1 4655 125 NEUROTROPHIN MEDIATED HPA AXIS DYSREGULATION IN STRESS INDUCED GENESIS OF PSYCHIATRIC DISORDERS: ORCHESTRATION BY EPIGENETIC MODIFICATIONS. APART FROM THEIR ESTABLISHED ROLE IN EMBRYONIC DEVELOPMENT, NEUROTROPHINS (NTS) HAVE DIVERSE FUNCTIONS IN THE NERVOUS SYSTEM. THEIR ROLE IN THE INTEGRATION OF PHYSIOLOGICAL AND BIOCHEMICAL ASPECTS OF THE NERVOUS SYSTEM IS CURRENTLY ATTRACTING MUCH ATTENTION. BASED ON A SYSTEMATIC ANALYSIS OF THE LITERATURE, WE HERE PROPOSE A NEW PARADIGM THAT, BY EXPLOITING A NOVEL ROLE OF NTS, MAY HELP EXPLAIN THE GENESIS OF STRESS-RELATED PSYCHIATRIC DISORDERS, OPENING NEW AVENUES FOR BETTER MANAGEMENT OF THE SAME. WE HYPOTHESIZE THAT NTS AS AN INTEGRATED NETWORK PLAY A CRUCIAL ROLE IN MAINTAINING AN INDIVDUAL'S PSYCHOLOGICAL WELLBEING. GIVEN THE EVIDENCE THAT STRESS CAN INDUCE CHRONIC DISRUPTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS WHICH, IN TURN, IS CAUSALLY LINKED TO SEVERAL PSYCHIATRIC DISORDERS, THIS FUNCTION MAY BE MEDIATED THROUGH THE HOMEOSTATIC MECHANISMS GOVERNING REGULATION OF THIS AXIS. IN FACT, NTS, SUCH AS NERVE GROWTH FACTOR (NGF) AND BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) ARE KNOWN TO PARTICIPATE IN NEUROENDOCRINE REGULATION. RECENT STUDIES SUGGEST EPIGENETIC MODIFICATION OF NT-HPA AXIS INTERPLAY IN THE PRECIPITATION OF PSYCHIATRIC DISORDERS. OUR ARTICLE HIGHLIGHTS WHY THIS NEW KNOWLEDGE REGARDING NTS SHOULD BE CONSIDERED IN THE ETIOGENESIS AND TREATMENT OF STRESS-INDUCED PSYCHOPATHOLOGY. 2019 2 5810 34 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 1364 41 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 4 2596 31 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 5 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 6 5829 27 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 7 678 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 8 6097 18 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 1639 33 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 10 1199 32 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 11 291 31 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 12 2913 28 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 13 2269 45 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 2386 29 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 15 6228 26 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 6846 33 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 17 2235 32 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 18 534 34 ASTROGLIA IN THE VULNERABILITY TO AND