1 1639 121 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 2 1364 40 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 3 5810 30 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 4 6853 34 [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 5 2235 36 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 6 678 37 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 7 2913 25 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 8 2471 31 EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ALTERED STRESS RESPONSES. ANCESTRAL ENVIRONMENTAL EXPOSURES HAVE PREVIOUSLY BEEN SHOWN TO PROMOTE EPIGENETIC TRANSGENERATIONAL INHERITANCE AND INFLUENCE ALL ASPECTS OF AN INDIVIDUAL'S LIFE HISTORY. IN ADDITION, PROXIMATE LIFE EVENTS SUCH AS CHRONIC STRESS HAVE DOCUMENTED EFFECTS ON THE DEVELOPMENT OF PHYSIOLOGICAL, NEURAL, AND BEHAVIORAL PHENOTYPES IN ADULTHOOD. WE USED A SYSTEMS BIOLOGY APPROACH TO INVESTIGATE IN MALE RATS THE INTERACTION OF THE ANCESTRAL MODIFICATIONS CARRIED TRANSGENERATIONALLY IN THE GERM LINE AND THE PROXIMATE MODIFICATIONS INVOLVING CHRONIC RESTRAINT STRESS DURING ADOLESCENCE. WE FIND THAT A SINGLE EXPOSURE TO A COMMON-USE FUNGICIDE (VINCLOZOLIN) THREE GENERATIONS REMOVED ALTERS THE PHYSIOLOGY, BEHAVIOR, METABOLIC ACTIVITY, AND TRANSCRIPTOME IN DISCRETE BRAIN NUCLEI IN DESCENDANT MALES, CAUSING THEM TO RESPOND DIFFERENTLY TO CHRONIC RESTRAINT STRESS. THIS ALTERATION OF BASELINE BRAIN DEVELOPMENT PROMOTES A CHANGE IN NEURAL GENOMIC ACTIVITY THAT CORRELATES WITH CHANGES IN PHYSIOLOGY AND BEHAVIOR, REVEALING THE INTERACTION OF GENETICS, ENVIRONMENT, AND EPIGENETIC TRANSGENERATIONAL INHERITANCE IN THE SHAPING OF THE ADULT PHENOTYPE. THIS IS AN IMPORTANT DEMONSTRATION IN AN ANIMAL THAT ANCESTRAL EXPOSURE TO AN ENVIRONMENTAL COMPOUND MODIFIES HOW DESCENDANTS OF THESE PROGENITOR INDIVIDUALS PERCEIVE AND RESPOND TO A STRESS CHALLENGE EXPERIENCED DURING THEIR OWN LIFE HISTORY. 2012 9 2586 26 EPIGENETICS OF PAIN MEDIATORS. PURPOSE OF REVIEW: THE FIELD OF EPIGENETICS CONTINUES ITS INFLUENTIAL RISE AS A MEANS TO BETTER UNDERSTAND AN ORGANISM'S UNIQUE DEVELOPMENTAL IDENTITY OVER A LIFESPAN. WHEREAS A GENOME IS CONSTANT AND UNCHANGING, AN EPIGENOME IS DYNAMIC AND ALTERABLE. EPIGENETIC CHANGES ARE IN RESPONSE TO INNUMERABLE INTERNAL AND EXTERNAL INFLUENCES INCLUDING ENVIRONMENTAL CHANGES SUCH AS DIET, EXERCISE, DISEASE, TOXINS, AND STRESS. EPIGENETICS IS OF PARTICULAR INTEREST IN THE MEDICAL RESEARCH COMMUNITY BOTH FOR THE POTENTIAL TO CAUSE DISEASE AND AS A TARGET FOR THERAPEUTIC INTERVENTIONS. THIS ARTICLE PROVIDES A SUCCINCT EXPLANATION OF THE POTENTIAL FOR EPIGENETICS TO INFLUENCE THE UNDERSTANDING OF PAIN AS WELL AS A REVIEW OF RELEVANT RESEARCH ON THE TOPIC. RECENT FINDINGS: STUDIES ON EPIGENETICS AND PAIN REMAIN LARGELY PRECLINICAL AND INVESTIGATE THE THEORETICAL ABILITY OF EPIGENETICS TO ALTER THE NOCICEPTIVE PATHWAYS BOTH IN THE PERIPHERY AND CENTRALLY. SIGNIFICANT EVIDENCE NOW EXISTS FOR THE ABILITY OF EPIGENETICS TO MODIFY BROADLY CATEGORIZED PAIN TYPES, INCLUDING INFLAMMATORY, NEUROPATHIC, VISCERAL, AND CANCER RELATED. SUMMARY: BOTH PATIENTS AND PROVIDERS RECOGNIZE THAT NOVEL MEDICATIONS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC PAIN CONDITIONS ARE SORELY NEEDED. THE UNDERSTANDING OF EPIGENETICS AND ITS INFLUENCE ON NOCICEPTION REMAINS IN RELATIVE INFANCY BUT EARLY EVIDENCE IS STRONG FOR POTENTIAL THERAPEUTIC BENEFITS TO TREAT THESE CONDITIONS. 