1 5073 101 PHYSICAL EXERCISE PREVENTED STRESS-INDUCED ANXIETY VIA IMPROVING BRAIN RNA METHYLATION. PHYSICAL EXERCISE IS EFFECTIVE IN ALLEVIATING MENTAL DISORDERS BY IMPROVING SYNAPTIC TRANSMISSION; HOWEVER, THE LINK BETWEEN BODY ENDURANCE TRAINING AND NEURAL ADAPTATION HAS NOT YET BEEN COMPLETELY RESOLVED. IN THIS STUDY, THE AUTHORS INVESTIGATED THE ROLE OF RNA N(6) -METHYLADENOSINE (M6A), AN EMERGING EPIGENETIC MECHANISM, IN IMPROVED RESILIENCE AGAINST CHRONIC RESTRAINT STRESS. A COMBINATION OF MOLECULAR, BEHAVIORAL, AND IN VIVO RECORDING DATA DEMONSTRATES EXERCISE-MEDIATED RESTORATION OF M6A IN THE MOUSE MEDIAL PREFRONTAL CORTEX, WHOSE ACTIVITY IS POTENTIATED TO EXERT ANXIOLYTIC EFFECTS. FURTHERMORE, IT IS REVEALED THAT HEPATIC BIOSYNTHESIS OF ONE METHYL DONOR IS NECESSARY FOR EXERCISE TO IMPROVE BRAIN RNA M6A TO COUNTERACT ENVIRONMENTAL STRESS. THIS NOVEL LIVER-BRAIN AXIS PROVIDES AN EXPLANATION FOR BRAIN NETWORK CHANGES UPON EXERCISE TRAINING AND PROVIDES NEW INSIGHTS INTO THE DIAGNOSIS AND TREATMENT OF ANXIETY DISORDERS. 2022 2 2598 24 EPIGENETICS OF THE DEPRESSED BRAIN: ROLE OF HISTONE ACETYLATION AND METHYLATION. MAJOR DEPRESSIVE DISORDER IS A CHRONIC, REMITTING SYNDROME INVOLVING WIDELY DISTRIBUTED CIRCUITS IN THE BRAIN. STABLE ALTERATIONS IN GENE EXPRESSION THAT CONTRIBUTE TO STRUCTURAL AND FUNCTIONAL CHANGES IN MULTIPLE BRAIN REGIONS ARE IMPLICATED IN THE HETEROGENEITY AND PATHOGENESIS OF THE ILLNESS. EPIGENETIC EVENTS THAT ALTER CHROMATIN STRUCTURE TO REGULATE PROGRAMS OF GENE EXPRESSION HAVE BEEN ASSOCIATED WITH DEPRESSION-RELATED BEHAVIOR, ANTIDEPRESSANT ACTION, AND RESISTANCE TO DEPRESSION OR 'RESILIENCE' IN ANIMAL MODELS, WITH INCREASING EVIDENCE FOR SIMILAR MECHANISMS OCCURRING IN POSTMORTEM BRAINS OF DEPRESSED HUMANS. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETIC CONTRIBUTIONS TO DEPRESSION, IN PARTICULAR THE ROLE OF HISTONE ACETYLATION AND METHYLATION, WHICH ARE REVEALING NOVEL MECHANISTIC INSIGHT INTO THE SYNDROME THAT MAY AID IN THE DEVELOPMENT OF NOVEL TARGETS FOR DEPRESSION TREATMENT. 2013 3 4642 30 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 4 5828 22 STRESS, EPIGENETICS, AND ALCOHOLISM. ACUTE AND CHRONIC STRESSORS HAVE BEEN ASSOCIATED WITH ALTERATIONS IN MOOD AND INCREASED ANXIETY THAT MAY EVENTUALLY RESULT IN THE DEVELOPMENT OF STRESS-RELATED PSYCHIATRIC DISORDERS. STRESS AND ASSOCIATED DISORDERS, INCLUDING ANXIETY, ARE KEY FACTORS IN THE DEVELOPMENT OF ALCOHOLISM BECAUSE ALCOHOL CONSUMPTION CAN TEMPORARILY REDUCE THE DRINKER'S DYSPHORIA. ONE MOLECULE THAT MAY HELP