MAINTENANCE OF STRESS-MEDIATED NEUROPATHOLOGY AND DEPRESSION. SIGNIFICANT STRESS EXPOSURE AND PSYCHIATRIC DEPRESSION ARE ASSOCIATED WITH MORPHOLOGICAL, BIOCHEMICAL, AND PHYSIOLOGICAL DISTURBANCES OF ASTROCYTES IN SPECIFIC BRAIN REGIONS RELEVANT TO THE PATHOPHYSIOLOGY OF THOSE DISORDERS, SUGGESTING THAT ASTROCYTES ARE INVOLVED IN THE MECHANISMS UNDERLYING THE VULNERABILITY TO OR MAINTENANCE OF STRESS-RELATED NEUROPATHOLOGY AND DEPRESSION. TO UNDERSTAND THOSE MECHANISMS A VARIETY OF STUDIES HAVE PROBED THE EFFECT OF VARIOUS MODALITIES OF STRESS EXPOSURE ON THE METABOLISM, GENE EXPRESSION AND PLASTICITY OF ASTROCYTES. THESE STUDIES HAVE UNCOVERED THE PARTICIPATION OF VARIOUS CELLULAR PATHWAYS, SUCH AS THOSE FOR INTRACELLULAR CALCIUM REGULATION, NEUROIMMUNE RESPONSES, EXTRACELLULAR IONIC REGULATION, GAP JUNCTIONS-BASED CELLULAR COMMUNICATION, AND REGULATION OF NEUROTRANSMITTER AND GLIOTRANSMITTER RELEASE AND UPTAKE. MORE RECENTLY EPIGENETIC MODIFICATIONS RESULTING FROM EXPOSURE TO CHRONIC FORMS OF STRESS OR TO EARLY LIFE ADVERSITY HAVE BEEN SUGGESTED TO AFFECT NOT ONLY NEURONAL MECHANISMS BUT ALSO GENE EXPRESSION AND PHYSIOLOGY OF ASTROCYTES AND OTHER GLIAL CELLS. HOWEVER, MUCH REMAINS TO BE LEARNED TO UNDERSTAND THE SPECIFIC ROLE OF THOSE AND OTHER MODIFICATIONS IN THE ASTROGLIAL CONTRIBUTION TO THE VULNERABILITY TO AND MAINTENANCE OF STRESS-RELATED DISORDERS AND DEPRESSION, AND FOR LEVERAGING THAT KNOWLEDGE TO ACHIEVE MORE EFFECTIVE PSYCHIATRIC THERAPIES. 2022 19 3708 26 INFLUENCE OF PHARMACOLOGICAL AND EPIGENETIC FACTORS TO SUPPRESS NEUROTROPHIC FACTORS AND ENHANCE NEURAL PLASTICITY IN STRESS AND MOOD DISORDERS. STRESS-INDUCED MAJOR DEPRESSION AND MOOD DISORDERS ARE CHARACTERIZED BY BEHAVIOURAL ABNORMALITIES AND PSYCHIATRIC ILLNESS, LEADING TO DISABILITY AND IMMATURE MORTALITY WORLDWIDE. NEUROBIOLOGICAL MECHANISMS OF STRESS AND MOOD DISORDERS ARE DISCUSSED CONSIDERING RECENT FINDINGS, AND CHALLENGES TO ENHANCE PHARMACOLOGICAL EFFECTS OF ANTIDEPRESSANT, AND MOOD STABILIZERS. PHARMACOLOGICAL ENHANCEMENT OF KETAMINE AND SCOPOLAMINE REGULATES DEPRESSION AT THE MOLECULAR LEVEL, INCREASING SYNAPTIC PLASTICITY IN PREFRONTAL REGIONS. BLOOD-DERIVED NEUROTROPHIC FACTORS FACILITATE MOOD-DEFICIT SYMPTOMS. EPIGENETIC FACTORS MAINTAIN STRESS-RESILIENCE IN HIPPOCAMPAL REGION. REGULATION OF NEUROTROPHIC FACTORS BLOCKADES STRESS, AND ENHANCES NEURONAL SURVIVAL THOUGH IT PARALYZES LIMBIC REGIONS. MOLECULAR AGENTS AND NEUROTROPHIC FACTORS ALSO CONTROL BEHAVIORAL AND SYNAPTIC PLASTICITY IN ADDICTION AND STRESS DISORDERS. FUTURE RESEARCH ON NEURONAL DYNAMICS AND CELLULAR ACTIONS CAN BE DIRECTED TO OBTAIN THE ETIOLOGY OF SYNAPTIC DYSREGULATION IN MOOD DISORDER AND STRESS. FOR THE FIRST TIME, THE CURRENT REVIEW CONTRIBUTES TO THE LITERATURE OF SYNAPTIC PLASTICITY REPRESENTING THE ROLE OF EPIGENETIC MECHANISMS AND GLUCOCORTICOID RECEPTORS TO PREDICT DEPRESSION AND ANXIETY IN CLINICAL CONDITIONS. 