1 2949 88 GENETIC AND EPIGENETIC CONSEQUENCE OF EARLY-LIFE SOCIAL STRESS ON DEPRESSION: ROLE OF SEROTONIN-ASSOCIATED GENES. EARLY-LIFE ADVERSITY CAUSED BY POOR SOCIAL BONDING AND DEPRIVED MATERNAL CARE IS KNOWN TO AFFECT MENTAL WELLBEING AND PHYSICAL HEALTH. IT IS A FORM OF CHRONIC SOCIAL STRESS THAT PERSISTS BECAUSE OF A NEGATIVE ENVIRONMENT, AND THE CONSEQUENCES ARE LONG-LASTING ON MENTAL HEALTH. THE PRESENCE OF SOCIAL STRESS DURING EARLY LIFE CAN HAVE AN EPIGENETIC EFFECT ON THE BODY, POSSIBLY RESULTING IN MANY COMPLEX MENTAL DISORDERS, INCLUDING DEPRESSION IN LATER LIFE. HERE, WE REVIEW THE EVIDENCE FOR EARLY-LIFE SOCIAL STRESS-INDUCED EPIGENETIC CHANGES THAT MODULATE JUVENILE AND ADULT SOCIAL BEHAVIOR (DEPRESSION AND ANXIETY). THIS REVIEW HAS A PARTICULAR EMPHASIS ON THE INTERACTION BETWEEN EARLY-LIFE SOCIAL STRESS AND GENETIC VARIATION OF SEROTONIN ASSOCIATE GENES INCLUDING THE SEROTONIN TRANSPORTER GENE (5-HTT; ALSO KNOWN AS SLC6A4), WHICH ARE KEY MOLECULES INVOLVED IN DEPRESSION. 2020 2 248 37 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 3 6119 29 THE EPIGENETIC IMPACTS OF SOCIAL STRESS: HOW DOES SOCIAL ADVERSITY BECOME BIOLOGICALLY EMBEDDED? EPIGENETIC MECHANISMS ARE IMPLICATED IN THE PROCESSES THROUGH WHICH SOCIAL STRESSORS ERODE HEALTH IN HUMANS AND OTHER ANIMALS. HERE I REVIEW PROGRESS IN ELUCIDATING THE BIOLOGICAL PATHWAYS UNDERLYING THE SOCIAL GRADIENT IN HEALTH, WITH PARTICULAR EMPHASIS ON HOW BEHAVIORAL STRESSES INFLUENCE EPIGENOMIC VARIATION LINKED TO HEALTH. THE EVIDENCE THAT EPIGENETIC CHANGES ARE INVOLVED IN EMBEDDING OF SOCIAL STATUS-LINKED CHRONIC STRESS IS REVIEWED IN THE CONTEXT OF CURRENT KNOWLEDGE ABOUT BEHAVIOR WITHIN ANIMAL DOMINANCE HIERARCHIES AND THE IMPACTS OF SOCIAL POSITION ON BEHAVIORS THAT AFFECT HEALTH. THE ROLES OF EPIGENETIC MECHANISMS IN RESPONSES TO TRAUMA AND THE EVIDENCE FOR THEIR INVOLVEMENT IN INTERGENERATIONAL TRANSMISSION OF THE BIOLOGICAL IMPACTS OF TRAUMATIC STRESS ARE ALSO CONSIDERED. TAKEN TOGETHER, THE EMERGING INSIGHTS HAVE IMPORTANT IMPLICATIONS FOR DEVELOPMENT OF STRATEGIES TO IMPROVE SOCIETAL HEALTH AND WELL-BEING. 2016 4 5316 36 PSYCHOLOGICAL STRESS IN EARLY LIFE AS A PREDISPOSING FACTOR FOR THE DEVELOPMENT OF CHRONIC PAIN: CLINICAL AND PRECLINICAL EVIDENCE AND NEUROBIOLOGICAL MECHANISMS. A WEALTH OF RESEARCH OVER THE PAST 2 DECADES HAS EXPANDED OUR UNDERSTANDING OF THE IMPACT OF EARLY-LIFE ADVERSITY ON PHYSIOLOGICAL FUNCTION AND, CONSEQUENTLY, HEALTH AND WELLBEING IN LATER LIFE. EARLY-LIFE ADVERSITY INCREASES THE RISK OF DEVELOPING A NUMBER OF DISORDERS, SUCH AS CHRONIC PAIN, FIBROMYALGIA, AND IRRITABLE BOWEL SYNDROME. ALTHOUGH MUCH OF THE RESEARCH HAS EXAMINED THE IMPACT OF PHYSICAL MALTREATMENT, AN INCREASING NUMBER OF