MEDIATE THE RELATIONSHIP BETWEEN STRESS AND ALCOHOL CONSUMPTION IS BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), A PROTEIN THAT REGULATES THE STRUCTURE AND FUNCTION OF THE SITES WHERE TWO NERVE CELLS INTERACT AND EXCHANGE NERVE SIGNALS (I.E., SYNAPSES) AND WHICH IS INVOLVED IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABERRANT REGULATION OF BDNF SIGNALING AND ALTERATIONS IN SYNAPSE ACTIVITY (I.E., SYNAPTIC PLASTICITY) HAVE BEEN ASSOCIATED WITH THE PATHOPHYSIOLOGY OF STRESS-RELATED DISORDERS AND ALCOHOLISM. MECHANISMS THAT CONTRIBUTE TO THE REGULATION OF GENETIC INFORMATION WITHOUT MODIFICATION OF THE DNA SEQUENCE (I.E., EPIGENETIC MECHANISMS) MAY PLAY A ROLE IN THE COMPLEX CONTROL OF BDNF SIGNALING AND SYNAPTIC PLASTICITY-FOR EXAMPLE, BY MODIFYING THE STRUCTURE OF THE DNA-PROTEIN COMPLEXES (I.E., CHROMATIN) THAT MAKE UP THE CHROMOSOMES AND THEREBY MODULATING THE EXPRESSION OF CERTAIN GENES. STUDIES REGARDING THE EPIGENETIC CONTROL OF BDNF SIGNALING AND SYNAPTIC PLASTICITY PROVIDE A PROMISING DIRECTION TO UNDERSTAND THE MECHANISMS MEDIATING THE INTERACTION BETWEEN STRESS AND ALCOHOLISM. 2012 5 110 22 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 6 6174 34 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 7 2235 25 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 8 584 31 BEHAVIORAL NEUROADAPTATION TO ALCOHOL: FROM GLUCOCORTICOIDS TO HISTONE ACETYLATION. A PRIME MECHANISM THAT CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF ALCOHOLISM IS THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVITY AND THE RELEASE OF GLUCOCORTICOIDS (CORTISOL IN HUMANS AND PRIMATES, CORTICOSTERONE IN RODENTS) FROM THE ADRENAL GLANDS. IN THE BRAIN, SUSTAINED, LOCAL ELEVATION OF GLUCOCORTICOID CONCENTRATION EVEN LONG AFTER CESSATION OF CHRONIC ALCOHOL CONSUMPTION COMPROMISES FUNCTIONAL INTEGRITY OF A CIRCUIT, INCLUDING THE PREFRONTAL CORTEX (PFC), THE HIPPOCAMPUS (HPC), AND THE AMYGDALA (AMG). THESE STRUCTURES ARE IMPLICATED IN LEARNING AND MEMORY PROCESSES AS WELL AS IN ORCHESTRATING NEUROADAPTIVE RESPONSES TO STRESS AND ANXIETY RESPONSES. THUS, POTENTIATION OF ANXIETY-RELATED NEUROADAPTATION BY ALCOHOL IS CHARACTERIZED BY AN ABNORMALLY AMG HYPERACTIVITY COUPLED WITH A HYPOFUNCTION OF THE PFC AND THE HPC. THIS REVIEW DESCRIBES RESEARCH ON MOLECULAR AND EPIGENETIC MECHANISMS BY WHICH ALCOHOL CAUSES DISTINCT REGION-SPECIFIC ADAPTIVE CHANGES IN GENE EXPRESSION PATTERNS AND ULTIMATELY LEADS TO A VARIETY OF COGNITIVE AND BEHAVIORAL IMPAIRMENTS ON PREFRONTAL- AND HIPPOCAMPAL-BASED TASKS. ALCOHOL-INDUCED