2019 20 4648 36 NEUROPEPTIDE Y IN ALCOHOL ADDICTION AND AFFECTIVE DISORDERS. NEUROPEPTIDE Y (NPY), A NEUROPEPTIDE HIGHLY CONSERVED THROUGHOUT EVOLUTION, IS PRESENT AT HIGH LEVELS IN THE CENTRAL NERVOUS SYSTEM (CNS), AS WELL AS IN PERIPHERAL TISSUES SUCH AS THE GUT AND CARDIOVASCULAR SYSTEM. THE PEPTIDE EXERTS ITS EFFECTS VIA MULTIPLE RECEPTOR SUBTYPES, ALL BELONGING TO THE G-PROTEIN-COUPLED RECEPTOR SUPERFAMILY. OF THESE SUBTYPES, THE Y1 AND THE Y2 ARE THE MOST THOROUGHLY CHARACTERIZED, FOLLOWED BY THE Y5 SUBTYPE. NPY AND ITS RECEPTORS HAVE BEEN SHOWN TO BE OF IMPORTANCE IN CENTRAL REGULATION OF EVENTS UNDERLYING, FOR EXAMPLE, AFFECTIVE DISORDERS, DRUG/ALCOHOL USE DISORDERS, AND ENERGY HOMEOSTASIS. FURTHERMORE, WITHIN THE CNS, NPY ALSO AFFECTS SLEEP REGULATION AND CIRCADIAN RHYTHM, MEMORY FUNCTION, TISSUE GROWTH, AND PLASTICITY. THE POTENTIAL ROLES OF NPY IN THE ETIOLOGY AND PATHOPHYSIOLOGY OF MOOD AND ANXIETY DISORDERS, AS WELL AS ALCOHOL USE DISORDERS, HAVE BEEN EXTENSIVELY STUDIED. THIS FOCUS WAS PROMPTED BY EARLY INDICATIONS FOR AN INVOLVEMENT OF NPY IN ACUTE RESPONSES TO STRESS, AND, LATER, ALSO DATA POINTING TO A ROLE IN ALTERATIONS WITHIN THE CNS DURING CHRONIC, OR REPEATED, EXPOSURE TO ADVERSE EVENTS. THESE FUNCTIONS OF NPY, IN ADDITION TO THE PEPTIDE'S REGULATION OF DISEASE STATES, SUGGEST THAT MODULATION OF THE ACTIVITY OF THE NPY SYSTEM VIA RECEPTOR AGONISTS/ANTAGONISTS MAY BE A PUTATIVE TREATMENT MECHANISM IN AFFECTIVE DISORDERS AS WELL AS ALCOHOL USE DISORDERS. IN THIS REVIEW, WE PRESENT AN OVERVIEW OF FINDINGS WITH REGARD TO THE NPY SYSTEM IN RELATION TO ANXIETY AND STRESS, ACUTE AS WELL AS CHRONIC; FURTHERMORE WE DISCUSS POST-TRAUMATIC STRESS DISORDER AND, IN PART DEPRESSION. IN ADDITION, WE SUMMARIZE FINDINGS ON ALCOHOL USE DISORDERS AND RELATED BEHAVIORS. FINALLY, WE BRIEFLY TOUCH UPON GENETIC AS WELL AS EPIGENETIC MECHANISMS THAT MAY BE OF IMPORTANCE FOR NPY FUNCTION AND REGULATION. IN CONCLUSION, WE SUGGEST THAT MODULATION OF NPY-ERGIC ACTIVITY WITHIN THE CNS, VIA LIGANDS AIMED AT DIFFERENT RECEPTOR SUBTYPES, MAY BE ATTRACTIVE TARGETS FOR TREATMENT DEVELOPMENT FOR AFFECTIVE DISORDERS, AS WELL AS FOR ALCOHOL USE DISORDERS. 2017