STUDIES HAVE BEEN PUBLISHED OVER THE PAST FEW YEARS EXAMINING THE EFFECT OF CHILDHOOD PSYCHOLOGICAL STRESS AND TRAUMA ON THE DEVELOPMENT OF VARIOUS TYPES OF CHRONIC PAIN CONDITIONS. WE REVIEW THE CLINICAL AND PRECLINICAL DATA EXAMINING THE LINK AMONG EARLY-LIFE PSYCHOLOGICAL STRESS, ALTERED NOCICEPTIVE BEHAVIOR, AND CHRONIC PAIN IN LATER LIFE. EVIDENCE SUPPORTING A ROLE FOR CERTAIN KEY NEUROBIOLOGICAL SUBSTRATES, INCLUDING THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS; MONOAMINERGIC, OPIOIDERGIC, ENDOCANNABINOID AND IMMUNE SYSTEMS; AND EPIGENETIC MECHANISMS IN THE ASSOCIATION BETWEEN EARLY-LIFE PSYCHOLOGICAL STRESS AND CHRONIC PAIN, IS PROVIDED. GREATER UNDERSTANDING OF THE IMPACT OF EARLY-LIFE STRESS MAY INFORM THE DEVELOPMENT OF PERSONALIZED TREATMENTS FOR CHRONIC PAIN IN LATER LIFE AND STRATEGIES TO PREVENT ITS ONSET IN SUSCEPTIBLE INDIVIDUALS. (C) 2016 WILEY PERIODICALS, INC. 2017 5 1364 34 DEVELOPMENTAL NEUROENDOCRINOLOGY OF EARLY-LIFE STRESS: IMPACT ON CHILD DEVELOPMENT AND BEHAVIOR. OUR INTERNAL BALANCE, OR HOMEOSTASIS, IS THREATENED OR PERCEIVED AS THREATENED BY STRESSFUL STIMULI, THE STRESSORS. THE STRESS SYSTEM IS A HIGHLY CONSERVED SYSTEM THAT ADJUSTS HOMEOSTASIS TO THE RESTING STATE. THROUGH THE CONCURRENT ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE LOCUS COERULEUS/NOREPINEPHRINE-AUTONOMIC NERVOUS SYSTEMS, THE STRESS SYSTEM PROVIDES THE APPROPRIATE PHYSICAL AND BEHAVIORAL RESPONSES, COLLECTIVELY TERMED AS "STRESS RESPONSE", TO RESTORE HOMEOSTASIS. IF THE STRESS RESPONSE IS PROLONGED, EXCESSIVE OR EVEN INADEQUATE, SEVERAL ACUTE OR CHRONIC STRESS-RELATED PATHOLOGIC CONDITIONS MAY DEVELOP IN CHILDHOOD, ADOLESCENCE AND ADULT LIFE. ON THE OTHER HAND, EARLY-LIFE EXPOSURE TO STRESSORS HAS BEEN RECOGNIZED AS A MAJOR CONTRIBUTING FACTOR UNDERLYING THE PATHOGENESIS OF NON-COMMUNICABLE DISORDERS, INCLUDING NEURODEVELOPMENTAL DISORDERS. ACCUMULATING EVIDENCE SUGGESTS THAT EARLY-LIFE STRESS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER AND AUTISM SPECTRUM DISORDER IN THE OFFSPRING, ALTHOUGH FINDINGS ARE STILL CONTROVERSIAL. NEVERTHELESS, AT THE MOLECULAR LEVEL, EARLY-LIFE STRESSORS ALTER THE CHEMICAL STRUCTURE OF CYTOSINES LOCAT- ED IN THE REGULATORY REGIONS OF GENES, MOSTLY THROUGH THE ADDITION OF METHYL GROUPS. THESE EPIGENETIC MODIFICATIONS RESULT IN THE SUPPRESSION OF GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. IN ADDITION TO DNA METHYLATION, SEVERAL LINES OF EVIDENCE SUPPORT THE ROLE OF NON-CODING RNAS IN THE EVOLVING FIELD OF EPIGENETICS. IN THIS REVIEW ARTICLE, WE PRESENT THE ANATOMICAL AND FUNCTIONAL COMPO- NENTS OF THE STRESS SYSTEM, DISCUSS THE PROPER, IN TERMS OF QUALITY AND QUANTITY, STRESS RESPONSE, AND PROVIDE AN UPDATE ON THE IMPACT OF EARLY-LIFE STRESS ON CHILD DEVELOPMENT AND BEHAVIOR. 