1 4213 145 METHIONINE MEDIATES RESILIENCE TO CHRONIC SOCIAL DEFEAT STRESS BY EPIGENETIC REGULATION OF NMDA RECEPTOR SUBUNIT EXPRESSION. RATIONALE: PREVIOUS STUDIES SUGGESTED THAT METHIONINE (MET) LEVELS ARE DECREASED IN DEPRESSED PATIENTS. HOWEVER, WHETHER THE DECREASE IN THIS AMINO ACID IS IMPORTANT FOR PHENOTYPIC BEHAVIORS ASSOCIATED WITH DEPRESSION HAS NOT BEEN DECIPHERED. OBJECTIVE: THE RESPONSE OF INDIVIDUALS TO CHRONIC STRESS IS VARIABLE, WITH SOME INDIVIDUALS DEVELOPING DEPRESSION AND OTHERS BECOMING RESILIENT TO STRESS. IN THIS STUDY, OUR OBJECTIVE WAS TO EXAMINE THE EFFECT OF MET ON SUSCEPTIBILITY TO STRESS. METHODS: MALE C57BL/6J MICE WERE SUBJECTED TO DAILY DEFEAT SESSIONS BY A CD1 AGGRESSOR, FOR 10 DAYS. ON DAY 11, THE BEHAVIOR OF MICE WAS ASSESSED USING SOCIAL INTERACTION AND OPEN-FIELD TESTS. MICE RECEIVED MET 4 H BEFORE EACH DEFEAT SESSION. EPIGENETIC TARGETS WERE ASSESSED EITHER THROUGH REAL-RIME RTPCR OR THROUGH WESTERN BLOTS. RESULTS: MET DID NOT MODULATE ANXIETY-LIKE BEHAVIORS, BUT RATHER PROMOTED RESILIENCE TO CHRONIC STRESS, RESCUED SOCIAL AVOIDANCE BEHAVIORS AND REVERSED THE INCREASE IN THE CORTICAL EXPRESSION LEVELS OF N-METHYL-D-ASPARTATE RECEPTOR (NMDAR) SUBUNITS. ACTIVATING NMDAR ACTIVITY ABOLISHED THE ABILITY OF MET TO PROMOTE RESILIENCE TO STRESS AND TO RESCUE SOCIAL AVOIDANCE BEHAVIOR, WHEREAS INHIBITING NMDAR DID NOT SHOW ANY SYNERGISTIC OR ADDITIVE PROTECTIVE EFFECTS. INDEED, MET INCREASED THE CORTICAL LEVELS OF THE HISTONE METHYLTRANSFERASE SETDB1, AND IN TURN, THE LEVELS OF THE REPRESSIVE HISTONE H3 LYSINE (K9) TRIMETHYLATION (ME3). CONCLUSIONS: OUR DATA INDICATE THAT MET RESCUES SUSCEPTIBILITY TO STRESS BY INACTIVATING CORTICAL NMDAR ACTIVITY THROUGH AN EPIGENETIC MECHANISM INVOLVING HISTONE METHYLATION. 2020 2 310 40 ALCOHOL AND NMDA RECEPTOR: CURRENT RESEARCH AND FUTURE DIRECTION. THE BRAIN IS ONE OF THE MAJOR TARGETS OF ALCOHOL ACTIONS. MOST OF THE EXCITATORY SYNAPTIC TRANSMISSION IN THE CENTRAL NERVOUS SYSTEM IS MEDIATED BY N-METHYL-D-ASPARTATE (NMDA) RECEPTORS. HOWEVER, ONE OF THE MOST DEVASTATING EFFECTS OF ALCOHOL LEADS TO BRAIN SHRINKAGE, LOSS OF NERVE CELLS AT SPECIFIC REGIONS THROUGH A MECHANISM INVOLVING EXCITOTOXICITY, OXIDATIVE STRESS. EARLIER STUDIES HAVE INDICATED THAT CHRONIC EXPOSURE TO ETHANOL BOTH IN VIVO AND IN VITRO, INCREASES NR1 AND NR2B GENE EXPRESSION AND THEIR POLYPEPTIDE LEVELS. THE EFFECT OF ALCOHOL AND MOLECULAR CHANGES ON THE REGULATORY PROCESS, WHICH MODULATES NMDAR FUNCTIONS INCLUDING FACTORS ALTERING TRANSCRIPTION, TRANSLATION, POST-TRANSLATIONAL MODIFICATIONS, AND PROTEIN EXPRESSION, AS WELL AS THOSE INFLUENCING THEIR INTERACTIONS WITH DIFFERENT REGULATORY PROTEINS (DOWNSTREAM EFFECTORS) ARE INCESSANTLY INCREASING AT THE CELLULAR LEVEL. FURTHER, I DISCUSS THE VARIOUS GENETICALLY ALTERED MICE APPROACHES THAT HAVE BEEN USED TO