NEUROADAPTATIONS INVOLVE THE DYSREGULATION OF NUMEROUS SIGNALING CASCADES, LEADING TO LONG-TERM CHANGES IN TRANSCRIPTIONAL PROFILES OF GENES, THROUGH THE ACTIONS OF TRANSCRIPTION FACTORS SUCH AS [CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB)] AND CHROMATIN REMODELING DUE TO POSTTRANSLATIONAL MODIFICATIONS OF HISTONE PROTEINS. WE DESCRIBE THE ROLE OF PREFRONTAL-HPC-AMG CIRCUIT IN MEDIATING THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL ON LEARNING AND MEMORY, AND REGION-SPECIFIC MOLECULAR AND EPIGENETIC MECHANISMS INVOLVED IN THIS PROCESS. THIS REVIEW FIRST DISCUSSES THE IMPORTANCE OF BRAIN REGION-SPECIFIC DYSREGULATION OF GLUCOCORTICOID CONCENTRATION IN THE DEVELOPMENT OF ALCOHOL DEPENDENCE AND DESCRIBES HOW PERSISTENTLY INCREASED GLUCOCORTICOID LEVELS IN PFC MAY BE INVOLVED IN MEDIATING WORKING MEMORY IMPAIRMENTS AND NEUROADAPTIVE CHANGES DURING WITHDRAWAL FROM CHRONIC ALCOHOL INTAKE. IT THEN HIGHLIGHTS THE ROLE OF CAMP-PKA-CREB SIGNALING CASCADE AND HISTONE ACETYLATION WITHIN THE PFC AND LIMBIC STRUCTURES IN ALCOHOL-INDUCED ANXIETY AND BEHAVIORAL IMPAIRMENTS, AND HOW AN UNDERSTANDING OF FUNCTIONAL ALTERATIONS OF THESE PATHWAYS MIGHT LEAD TO BETTER TREATMENTS FOR NEUROPSYCHIATRIC DISORDERS. 2016 9 6400 22 THE ROLES OF CLASS I HISTONE DEACETYLASES (HDACS) IN MEMORY, LEARNING, AND EXECUTIVE COGNITIVE FUNCTIONS: A REVIEW. COORDINATED CHANGES IN GENE EXPRESSION ARE CRITICAL FOR SYNAPTIC PLASTICITY SUPPORTING LEARNING, MEMORY, AND OPTIMAL COGNITIVE TASK PERFORMANCE. THESE GENE EXPRESSION CHANGES ARE NOT ONLY MEDIATED BY SIGNALING PATHWAYS THAT ACTIVATE TRANSCRIPTION FACTORS, BUT ALSO BY CHROMATIN MODIFICATIONS THAT INFLUENCE THE ACCESSIBILITY OF THE TRANSCRIPTIONAL MACHINERY TO SPECIFIC GENOMIC REGIONS. DURING THE PAST DECADE, EVIDENCE ACCUMULATED THAT ALTERATIONS IN CHROMATIN-BASED EPIGENETIC REGULATION OF GENE EXPRESSION ARE LINKED TO COGNITIVE DYSFUNCTIONS IN THE AGEING OR NEURODEGENERATING BRAIN AS WELL AS TO COGNITIVE DYSFUNCTIONS RESULTING FROM CHRONIC STRESS EXPOSURE. THIS REVIEW SUMMARIZES THE RESULTS OF STUDIES THAT UNRAVELED A ROLE OF HISTONE MODIFYING ENZYMES AND HISTONE MODIFICATIONS IN NORMAL AND IMPAIRED LEARNING AND MEMORY, AND IN THE DISRUPTION OF EXECUTIVE COGNITIVE TASK PERFORMANCE. IT EMPHASIZES THE DIFFERENT ROLES OF SPECIFIC CLASS I HISTONE DEACETYLASES (HDACS) IN COGNITIVE PROCESSES GOVERNED BY THE HIPPOCAMPUS AND PREFRONTAL CORTEX AND DISCUSSES THE POTENTIAL THERAPEUTIC IMPLICATIONS OF TARGETING THEM TO HOLD THE PROGRESSION OF DISEASE-RELATED COGNITIVE DYSFUNCTIONS. 