2023 6 1774 30 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY. 2018 7 1754 33 EARLY LIFE STRESS, THE DEVELOPMENT OF AGGRESSION AND NEUROENDOCRINE AND NEUROBIOLOGICAL CORRELATES: WHAT CAN WE LEARN FROM ANIMAL MODELS? EARLY LIFE STRESS (CHILD AND ADOLESCENT ABUSE, NEGLECT AND TRAUMA) INDUCES ROBUST ALTERATIONS IN EMOTIONAL AND SOCIAL FUNCTIONING RESULTING IN ENHANCED RISK FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS MOOD AND AGGRESSIVE DISORDERS. HERE, AN OVERVIEW IS GIVEN ON RECENT FINDINGS IN PRIMATE AND RODENT MODELS OF EARLY LIFE STRESS, DEMONSTRATING THAT CHRONIC DEPRIVATION OF EARLY MATERNAL CARE AS WELL AS CHRONIC DEPRIVATION OF EARLY PHYSICAL INTERACTIONS WITH PEERS ARE PROFOUND RISK FACTORS FOR THE DEVELOPMENT OF INAPPROPRIATE AGGRESSIVE BEHAVIORS. ALTERATIONS IN THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA), VASOPRESSIN AND SEROTONIN SYSTEMS AND THEIR RELEVANCE FOR THE REGULATION OF AGGRESSION ARE DISCUSSED. DATA SUGGEST THAT SOCIAL DEPRIVATION-INDUCED INAPPROPRIATE FORMS OF AGGRESSION ARE ASSOCIATED WITH HIGH OR LOW HPA AXIS (RE)ACTIVITY AND A GENERALLY LOWER FUNCTIONING OF THE SEROTONIN SYSTEM IN ADULTHOOD. MOREOVER, GENETIC AND EPIGENETIC MODIFICATIONS IN HPA AND SEROTONIN SYSTEMS INFLUENCE THE OUTCOME OF EARLY LIFE STRESS AND MAY EVEN MODERATE ADVERSE EFFECTS OF EARLY SOCIAL DEPRIVATION ON AGGRESSION. A MORE COMPREHENSIVE STUDY OF AGGRESSION, NEUROENDOCRINE, NEUROBIOLOGICAL AND (EPI)GENETIC CORRELATES OF EARLY LIFE STRESS USING ANIMAL MODELS IS NECESSARY TO PROVIDE A BETTER UNDERSTANDING OF THE INVASIVE AGGRESSIVE DEFICITS OBSERVED IN HUMANS EXPOSED TO CHILD MALTREATMENT. 2009 8 4622 20 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 9 1766 40 EARLY-LIFE EXPERIENCES AND THE DEVELOPMENT OF ADULT DISEASES WITH A FOCUS ON MENTAL ILLNESS: THE HUMAN BIRTH THEORY. IN MAMMALS, EARLY ADVERSE EXPERIENCES, INCLUDING MOTHER-PUP INTERACTIONS, SHAPE THE RESPONSE OF AN INDIVIDUAL TO CHRONIC STRESS OR TO STRESS-RELATED DISEASES DURING ADULT LIFE. THIS HAS LED TO THE ELABORATION OF THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, IN PARTICULAR ADULT DISEASES SUCH AS CARDIOVASCULAR AND METABOLIC DISORDERS. IN ADDITION, IN HUMANS, AS STATED BY MASSIMO FAGIOLI'S HUMAN BIRTH THEORY, BIRTH IS HEALTHY AND EQUAL FOR ALL INDIVIDUALS, SO THAT MENTAL ILLNESS DEVELOP EXCLUSIVELY IN THE POSTNATAL PERIOD BECAUSE OF THE QUALITY OF THE RELATIONSHIP IN THE FIRST YEAR OF LIFE. THUS, THIS REVIEW FOCUSES ON THE IMPORTANCE OF PROGRAMMING DURING THE EARLY DEVELOPMENTAL PERIOD ON THE MANIFESTATION OF ADULT DISEASES IN BOTH ANIMAL MODELS AND HUMANS. CONSIDERING THE OBVIOUS DIFFERENCES BETWEEN ANIMALS AND HUMANS WE CANNOT