2018 10 6886 30 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 11 6119 24 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 12 1453 27 DISCOVERING HOW ENVIRONMENTAL EXPOSURES ALTER GENES COULD LEAD TO NEW TREATMENTS FOR CHRONIC ILLNESSES. EMERGING RESEARCH DEMONSTRATES THAT DIET, POLLUTION, AND OTHER ENVIRONMENTAL TRIGGERS CAN ALTER BOTH THE FUNCTION AND EXPRESSION OF HUMAN GENES AND LEAD TO A HEIGHTENED DISEASE RISK. THESE ENVIRONMENT-GENE INTERACTIONS CAN CAUSE SO-CALLED EPIGENETIC CHANGES IN GENE EXPRESSION-PATTERNS OF WHICH GENES ARE SWITCHED "ON" OR "OFF"-THAT MAY ACCOUNT FOR THE RISING MORTALITY FROM CHRONIC DISEASES IN INDUSTRIALIZED NATIONS. IN THIS PAPER, WE CALL FOR A NEW TRANSDISCIPLINARY APPROACH TO PUBLIC HEALTH THAT WOULD EXAMINE HOW ENVIRONMENTAL EXPOSURES, BOTH PHYSICAL AND SOCIAL, INFLUENCE GENE EXPRESSION AND A PERSON'S SUSCEPTIBILITY TO CHRONIC DISEASE. THIS INITIATIVE COULD LEAD TO NEW WAYS TO PREVENT AND TREAT SUCH ILLNESSES. 2011 13 2596 33 EPIGENETICS OF STRESS ADAPTATIONS IN THE BRAIN. RECENT FINDINGS IN EPIGENETICS SHED NEW LIGHT ON THE REGULATION OF GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM (CNS) DURING STRESS. THE MOST FREQUENTLY STUDIED EPIGENETIC MECHANISMS ARE DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNA ACTIVITY. THESE MECHANISMS STABLY DETERMINE CELL PHENOTYPE BUT CAN ALSO BE RESPONSIBLE FOR DYNAMIC MOLECULAR ADAPTATIONS OF THE CNS TO STRESSORS. THE LIMBIC-HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (LHPA) IS THE PRIMARY CIRCUIT THAT INITIATES, REGULATES AND TERMINATES A STRESS RESPONSE. THE SAME BRAIN AREAS THAT CONTROL STRESS ALSO REACT TO STRESS DYNAMICALLY AND WITH LONG-TERM CONSEQUENCES. ONE OF THE BIOLOGICAL PROCESSES EVOKING POTENT ADAPTIVE CHANGES IN THE CNS SUCH AS CHANGES IN BEHAVIOR, GENE ACTIVITY OR SYNAPTIC PLASTICITY IN THE HIPPOCAMPUS IS PSYCHOGENIC STRESS. THIS REVIEW SUMMARIZES THE CURRENT DATA REGARDING THE EPIGENETIC BASIS OF MOLECULAR ADAPTATIONS IN THE BRAIN INCLUDING GENOME-WIDE EPIGENETIC CHANGES OF DNA METHYLATION AND PARTICULAR GENES INVOLVED IN EPIGENETIC RESPONSES THAT PARTICIPATE IN THE BRAIN RESPONSE TO CHRONIC PSYCHOGENIC STRESSORS. IT IS CONCLUDED THAT SPECIFIC EPIGENETIC MECHANISMS IN THE CNS ARE INVOLVED IN THE STRESS RESPONSE. 2013 14 6755 36 WILL WIDESPREAD SYNTHETIC OPIOID CONSUMPTION INDUCE EPIGENETIC CONSEQUENCES IN FUTURE GENERATIONS? A GROWING NUMBER OF EVIDENCE DEMONSTRATES THAT ANCESTRAL EXPOSURE TO XENOBIOTICS (POLLUTANTS, DRUGS OF ABUSE, ETC.) CAN PERTURB THE PHYSIOLOGY AND BEHAVIOR OF DESCENDANTS. BOTH MATERNAL AND PATERNAL TRANSMISSION OF PHENOTYPE ACROSS GENERATIONS HAS BEEN PROVED, DEMONSTRATING THAT PARENTAL DRUG HISTORY MAY HAVE SIGNIFICANT IMPLICATIONS FOR SUBSEQUENT GENERATIONS. IN THE LAST YEARS, THE BURDEN OF NOVEL SYNTHETIC OPIOID (NSO) CONSUMPTION, DUE TO INCREASED MEDICAL PRESCRIPTION OF PAIN MEDICATIONS AND TO EASIER ACCESSIBILITY OF THESE SUBSTANCES ON ILLEGAL MARKET, IS RAISING NEW QUESTIONS FIRST IN TERM OF PUBLIC HEALTH, BUT ALSO ABOUT THE CONSEQUENCES OF THE PARENTAL USE OF THESE DRUGS ON