2017 10 1981 24 EPIGENETIC ALTERATIONS IN DNA AND HISTONE MODIFICATIONS CAUSED BY DEPRESSION AND ANTIDEPRESSANT DRUGS: LESSONS FROM THE RODENT MODELS. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN FOLDING AND FUNCTION. EPIGENETIC MECHANISMS REGULATE TRANSCRIPTION MEDIATING EFFECTS OF VARIOUS STIMULI ON GENE EXPRESSION. THESE MECHANISMS ARE INVOLVED IN TRANSCRIPTIONAL CONTROL IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS INCLUDING NEUROPSYCHIATRIC DISORDERS AND BEHAVIORAL ABNORMALITIES SUCH AS DEPRESSION. IN RODENTS, EXPOSURE TO CHRONIC SOCIAL STRESS WAS SHOWN TO INDUCE BEHAVIORAL IMPAIRMENTS AND MEMORY/LEARNING DEFICITS THAT RESEMBLE DEPRESSIVE-LIKE PHENOTYPE IN HUMANS. THE RODENT MODELS OF CHRONIC STRESS WERE WIDELY USED TO STUDY MOLECULAR MECHANISMS OF DEPRESSION. IN THESE MODELS, EARLY EXPOSURE TO CHRONIC STRESS SUCH AS PRENATAL OR POSTNATAL STRESS INDUCES LONG-TERM HYPERACTIVE STRESS RESPONSES, BEHAVIORAL ABNORMALITIES, AND FUNCTIONAL IMPAIRMENTS IN BRAIN FUNCTION THAT PERSIST IN ADULTHOOD. FURTHERMORE, THESE ALTERATIONS CAN BE TRANSMITTED TO OFFSPRING OF CHRONICALLY STRESSED ANIMALS ACROSS SEVERAL GENERATIONS. MOLECULAR STUDIES IN ANIMAL MODELS SHOWED THAT CHRONIC STRESS INDUCES STABLE EPIGENETIC CHANGES IN SPECIFIC BRAIN REGIONS, PRIMARILY IN THE LIMBIC SYSTEM. THESE CHANGES LEAD TO LONG-LASTING ABNORMALITIES IN BEHAVIOR THAT PERSIST IN ADULTHOOD AND CAN BE TRANSMITTED TO OFFSPRING. TREATMENT WITH EPIGENETICALLY ACTIVE ANTIDEPRESSANTS DISRUPTS THE ABNORMAL STRESS-INDUCED EPIGENETIC PROGRAMMING AND PROVIDES EPIGENETIC PATTERNS THAT RESEMBLE EPIGENETIC BACKGROUND OF STRESS RESILIENT INDIVIDUALS. 2017 11 291 33 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 2252 24 EPIGENETIC MODULATION OF VISCERAL NOCICEPTION. EPIGENETICS IS A PROCESS THAT ALTERS GENE ACTIVITY OR PHENOTYPE WITHOUT ANY CHANGES IN THE UNDERLYING DNA SEQUENCE OR GENOTYPE. THESE BIOLOGICAL CHANGES MAY HAVE DELETERIOUS EFFECTS AND CAN LEAD TO VARIOUS HUMAN DISEASES. ONGOING RESEARCH IS CONTINUING TO ILLUMINATE THE ROLE OF EPIGENETICS IN A VARIETY OF PATHOPHYSIOLOGIC PROCESSES. SEVERAL CATEGORIES OF EPIGENETIC MECHANISMS HAVE BEEN STUDIED INCLUDING CHROMATIN REMODELING, DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MECHANISMS. THESE EPIGENETIC CHANGES CAN HAVE A LONG-TERM EFFECT ON GENE EXPRESSION WITHOUT ANY UNDERLYING CHANGES IN THE DNA SEQUENCES. THE UNDERLYING PATHOPHYSIOLOGY OF DISORDERS OF BRAIN-GUT INTERACTION AND STRESS-INDUCED VISCERAL PAIN ARE NOT FULLY UNDERSTOOD AND THE ROLE OF EPIGENETIC MECHANISMS