STUDY NMDA RECEPTOR SUBUNITS AND THEIR FUNCTIONAL IMPLICATION. IN A RECENT COUNTABLE REVIEW, EPIGENETIC DIMENSION (I.E., HISTONE MODIFICATION-INDUCED CHROMATIN REMODELING AND DNA METHYLATION, IN THE PROCESS OF ALCOHOL RELATED NEUROADAPTATION) IS ONE OF THE KEY MOLECULAR MECHANISMS IN ALCOHOL MEDIATED NMDAR ALTERATION. HERE, I PROVIDE A RECOUNT ON WHAT HAS ALREADY BEEN ACHIEVED, CURRENT TRENDS AND HOW THE FUTURE RESEARCH/STUDIES OF THE NMDA RECEPTOR MIGHT LEAD TO EVEN GREATER ENGAGEMENT WITH MANY POSSIBLE NEW INSIGHTS INTO THE NEUROBIOLOGY AND TREATMENT OF ALCOHOLISM. 2013 3 1191 37 CORRELATION BETWEEN THE EPIGENETIC MODIFICATION OF HISTONE H3K9 ACETYLATION OF NR2B GENE PROMOTER IN RAT HIPPOCAMPUS AND ETHANOL WITHDRAWAL SYNDROME. PATIENTS WITH ALCOHOL USE DISORDER MAY DEVELOP ACUTE ETHANOL WITHDRAWAL SYNDROME (EWS). PREVIOUS STUDIES SHOWED THAT AN EPIGENETIC MODIFICATION OF THE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR, ESPECIALLY NMDA RECEPTOR 2B SUBUNIT (NR2B), WAS INVOLVED IN THE PATHOLOGICAL PROCESS OF EWS. HOWEVER, THE RELATIONSHIP BETWEEN THE EPIGENETIC REGULATION OF THE NR2B GENE IN THE RAT HIPPOCAMPUS REGION AND EWS WERE INCONSISTENT. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE ROLE OF THE HISTONE H3K9 ACETYLATION OF THE NR2B GENE IN THE RAT HIPPOCAMPUS REGION IN EWS. A RAT MODEL OF CHRONIC ETHANOL EXPOSURE WAS ESTABLISHED. EWS SCORE AND THE BEHAVIORAL CHANGES WERE RECORDED AT DIFFERENT TIME POINTS. THE NR2B EXPRESSION LEVELS AND THE HISTONE H3K9 ACETYLATION LEVEL IN THE NR2B GENE PROMOTER REGION WERE MEASURED USING QRT-PCR, WESTERN BLOT, IMMUNOFLUORESCENCE, AND CHROMATIN IMMUNOPRECIPITATION, RESPECTIVELY. FINALLY, THE RELATIONSHIP BETWEEN THE EPIGENETIC MODIFICATION OF HISTONE H3K9 ACETYLATION OF NR2B GENE PROMOTER AND EWS WERE EXAMINED. OUR ULTIMATE RESULTS SHOWED THAT THE EWS SCORE WAS INCREASED AT 2 H, PEAKED AT 6 H AFTER WITHDRAWAL OF ETHANOL, AND REDUCED TO THE LEVEL PARALLEL TO THE NORMAL CONTROL GROUP AT DAY 3 AFTER ETHANOL WITHDRAWAL. THE NR2B MRNA EXPRESSION AND PROTEIN LEVELS SHOWED SIMILAR PATTERNS. FURTHER CORRELATION ANALYSES INDICTED THAT BOTH HISTONE H3K9 ACETYLATION IN NR2B GENE PROMOTER AND THE EXPRESSION LEVELS OF NR2B WERE POSITIVELY ASSOCIATED WITH EWS. OUR RESULTS SUGGEST THAT CHRONIC ETHANOL EXPOSURE MAY RESULT IN EPIGENETIC MODIFICATION OF HISTONE H3K9 ACETYLATION IN NR2B GENE PROMOTER IN RAT HIPPOCAMPUS, AND THE EXPRESSION LEVELS OF NR2B WERE FOUND TO BE POSITIVELY CORRELATED WITH ETHANOL WITHDRAWAL SYNDROME. 