SYSTEMATICALLY MOVE FROM ANIMAL MODELS TO HUMANS. CONSEQUENTLY, IN THE FIRST PART OF THIS REVIEW, WE WILL DISCUSS HOW ANIMAL MODELS CAN BE USED TO DISSECT THE INFLUENCE OF ADVERSE EVENTS OCCURRING DURING THE PRENATAL AND POSTNATAL PERIODS ON THE DEVELOPMENTAL TRAJECTORIES OF THE OFFSPRING, AND IN THE SECOND PART, WE WILL DISCUSS THE ROLE OF POSTNATAL CRITICAL PERIODS ON THE DEVELOPMENT OF MENTAL DISEASES IN HUMANS. EPIGENETIC MECHANISMS THAT CAUSE REVERSIBLE MODIFICATIONS IN GENE EXPRESSION, DRIVING THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE IN RESPONSE TO A NEGATIVE EARLY POSTNATAL ENVIRONMENT, MAY LIE AT THE CORE OF THIS PROGRAMMING, THEREBY PROVIDING POTENTIAL NEW THERAPEUTIC TARGETS. THE CONCEPT OF THE HUMAN BIRTH THEORY LEADS TO A COMPREHENSION OF THE MENTAL ILLNESS AS A PATHOLOGY OF THE HUMAN RELATIONSHIP IMMEDIATELY AFTER BIRTH AND DURING THE FIRST YEAR OF LIFE. 2017 10 6853 36 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 11 2159 31 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 12 678 35 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 13 2269 47 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 14 291 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 15 6228 28 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 16 1745 31 EARLY LIFE ADVERSITY AS A RISK FACTOR FOR FIBROMYALGIA IN LATER LIFE. THE IMPACT OF EARLY LIFE EVENTS IS INCREASINGLY BECOMING APPARENT, AS STUDIES INVESTIGATE HOW EARLY CHILDHOOD CAN SHAPE LONG-TERM PHYSIOLOGY AND BEHAVIOUR. FIBROMYALGIA (FM), WHICH IS CHARACTERISED BY INCREASED PAIN SENSITIVITY AND A NUMBER OF AFFECTIVE CO-MORBIDITIES, HAS AN UNCLEAR ETIOLOGY. THIS PAPER DISCUSSES RISK FACTORS FROM EARLY LIFE THAT MAY INCREASE THE OCCURRENCE OR SEVERITY OF FM IN LATER LIFE: PAIN EXPERIENCE DURING NEONATAL LIFE CAUSES LONG-LASTING CHANGES IN NOCICEPTIVE CIRCUITRY AND INCREASES PAIN SENSITIVITY IN THE OLDER ORGANISM; PREMATURE BIRTH AND RELATED STRESSOR EXPOSURE CAUSE LASTING CHANGES IN STRESS RESPONSIVITY; MATERNAL DEPRIVATION AFFECTS ANXIETY-LIKE BEHAVIOURS THAT MAY BE PARTIALLY MEDIATED BY EPIGENETIC MODULATION OF THE GENOME-ALL THESE ADULT PHENOTYPES ARE STRIKINGLY SIMILAR TO SYMPTOMS DISPLAYED BY FM SUFFERERS. IN ADDITION, CHILDHOOD TRAUMA AND EXPOSURE TO SUBSTANCES OF ABUSE MAY CAUSE LASTING CHANGES IN DEVELOPING NEUROTRANSMITTER AND ENDOCRINE CIRCUITS THAT ARE LINKED TO ANXIETY AND STRESS RESPONSES. 