IN THESE DISORDERS ARE STARTING TO BE BETTER UNDERSTOOD. CURRENT WORK IS UNDERWAY TO DETERMINE HOW EPIGENETICS PLAYS A ROLE IN THE NEUROBIOLOGY OF PATIENTS WITH CHRONIC VISCERAL PAIN AND HEIGHTENED VISCERAL NOCICEPTION. MORE RECENTLY, BOTH ANIMAL MODELS AND HUMAN STUDIES HAVE SHOWN HOW EPIGENETIC REGULATION MODULATES STRESS-INDUCED VISCERAL PAIN. WHILE MUCH MORE WORK IS NEEDED TO FULLY DELINEATE THE MECHANISTIC ROLE OF EPIGENETICS IN THE NEUROBIOLOGY OF CHRONIC VISCERAL NOCICEPTION, THE CURRENT STUDY BY LOUWIES ET AL., IN NEUROGASTROENTEROLOGY AND MOTILITY PROVIDES ADDITIONAL EVIDENCE SUPPORTING THE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN RODENTS. 2022 13 4578 33 N(6) -METHYLADENOSINE MODIFICATION IN CHRONIC STRESS RESPONSE DUE TO SOCIAL HIERARCHY POSITIONING OF MICE. APPROPRIATELY RESPONDING TO STRESSFUL EVENTS IS ESSENTIAL FOR MAINTAINING HEALTH AND WELL-BEING OF ANY ORGANISM. CONCERNING SOCIAL STRESS, THE RESPONSE IS NOT ALWAYS AS STRAIGHTFORWARD AS REACTING TO PHYSICAL STRESSORS, E.G., EXTREME HEAT, AND THUS HAS TO BE BALANCED SUBTLY. PARTICULARLY, REGULATORY MECHANISMS CONTRIBUTING TO GAINING RESILIENCE IN THE FACE OF MILD SOCIAL STRESS ARE NOT FULLY DECIPHERED YET. WE EMPLOYED AN INTRINSIC SOCIAL HIERARCHY STRESS PARADIGM IN MICE OF BOTH SEXES TO IDENTIFY CRITICAL FACTORS FOR POTENTIAL COPING STRATEGIES. WHILE GLOBAL TRANSCRIPTOMIC CHANGES COULD NOT BE OBSERVED IN MALE MICE, SEVERAL GENES PREVIOUSLY REPORTED TO BE INVOLVED IN SYNAPTIC PLASTICITY, LEARNING, AND ANXIETY-LIKE BEHAVIOR WERE DIFFERENTIALLY REGULATED IN FEMALE MICE. MOREOVER, CHANGES IN N(6)-METHYLADENOSINE (M(6)A)-MODIFICATION OF MRNA OCCURRED ASSOCIATED WITH CORTICOSTERONE LEVEL IN BOTH SEXES WITH, E.G., INCREASED GLOBAL AMOUNT IN SUBMISSIVE FEMALE MICE. IN ACCORDANCE WITH THIS, METTL14 AND WTAP, SUBUNITS OF THE METHYLTRANSFERASE COMPLEX, SHOWED ELEVATED LEVELS IN SUBMISSIVE FEMALE MICE. N(6)-ADENOSYL-METHYLATION IS THE MOST PROMINENT TYPE OF MRNA METHYLATION AND PLAYS A CRUCIAL ROLE IN PROCESSES SUCH AS METABOLISM, BUT ALSO RESPONSE TO PHYSICAL STRESS. OUR FINDINGS UNDERPIN ITS ESSENTIAL ROLE BY ALSO PROVIDING A LINK TO SOCIAL STRESS EVOKED BY HIERARCHY BUILDING WITHIN SAME-SEX GROUPS. AS RECENTLY, SEARCH FOR SMALL MOLECULE MODIFIERS FOR THE RESPECTIVE CLASS OF RNA MODIFYING ENZYMES HAS STARTED, THIS MIGHT EVEN LEAD TO NEW THERAPEUTIC APPROACHES AGAINST STRESS DISORDERS. 