION. MATERNAL MALNUTRITION MAY ALSO HAVE A DIRECT INFLUENCE, AS EVIDENCED BY NUTRIENT-DRIVEN EPIGENETIC CHANGES TO DEVELOPING T REGULATORY CELLS AND SUBSEQUENT RISK OF ALLERGY OR ASTHMA. A 3RD PROGRAMMING PATHWAY INVOLVES PLACENTAL OR BREAST MILK TRANSFER OF MATERNAL IMMUNE FACTORS WITH IMMUNOMODULATORY FUNCTIONS (E.G. CYTOKINES). MATERNAL MALNUTRITION CAN DIRECTLY AFFECT TRANSFER MECHANISMS OR INFLUENCE THE QUALITY OR QUANTITY OF TRANSFERRED FACTORS. THE PUBLIC HEALTH IMPLICATIONS OF NUTRITION-MEDIATED IMMUNE PROGRAMMING ARE OF PARTICULAR IMPORTANCE IN THE DEVELOPING WORLD, WHERE PREVALENT MATERNAL UNDERNUTRITION IS COUPLED WITH PERSISTENT INFECTIOUS CHALLENGES. HOWEVER, EARLY ALTERATIONS TO THE IMMUNE SYSTEM, RESULTING FROM EITHER NUTRITIONAL DEFICIENCIES OR EXCESSES, HAVE BROAD RELEVANCE FOR IMMUNE-MEDIATED DISEASES, SUCH AS ASTHMA, AND CHRONIC INFLAMMATORY CONDITIONS LIKE CARDIOVASCULAR DISEASE. 2011 15 4420 40 MOLECULAR AND EPIGENETIC MECHANISMS FOR THE COMPLEX EFFECTS OF STRESS ON SYNAPTIC PHYSIOLOGY AND COGNITIVE FUNCTIONS. EVIDENCE OVER THE PAST DECADES HAS FOUND THAT STRESS, PARTICULARLY THROUGH THE CORTICOSTERONE STRESS HORMONES, PRODUCES COMPLEX CHANGES IN GLUTAMATERGIC SIGNALING IN PREFRONTAL CORTEX, WHICH LEADS TO THE ALTERATION OF COGNITIVE PROCESSES MEDICATED BY THIS BRAIN REGION. INTERESTINGLY, THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION APPEAR TO BE "U-SHAPED," DEPENDING UPON THE DURATION AND SEVERITY OF THE STRESSOR. THESE BIPHASIC EFFECTS OF ACUTE VS CHRONIC STRESS REPRESENT THE ADAPTIVE VS MALADAPTIVE RESPONSES TO STRESSFUL STIMULI. ANIMAL STUDIES SUGGEST THAT THE STRESS-INDUCED MODULATION OF EXCITATORY SYNAPTIC TRANSMISSION INVOLVES CHANGES IN PRESYNAPTIC GLUTAMATE RELEASE, POSTSYNAPTIC GLUTAMATE RECEPTOR MEMBRANE TRAFFICKING AND DEGRADATION, SPINE STRUCTURE AND CYTOSKELETON NETWORK, AND EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW WILL DISCUSS CURRENT FINDINGS ON THE KEY MOLECULES INVOLVED IN THE STRESS-INDUCED REGULATION OF PREFRONTAL CORTEX SYNAPTIC PHYSIOLOGY AND PREFRONTAL CORTEX-MEDIATED FUNCTIONS. UNDERSTANDING THE MOLECULAR AND EPIGENETIC MECHANISMS THAT UNDERLIE THE COMPLEX EFFECTS OF STRESS WILL HELP TO DEVELOP NOVEL STRATEGIES TO COPE WITH STRESS-RELATED MENTAL DISORDERS. 2017 16 3119 28 GESTATIONAL EXPOSURE TO PARTICULATE AIR POLLUTION EXACERBATES THE GROWTH PHENOTYPES INDUCED BY PRECONCEPTION PATERNAL ALCOHOL USE: A MULTIPLEX MODEL OF EXPOSURE. IT IS NOW CLEAR THAT PARENTAL HISTORIES OF DRUG USE, TOXICANT EXPOSURE, AND SOCIAL STRESS ALL HAVE A SIGNIFICANT INFLUENCE ON THE HEALTH AND DEVELOPMENT OF THE NEXT GENERATION. HOWEVER, THE ABILITY OF EPIGENETIC PARENTAL LIFE MEMORIES TO INTERACT WITH SUBSEQUENT GESTATIONAL EXPOSURES AND CUMULATIVELY MODIFY THE DEVELOPMENTAL TRAJECTORY OF THE OFFSPRING REMAINS AN UNEXPLORED