2012 17 1770 32 EARLY-LIFE ORIGIN OF ADULT INSOMNIA: DOES PRENATAL-EARLY-LIFE STRESS PLAY A ROLE? INSOMNIA IS VERY COMMON IN THE ADULT POPULATION AND IT INCLUDES A WIDE SPECTRUM OF SEQUELAE, THAT IS, NEUROENDOCRINE AND CARDIOVASCULAR ALTERATIONS AS WELL AS PSYCHIATRIC AND NEURODEGENERATIVE DISORDERS. ACCORDING TO THE CONCEPTUALIZATION OF INSOMNIA IN THE CONTEXT OF THE 3-P MODEL, THE IMPORTANCE OF PREDISPOSING, PRECIPITATING, AND PERPETUATING FACTORS HAS BEEN STRESSED. PREDISPOSING FACTORS ARE PRESENT BEFORE INSOMNIA IS MANIFESTED AND THEY ARE HYPOTHESIZED TO INTERACT WITH PRECIPITATING FACTORS, SUCH AS ENVIRONMENTAL STRESSFUL EVENTS, CONTRIBUTING TO THE ONSET OF INSOMNIA. UNDERSTANDING THE EARLY-LIFE ORIGINS OF INSOMNIA MAY BE PARTICULARLY USEFUL IN ORDER TO PREVENT AND TREAT THIS COSTLY PHENOMENON. BASED ON RECENT EVIDENCE, PRENATAL-EARLY-LIFE STRESS EXPOSURE RESULTS IN A SERIES OF RESPONSES THAT INVOLVE THE STRESS SYSTEM IN THE CHILD AND COULD PERSIST INTO ADULTHOOD. THIS MAY ENCOMPASS AN ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACCOMPANIED BY LONG-LASTING MODIFICATIONS IN STRESS REACTIVITY. FURTHERMORE, EARLY-LIFE STRESS EXPOSURE MIGHT PLAY AN IMPORTANT ROLE IN PREDISPOSING TO A VULNERABILITY TO HYPERAROUSAL REACTIONS TO NEGATIVE LIFE EVENTS IN THE ADULT CONTRIBUTING TO THE DEVELOPMENT OF CHRONIC INSOMNIA. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MALADAPTIVE STRESS RESPONSES IN THE NEWBORN, ULTIMATELY PREDISPOSING TO DEVELOP A VARIETY OF (PSYCHO-) PATHOLOGICAL STATES IN ADULT LIFE. 2015 18 5829 28 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 19 634 31 BIOLOGICAL EMBEDDING OF EARLY-LIFE ADVERSITY AND A SCOPING REVIEW OF THE EVIDENCE FOR INTERGENERATIONAL EPIGENETIC TRANSMISSION OF STRESS AND TRAUMA IN HUMANS. SEVERE OR CHRONIC STRESS AND TRAUMA CAN HAVE A DETRIMENTAL IMPACT ON HEALTH. EVIDENCE SUGGESTS THAT EARLY-LIFE ADVERSITY CAN BECOME BIOLOGICALLY EMBEDDED AND HAS THE POTENTIAL TO INFLUENCE HEALTH OUTCOMES DECADES LATER. EPIGENETICS IS ONE MECHANISM THAT HAS BEEN IMPLICATED IN THESE LONG-LASTING EFFECTS. OBSERVATIONAL STUDIES IN HUMANS INDICATE THAT THE EFFECTS OF STRESS COULD EVEN PERSIST ACROSS GENERATIONS, ALTHOUGH WHETHER OR NOT EPIGENETIC MECHANISMS ARE INVOLVED REMAINS UNDER DEBATE. HERE, WE PROVIDE AN OVERVIEW OF STUDIES IN ANIMALS AND HUMANS THAT DEMONSTRATE THE EFFECTS OF EARLY-LIFE STRESS ON DNA METHYLATION, ONE OF THE MOST WIDELY STUDIED EPIGENETIC MECHANISMS, AND SUMMARIZE FINDINGS FROM ANIMAL MODELS DEMONSTRATING THE INVOLVEMENT OF EPIGENETICS IN THE TRANSMISSION OF STRESS ACROSS GENERATIONS. WE THEN DESCRIBE THE RESULTS OF A SCOPING REVIEW TO DETERMINE THE EXTENT TO WHICH THE TERMS INTERGENERATIONAL OR TRANSGENERATIONAL HAVE BEEN USED IN HUMAN STUDIES INVESTIGATING THE TRANSMISSION OF TRAUMA AND STRESS VIA EPIGENETIC MECHANISMS. WE END WITH A DISCUSSION OF KEY AREAS FOR FUTURE RESEARCH TO ADVANCE UNDERSTANDING OF THE ROLE OF EPIGENETICS IN THE LEGACY EFFECTS OF STRESS AND TRAUMA. 2023 20 1750 30 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD. 2020