2021 14 6097 17 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 15 5645 23 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 16 2058 20 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE ALCOHOLIC BRAIN. CHRONIC ALCOHOL EXPOSURE CAUSES WIDESPREAD CHANGES IN BRAIN GENE EXPRESSION IN HUMANS AND ANIMAL MODELS. MANY OF THESE CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THERE IS AN EMERGING APPRECIATION FOR THE ROLE OF EPIGENETIC PROCESSES IN ALCOHOL-INDUCED CHANGES IN BRAIN GENE EXPRESSION AND BEHAVIOR. FOR EXAMPLE, CHRONIC ALCOHOL EXPOSURE PRODUCES CHANGES IN DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION THAT AFFECT EXPRESSION OF MULTIPLE GENES IN VARIOUS TYPES OF BRAIN CELLS (I.E., NEURONS AND GLIA) AND CONTRIBUTE TO BRAIN PATHOLOGY AND BRAIN PLASTICITY ASSOCIATED WITH ALCOHOL ABUSE AND DEPENDENCE. DRUGS TARGETING THE EPIGENETIC "MASTER REGULATORS" ARE EMERGING AS POTENTIAL THERAPEUTICS FOR NEURODEGENERATIVE DISORDERS AND DRUG ADDICTION. 2013 17 2013 29 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 18 5467 29 RESILIENT PHENOTYPE IN CHRONIC MILD STRESS PARADIGM IS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF MIR-18A-5P AND SEROTONIN 5-HT(1A) RECEPTOR IN DORSAL PART OF THE HIPPOCAMPUS. DISTURBED SEROTONERGIC SIGNALING IN THE HIPPOCAMPUS OBSERVED IN MANY INDIVIDUALS VULNERABLE TO STRESS HAS BEEN SUGGESTED AS ONE OF THE PRIMARY FACTORS CONTRIBUTING TO THE DEVELOPMENT OF DEPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PHYSIOLOGY OF THE BRAIN IN THE RESILIENT PHENOTYPE. RESILIENT SUBJECTS MAINTAIN A POSITIVE MOOD AND PSYCHOLOGICAL BALANCE DESPITE BEING UNDER THE STRESS INFLUENCE. IN OUR STUDY, WE GENERATED STRESS-VULNERABLE AND RESILIENT RATS BY USING A CHRONIC MILD STRESS (CMS) PARADIGM. USING DIFFERENT MOLECULAR APPROACHES, WE REVEALED THAT RESILIENT ANIMALS EXHIBITED A SIGNIFICANTLY DECREASED EXPRESSION LEVEL OF MIR-18A-5P AND, IN THE SAME TIME, AN ELEVATED LEVEL OF 5-HT1AR IN DORSAL, BUT NOT VENTRAL, PART OF THE HIPPOCAMPUS. DESCRIBED BIOCHEMICAL CHANGES WERE NOT OBSERVED IN ANIMALS BEHAVIORALLY VULNERABLE TO STRESS. FURTHER, IN VITRO ANALYSIS SHOWED THAT MIR-18A-5P MAY BE A NEGATIVE EPIGENETIC REGULATOR OF 5-HT1AR SINCE THE TREATMENT OF ADULT HIPPOCAMPAL NEURONS WITH MIR-18A-5P MIMIC SIGNIFICANTLY LOWERED THE EXPRESSION LEVEL OF MRNA ENCODING 5-HT1AR. MOREOVER, BIOINFORMATIC ANALYSIS OF POTENTIAL TARGET GENES EXPRESSED IN THE HIPPOCAMPUS AND BEING REGULATED BY MIR-18A-5P SHOWED THAT THIS MICRORNA MAY REGULATE BIOLOGICAL PROCESSES, SUCH AS AXONOGENESIS, WHICH ARE IMPORTANT IN THE FUNCTIONING OF THE HIPPOCAMPUS IN BOTH RATS AND HUMANS. ALL THESE MOLECULAR FEATURES MAY CONTRIBUTE TO SEROTONERGIC HOMEOSTATIC BALANCE AT THE LEVEL OF SEROTONIN TURNOVER OBSERVED IN HIPPOCAMPI OF RESILIENT BUT NOT STRESS-VULNERABLE RATS. DELINEATION OF FURTHER MOLECULAR AND BIOCHEMICAL MARKERS UNDERLYING RESILIENCE TO STRESS MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW ANTIDEPRESSANT STRATEGIES WHICH WILL RESTORE RESILIENT PHENOTYPE IN DEPRESSED PATIENTS. 