FUTURE GENERATIONS. BESIDES BEING ASSOCIATED TO THE NEONATAL ABSTINENCE SYNDROME, IN UTERO EXPOSURE TO OPIOIDS HAS AN IMPACT ON NEURONAL DEVELOPMENT WITH LONG-TERM REPERCUSSIONS THAT ARE POTENTIALLY TRANSMITTED TO SUBSEQUENT GENERATIONS. IN ADDITION, RECENT REPORTS SUGGEST THAT OPIOID USE EVEN BEFORE CONCEPTION INFLUENCES THE REACTIVITY TO OPIOIDS OF THE PROGENY AND THE FOLLOWING GENERATIONS, LIKELY THROUGH EPIGENETIC MECHANISMS. THIS REVIEW DESCRIBES THE CURRENT KNOWLEDGE ABOUT THE TRANSGENERATIONAL EFFECTS OF OPIOID CONSUMPTION. WE SUMMARIZE THE PRECLINICAL AND CLINICAL FINDINGS SHOWING THE IMPLICATIONS FOR THE SUBSEQUENT GENERATIONS OF PARENTAL EXPOSURE TO OPIOIDS EARLIER IN LIFE. LIMITATIONS OF THE EXISTING DATA ON NSOS AND NEW PERSPECTIVES OF THE RESEARCH ARE ALSO DISCUSSED, AS WELL AS CLINICAL AND FORENSIC CONSEQUENCES. 2018 15 634 35 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 16 2520 29 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 17 1766 48 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 18 2528 27 EPIGENETICS AS A KEY LINK BETWEEN PSYCHOSOCIAL STRESS AND AGING: CONCEPTS, EVIDENCE, MECHANISMS . PSYCHOSOCIAL STRESS-ESPECIALLY WHEN CHRONIC, EXCESSIVE, OR OCCURRING EARLY IN LIFE-HAS BEEN ASSOCIATED WITH ACCELERATED AGING AND INCREASED DISEASE RISK. WITH RAPID AGING OF THE WORLD POPULATION, THE NEED TO ELUCIDATE THE UNDERLYING MECHANISMS IS PRESSING, NOW MORE SO THAN EVER. AMONG MOLECULAR MECHANISMS LINKING STRESS AND AGING, THE PRESENT ARTICLE REVIEWS EVIDENCE ON THE ROLE OF EPIGENETICS, BIOCHEMICAL PROCESSES THAT CAN BE SET INTO MOTION BY STRESSORS AND IN TURN INFLUENCE GENOMIC FUNCTION AND COMPLEX PHENOTYPES, INCLUDING AGING-RELATED OUTCOMES. THE ARTICLE FURTHER PROVIDES A CONCEPTUAL MECHANISTIC FRAMEWORK ON HOW STRESS MAY DRIVE EPIGENETIC CHANGES AT SUSCEPTIBLE GENOMIC SITES, THEREBY EXERTING SYSTEMS-LEVEL EFFECTS ON THE AGING EPIGENOME WHILE ALSO REGULATING THE EXPRESSION OF MOLECULES IMPLICATED IN AGING-RELATED PROCESSES. THIS EMERGING EVIDENCE, TOGETHER WITH WORK EXAMINING RELATED BIOLOGICAL PROCESSES, BEGINS TO SHED LIGHT ON THE EPIGENETIC AND, MORE BROADLY, MOLECULAR UNDERPINNINGS OF THE LONG-HYPOTHESIZED CONNECTION BETWEEN STRESS AND AGING. . 2019 19 6063 32 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 20 2049 25 EPIGENETIC CODE AND POTENTIAL EPIGENETIC-BASED THERAPIES AGAINST CHRONIC DISEASES IN DEVELOPMENTAL ORIGINS. ACCUMULATED FINDINGS HAVE DEMONSTRATED THAT THE EPIGENETIC CODE PROVIDES A POTENTIAL LINK BETWEEN PRENATAL STRESS AND CHANGES IN GENE EXPRESSION THAT COULD BE INVOLVED IN THE DEVELOPMENTAL PROGRAMMING OF VARIOUS CHRONIC DISEASES IN LATER LIFE. MEANWHILE, BASED ON THE FACT THAT EPIGENETIC MODIFICATIONS ARE REVERSIBLE AND CAN BE MANIPULATED, THIS PROVIDES A UNIQUE CHANCE TO DEVELOP MULTIPLE NOVEL EPIGENETIC-BASED THERAPEUTIC STRATEGIES AGAINST MANY CHRONIC DISEASES IN EARLY DEVELOPMENTAL PERIODS. THIS ARTICLE WILL GIVE A SHORT REVIEW OF RECENT FINDINGS OF PRENATAL INSULT-INDUCED EPIGENETIC CHANGES IN DEVELOPMENTAL ORIGINS OF SEVERAL CHRONIC DISEASES, AND WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE CURRENT EPIGENETIC-BASED STRATEGIES APPLIED IN THE EARLY PREVENTION, DIAGNOSIS AND POSSIBLE THERAPIES FOR HUMAN CHRONIC DISEASES. 2014