PERSPECTIVE IN TOXICOLOGY. STUDIES FROM OUR LABORATORY HAVE IDENTIFIED MALE-SPECIFIC POSTNATAL GROWTH RESTRICTION IN A MOUSE MODEL OF CHRONIC, PRECONCEPTION PATERNAL ALCOHOL EXPOSURE. THE GOAL OF THE CURRENT STUDY WAS TO DETERMINE IF PATERNAL ALCOHOL USE, BEFORE CONCEPTION, COULD MODIFY THE SUSCEPTIBILITY OF THE OFFSPRING TO A COMPLETELY SEPARATE EXPOSURE ENCOUNTERED BY THE MOTHER DURING PREGNANCY. IN INDEPENDENT EXPERIMENTS, WE PREVIOUSLY IDENTIFIED ALTERED DEVELOPMENTAL PROGRAMMING AND INCREASED MARKERS OF SEVERE ASTHMA INDUCED BY GESTATIONAL EXPOSURE TO PARTICULATE AIR POLLUTION. IN THIS STUDY, MALE MICE WERE EXPOSED TO EITHER THE CONTROL OR ALCOHOL PRECONCEPTION TREATMENTS, THEN MATED TO NAIVE FEMALES, WHICH WE SUBSEQUENTLY EXPOSED TO AN ULTRAFINE MIXTURE OF PARTICULATE MATTER VIA INHALATION. INDIVIDUALLY, NEITHER PRECONCEPTION PATERNAL DRINKING NOR GESTATIONAL EXPOSURES TO PARTICULATE AIR POLLUTION IMPACTED THE POSTNATAL GROWTH OF FEMALE OFFSPRING. HOWEVER, WHEN BOTH EXPOSURES WERE COMBINED, FEMALES DISPLAYED A 30% REDUCTION IN WEIGHT GAIN. UNEXPECTEDLY, THIS EXPOSURE PARADIGM RESULTED IN A DRAMATIC POSTNATAL INCREASE IN LITTER LOSS DUE TO MATERNAL CANNIBALISM, WHICH PREVENTED ADDITIONAL MEASURES OF OFFSPRING HEALTH. THESE PRELIMINARY STUDIES PROVIDE EVIDENCE OF A COMPLEX INTERPLAY BETWEEN PRECONCEPTION LIFE HISTORY AND INTRAUTERINE ENVIRONMENTAL FACTORS IN THE CONTROL OF POSTNATAL GROWTH. 2020 17 4064 35 MATERNAL AND EARLY-LIFE CIRCADIAN DISRUPTION HAVE LONG-LASTING NEGATIVE CONSEQUENCES ON OFFSPRING DEVELOPMENT AND ADULT BEHAVIOR IN MICE. MODERN LIFE INVOLVES CHRONIC CIRCADIAN DISRUPTION THROUGH ARTIFICIAL LIGHT AND THESE DISRUPTIONS ARE ASSOCIATED WITH NUMEROUS MENTAL AND PHYSICAL HEALTH MALADIES. BECAUSE THE DEVELOPING NERVOUS SYSTEM IS PARTICULARLY VULNERABLE TO PERTURBATION, WE HYPOTHESIZED THAT EARLY-LIFE CIRCADIAN DISRUPTION WOULD NEGATIVELY IMPACT OFFSPRING DEVELOPMENT AND ADULT FUNCTION. PREGNANT MICE WERE SUBJECTED TO CHRONIC CIRCADIAN DISRUPTION FROM THE TIME OF UTERINE IMPLANTATION THROUGH WEANING. TO DISSOCIATE IN UTERO FROM POSTNATAL EFFECTS, A SUBSET OF LITTERS WAS CROSS-FOSTERED AT BIRTH FROM DISRUPTED DAMS TO CONTROL DAMS AND VICE VERSA. POSTNATAL CIRCADIAN DISRUPTION WAS ASSOCIATED WITH REDUCED ADULT BODY MASS, SOCIAL AVOIDANCE, AND HYPERACTIVITY. IN UTERO DISRUPTION RESULTED IN MORE PRONOUNCED SOCIAL AVOIDANCE AND HYPERACTIVITY, PHENOTYPES NOT ABROGATED BY CROSS-FOSTERING TO CONTROL MOTHERS. TO EXAMINE WHETHER CIRCADIAN DISRUPTION AFFECTS DEVELOPMENT BY ACTING AS AN EARLY LIFE STRESSOR, WE EXAMINED BIRTHWEIGHT, LITTER SIZE, MATERNAL CANNIBALISM, AND EPIGENETIC MODIFICATIONS. NONE OF THESE VARIABLES DIFFERED BETWEEN CONTROL AND DISRUPTED DAMS, OR RESEMBLED PATTERNS SEEN FOLLOWING EARLY-LIFE STRESS. OUR FINDINGS INDICATE THAT DEVELOPMENTAL CHRONIC CIRCADIAN