2019 19 1181 19 CONVERGENT ACTIONS OF STRESS AND STIMULANTS VIA EPIGENETIC REGULATION OF NEURAL CIRCUITRY. THE DORSAL STRIATUM INTEGRATES PRIOR AND CURRENT INFORMATION TO GUIDE APPROPRIATE DECISION-MAKING. CHRONIC STRESS AND STIMULANT EXPOSURE INTERFERES WITH DECISION-MAKING, AND CAN CONFER SIMILAR COGNITIVE AND BEHAVIORAL INFLEXIBILITIES. THIS REVIEW EXAMINES THE LITERATURE ON ACUTE AND CHRONIC REGULATION OF THE EPIGENOME BY STRESS AND STIMULANTS. RECENT EVIDENCE SUGGESTS THAT EXPOSURES TO STRESS AND STIMULANTS SHARE SIMILARITIES IN THE MANNERS IN WHICH THEY REGULATE THE DORSAL STRIATUM EPIGENOME THROUGH DNA METHYLATION, TRANSPOSABLE ELEMENT ACTIVITY, AND HISTONE POST-TRANSLATIONAL MODIFICATIONS. THESE FINDINGS SUGGEST THAT CHRONIC STRESS AND STIMULANT EXPOSURE LEADS TO THE ACCUMULATION OF EPIGENETIC MODIFICATIONS THAT IMPAIR IMMEDIATE AND FUTURE NEURON FUNCTION AND ACTIVITY. SUCH EPIGENETIC MECHANISMS REPRESENT POTENTIAL THERAPEUTIC TARGETS FOR AMELIORATING CONVERGENT SYMPTOMS OF STRESS AND ADDICTION. 2022 20 4653 21 NEUROSCIENCE OF ALCOHOLISM: MOLECULAR AND CELLULAR MECHANISMS. ALCOHOL USE AND ABUSE APPEAR TO BE RELATED TO NEUROADAPTIVE CHANGES AT FUNCTIONAL, NEUROCHEMICAL, AND STRUCTURAL LEVELS. ACUTE AND CHRONIC ETHANOL EXPOSURE HAVE BEEN SHOWN TO MODULATE FUNCTION OF THE ACTIVITY-DEPENDENT GENE TRANSCRIPTION FACTOR, CAMP-RESPONSIVE ELEMENT BINDING (CREB) PROTEIN IN THE BRAIN, WHICH MAY BE ASSOCIATED WITH THE DEVELOPMENT OF ALCOHOLISM. STUDY OF THE DOWNSTREAM EFFECTORS OF CREB HAVE IDENTIFIED SEVERAL IMPORTANT CREB-RELATED GENES, SUCH AS NEUROPEPTIDE Y, BRAIN-DERIVED NEUROTROPHIC FACTOR, ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN, AND CORTICOTROPHIN-RELEASING FACTOR, THAT MAY PLAY A CRUCIAL ROLE IN THE BEHAVIORAL EFFECTS OF ETHANOL AND MOLECULAR CHANGES IN THE SPECIFIC NEUROCIRCUITRY THAT UNDERLIE BOTH ALCOHOL ADDICTION AND A GENETIC PREDISPOSITION TO ALCOHOLISM. BRAIN CHROMATIN REMODELING DUE TO HISTONE COVALENT MODIFICATIONS MAY ALSO BE INVOLVED IN MEDIATING THE BEHAVIORAL EFFECTS AND NEUROADAPTIVE CHANGES THAT OCCUR DURING ETHANOL EXPOSURE. THIS REVIEW OUTLINES PROGRESSIVE NEUROSCIENCE RESEARCH INTO MOLECULAR AND EPIGENETIC MECHANISMS OF ALCOHOLISM. 2010