1 1364 155 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 2 5810 36 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 3 1639 40 DOES EPIGENETIC 'MEMORY' OF EARLY-LIFE STRESS PREDISPOSE TO CHRONIC PAIN IN LATER LIFE? A POTENTIAL ROLE FOR THE STRESS REGULATOR FKBP5. ANIMAL BEHAVIOURS ARE AFFECTED NOT ONLY BY INHERITED GENES BUT ALSO BY ENVIRONMENTAL EXPERIENCES. FOR EXAMPLE, IN BOTH RATS AND HUMANS, STRESSFUL EARLY-LIFE EVENTS SUCH AS BEING REARED BY AN INATTENTIVE MOTHER CAN LEAVE A LASTING TRACE AND AFFECT LATER STRESS RESPONSE IN ADULT LIFE. THIS IS OWING TO A CHEMICAL TRACE LEFT ON THE CHROMATIN ATTRIBUTED TO SO-CALLED EPIGENETIC MECHANISMS. SUCH AN EPIGENETIC TRACE OFTEN HAS CONSEQUENCES, SOMETIMES LONG-LASTING, ON THE FUNCTIONING OF OUR GENES, THEREBY ALLOWING INDIVIDUALS TO RAPIDLY ADAPT TO A NEW ENVIRONMENT. ONE GENE UNDER SUCH EPIGENETIC CONTROL IS FKBP5, THE GENE THAT ENCODES THE PROTEIN FKPB51, A CRUCIAL REGULATOR OF THE STRESS AXIS AND A SIGNIFICANT DRIVER OF CHRONIC PAIN STATES. IN THIS ARTICLE, WE WILL DISCUSS THE POSSIBILITY THAT EXPOSURE TO STRESS COULD DRIVE THE SUSCEPTIBLY TO CHRONIC PAIN VIA EPIGENETIC MODIFICATIONS OF GENES WITHIN THE STRESS AXIS SUCH AS FKBP5. THE POSSIBILITY THAT SUCH MODIFICATIONS, AND THEREFORE, THE SUSCEPTIBILITY TO CHRONIC PAIN, COULD BE TRANSMITTED ACROSS GENERATIONS IN MAMMALS AND WHETHER SUCH MECHANISMS MAY BE EVOLUTIONARILY CONSERVED ACROSS PHYLA WILL ALSO BE DEBATED. THIS ARTICLE IS PART OF THE THEO MURPHY MEETING ISSUE 'EVOLUTION OF MECHANISMS AND BEHAVIOUR IMPORTANT FOR PAIN'. 2019 4 5829 26 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 5 6119 23 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 6 6853 52 [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 7 5164 43 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 8 6228 34 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016 9 291 34 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 10 678 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 11 634 34 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 12 2520 35 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 13 2913 38 GENE REGULATORY MECHANISMS UNDERLYING SEX DIFFERENCES IN BRAIN DEVELOPMENT AND PSYCHIATRIC DISEASE. THE SEXUAL DIFFERENTIATION OF THE MAMMALIAN NERVOUS SYSTEM REQUIRES THE PRECISE COORDINATION OF THE TEMPORAL AND SPATIAL REGULATION OF GENE EXPRESSION IN DIVERSE CELL TYPES. SEX HORMONES ACT AT MULTIPLE DEVELOPMENTAL TIME POINTS TO SPECIFY SEX-TYPICAL DIFFERENTIATION DURING EMBRYONIC AND EARLY DEVELOPMENT AND TO COORDINATE SUBSEQUENT RESPONSES TO GONADAL HORMONES LATER IN LIFE BY ESTABLISHING SEX-TYPICAL PATTERNS OF EPIGENETIC MODIFICATIONS ACROSS THE GENOME. THUS, MUTATIONS ASSOCIATED WITH NEUROPSYCHIATRIC CONDITIONS MAY RESULT IN SEXUALLY DIMORPHIC SYMPTOMS BY ACTING ON DIFFERENT NEURAL SUBSTRATES OR CHROMATIN LANDSCAPES IN MALES AND FEMALES. FINALLY, AS STRESS HORMONE SIGNALING MAY DIRECTLY