DISRUPTION PERMANENTLY AFFECTS SOMATIC AND BEHAVIORAL DEVELOPMENT IN A STAGE-OF-LIFE-DEPENDENT MANNER, INDEPENDENT OF EARLY LIFE STRESS MECHANISMS, UNDERSCORING THE IMPORTANCE OF TEMPORAL STRUCTURE DURING DEVELOPMENT, BOTH IN UTERO AND EARLY POSTNATAL LIFE. 2017 18 23 38 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015 19 6426 28 THE TRANSGENERATIONAL TRANSMISSION OF THE PATERNAL TYPE 2 DIABETES-INDUCED SUBFERTILITY PHENOTYPE. DIABETES IS A CHRONIC METABOLIC DISORDER CHARACTERIZED BY HYPERGLYCEMIA AND ASSOCIATED WITH MANY HEALTH COMPLICATIONS DUE TO THE LONG-TERM DAMAGE AND DYSFUNCTION OF VARIOUS ORGANS. A CONSEQUENTIAL COMPLICATION OF DIABETES IN MEN IS REPRODUCTIVE DYSFUNCTION, REDUCED FERTILITY, AND POOR REPRODUCTIVE OUTCOMES. HOWEVER, THE MOLECULAR MECHANISMS RESPONSIBLE FOR DIABETIC ENVIRONMENT-INDUCED SPERM DAMAGE AND OVERALL DECREASED REPRODUCTIVE OUTCOMES ARE NOT FULLY ESTABLISHED. WE EVALUATED THE EFFECTS OF TYPE 2 DIABETES EXPOSURE ON THE REPRODUCTIVE SYSTEM AND THE REPRODUCTIVE OUTCOMES OF MALES AND THEIR MALE OFFSPRING, USING A MOUSE MODEL. WE DEMONSTRATE THAT PATERNAL EXPOSURE TO TYPE 2 DIABETES MEDIATES INTERGENERATIONAL AND TRANSGENERATIONAL EFFECTS ON THE REPRODUCTIVE HEALTH OF THE OFFSPRING, ESPECIALLY ON SPERM QUALITY, AND ON METABOLIC CHARACTERISTICS. GIVEN THE TRANSGENERATIONAL IMPAIRMENT OF REPRODUCTIVE AND METABOLIC PARAMETERS THROUGH TWO GENERATIONS, THESE CHANGES LIKELY TAKE THE FORM OF INHERITED EPIGENETIC MARKS THROUGH THE GERMLINE. OUR RESULTS EMPHASIZE THE IMPORTANCE OF IMPROVING METABOLIC HEALTH NOT ONLY IN WOMEN OF REPRODUCTIVE AGE, BUT ALSO IN POTENTIAL FATHERS, IN ORDER TO REDUCE THE NEGATIVE IMPACTS OF DIABETES ON SUBSEQUENT GENERATIONS. 2021 20 4621 38 NEUROBIOLOGICAL AND SYSTEMIC EFFECTS OF CHRONIC 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, WHICH PROMOTE ADAPTATION ("ALLOSTASIS") BUT ALSO CONTRIBUTE TO PATHOPHYSIOLOGY ("ALLOSTATIC LOAD/OVERLOAD") WHEN OVERUSED AND DYSREGULATED. THE ADULT AS WELL AS DEVELOPING BRAIN POSSESSES A REMARKABLE ABILITY TO SHOW STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING AND SYNAPSE TURNOVER. STRESS CAN 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. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE THREAT PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION REQUIRES INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES. THERE ARE IMPORTANT SEX DIFFERENCES IN HOW THE BRAIN RESPONDS TO STRESSORS. MOREOVER, ADVERSE EARLY LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCES LASTING EFFECTS ON BRAIN AND BODY VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS KEY, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT UTILIZE BRAIN-BODY INTERACTIONS. POLICIES OF GOVERNMENT AND THE PRIVATE SECTOR ARE IMPORTANT TO PROMOTE HEALTH AND INCREASE "HEALTHSPAN." 2017