ALTER THE MOLECULAR MACHINERY THAT INTERACTS WITH SEX HORMONE RECEPTORS TO REGULATE GENE EXPRESSION, THE CONTRIBUTION OF CHRONIC STRESS TO THE PATHOGENESIS OR PRESENTATION OF MENTAL ILLNESS MAY BE ADDITIONALLY DIFFERENT BETWEEN THE SEXES. HERE, WE REVIEW THE MECHANISMS THAT CONTRIBUTE TO SEXUAL DIFFERENTIATION IN THE MAMMALIAN NERVOUS SYSTEM AND CONSIDER SOME OF THE IMPLICATIONS OF THESE PROCESSES FOR SEX DIFFERENCES IN NEUROPSYCHIATRIC CONDITIONS. 2018 14 6063 36 THE DEVELOPMENTAL ENVIRONMENT, EPIGENETIC BIOMARKERS AND LONG-TERM HEALTH. EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES HAS SHOWN THAT THE PRENATAL AND EARLY POSTNATAL ENVIRONMENTS INFLUENCE SUSCEPTIBILITY TO CHRONIC DISEASE IN LATER LIFE AND SUGGESTS THAT EPIGENETIC PROCESSES ARE AN IMPORTANT MECHANISM BY WHICH THE ENVIRONMENT ALTERS LONG-TERM DISEASE RISK. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND NON-CODING RNAS, PLAY A CENTRAL ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME IS HIGHLY SENSITIVE TO ENVIRONMENTAL FACTORS IN EARLY LIFE, SUCH AS NUTRITION, STRESS, ENDOCRINE DISRUPTION AND POLLUTION, AND CHANGES IN THE EPIGENOME CAN INDUCE LONG-TERM CHANGES IN GENE EXPRESSION AND PHENOTYPE. IN THIS REVIEW WE FOCUS ON HOW THE EARLY LIFE NUTRITIONAL ENVIRONMENT CAN ALTER THE EPIGENOME LEADING TO AN ALTERED SUSCEPTIBILITY TO DISEASE IN LATER LIFE. 2015 15 2235 35 EPIGENETIC MODIFICATIONS, ALCOHOLIC BRAIN AND POTENTIAL DRUG TARGETS. ACUTE AND CHRONIC ALCOHOL EXPOSURE EVIDENTLY INFLUENCES EPIGENETIC CHANGES, BOTH TRANSIENTLY AND PERMANENTLY, AND THESE CHANGES IN TURN INFLUENCE A VARIETY OF CELLS AND ORGAN SYSTEMS THROUGHOUT THE BODY. MANY OF THE ALCOHOL-INDUCED EPIGENETIC MODIFICATIONS CAN CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THE PERSISTENCE OF BEHAVIORAL CHANGES DEMONSTRATES THAT LONG-LASTING CHANGES IN GENE EXPRESSION, WITHIN PARTICULAR REGIONS OF THE BRAIN, MAY CONTRIBUTE IMPORTANTLY TO THE ADDICTION PHENOTYPE. THE RESEARCH ACTIVITIES OVER THE PAST YEARS HAVE DEMONSTRATED A CRUCIAL ROLE OF EPIGENETIC MECHANISMS IN CAUSING LONG LASTING AND TRANSIENT CHANGES IN THE EXPRESSION OF SEVERAL GENES IN DIVERSE TISSUES, INCLUDING BRAIN. THIS HAS STIMULATED RECENT RESEARCH WORK THAT IS AIMED AT CHARACTERIZING THE INFLUENCE OF EPIGENETIC REGULATORY EVENTS IN MEDIATING THE LONG LASTING AND TRANSIENT EFFECTS OF ALCOHOL ABUSE ON THE BRAIN IN HUMANS AND ANIMAL MODELS OF ALCOHOL ADDICTION. IN THIS STUDY, WE UPDATE OUR CURRENT UNDERSTANDING OF THE IMPACT OF ALCOHOL EXPOSURE ON EPIGENETIC MECHANISMS IN THE BRAIN AND REFURBISH THE KNOWLEDGE OF EPIGENETICS IN THE DIRECTION OF NEW DRUGS DEVELOPMENT. 2016 16 1766 43 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 17 2386 34 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 18 1770 46 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 19 2159 37 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 20 679 22 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