2019 4 4212 36 METHAMPHETAMINE DOWNREGULATES STRIATAL GLUTAMATE RECEPTORS VIA DIVERSE EPIGENETIC MECHANISMS. BACKGROUND: CHRONIC METHAMPHETAMINE (METH) EXPOSURE CAUSES NEUROADAPTATIONS AT GLUTAMATERGIC SYNAPSES. METHODS: TO IDENTIFY THE METH-INDUCED EPIGENETIC UNDERPINNINGS OF THESE NEUROADAPTATIONS, WE INJECTED INCREASING METH DOSES TO RATS FOR 2 WEEKS AND MEASURED STRIATAL GLUTAMATE RECEPTOR EXPRESSION. WE THEN QUANTIFIED THE EFFECTS OF METH EXPOSURE ON HISTONE ACETYLATION. WE ALSO MEASURED METH-INDUCED CHANGES IN DNA METHYLATION AND DNA HYDROXYMETHYLATION. RESULTS: CHRONIC METH DECREASED TRANSCRIPT AND PROTEIN EXPRESSION OF GLUA1 AND GLUA2 ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLE PROPIONIC ACID RECEPTOR (AMPAR) AND GLUN1 N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS. THESE CHANGES WERE ASSOCIATED WITH ALTERED ELECTROPHYSIOLOGICAL GLUTAMATERGIC RESPONSES IN STRIATAL NEURONS. CHROMATIN IMMUNOPRECIPITATION-POLYMERASE CHAIN REACTION REVEALED THAT METH DECREASED ENRICHMENT OF ACETYLATED HISTONE H4 ON GLUA1, GLUA2, AND GLUN1 PROMOTERS. METHAMPHETAMINE EXPOSURE ALSO INCREASED REPRESSOR ELEMENT-1 SILENCING TRANSCRIPTION FACTOR (REST) COREPRESSOR 1, METHYLATED CPG BINDING PROTEIN 2, AND HISTONE DEACETYLASE 2 ENRICHMENT, BUT NOT OF SIRTUIN 1 OR SIRTUIN 2, ONTO GLUA1 AND GLUA2 GENE SEQUENCES. MOREOVER, METH CAUSED INTERACTIONS OF REST COREPRESSOR 1 AND METHYLATED CPG BINDING PROTEIN 2 WITH HISTONE DEACETYLASE 2 AND OF REST WITH HISTONE DEACETYLASE 1. SURPRISINGLY, METHYLATED DNA IMMUNOPRECIPITATION AND HYDROXYMETHYLATED DNA IMMUNOPRECIPITATION-POLYMERASE CHAIN REACTION REVEALED METH-INDUCED DECREASED ENRICHMENT OF 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE AT GLUA1 AND GLUA2 PROMOTER SEQUENCES. IMPORTANTLY, THE HISTONE DEACETYLASE INHIBITOR, VALPROIC ACID, BLOCKED METH-INDUCED DECREASED EXPRESSION OF AMPAR AND N-METHYL-D-ASPARTATE RECEPTOR SUBUNITS. FINALLY, VALPROIC ACID ALSO ATTENUATED METH-INDUCED DECREASE H4K16AC RECRUITMENT ON AMPAR GENE SEQUENCES. CONCLUSIONS: THESE OBSERVATIONS SUGGEST THAT HISTONE H4 HYPOACETYLATION MAY BE THE MAIN DETERMINANT OF METH-INDUCED DECREASED STRIATAL GLUTAMATE RECEPTOR EXPRESSION. 2014 5 2156 46 EPIGENETIC MECHANISMS ARE INVOLVED IN THE REGULATION OF ETHANOL CONSUMPTION IN MICE. BACKGROUND: REPEATED ALCOHOL EXPOSURE IS KNOWN TO INCREASE SUBSEQUENT ETHANOL CONSUMPTION IN MICE. HOWEVER, THE UNDERLYING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. ONE POSTULATED MECHANISM INVOLVES EPIGENETIC MODIFICATIONS, INCLUDING HISTONE MODIFICATIONS AND DNA METHYLATION OF RELEVANT GENES SUCH AS NR2B OR BDNF. METHODS: TO INVESTIGATE THE ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF ALCOHOL DRINKING BEHAVIOR, AN ESTABLISHED CHRONIC INTERMITTENT ETHANOL EXPOSURE REINFORCED ETHANOL DRINKING MOUSE MODEL WITH VAPOR INHALATION OVER TWO 9-DAY TREATMENT REGIMENS WAS USED. THE DNA METHYLTRANSFERASE INHIBITOR, 5-AZACYTIDINE OR THE HISTONE DEACETYLASE INHIBITOR, TRICHOSTATIN A WAS ADMINISTERED (INTRAPERITONEALLY) TO C57BL/6 MICE 30 MIN BEFORE DAILY EXPOSURE TO CHRONIC INTERMITTENT ETHANOL. CHANGES IN ETHANOL CONSUMPTION WERE MEASURED USING THE 2-BOTTLE CHOICE TEST. RESULTS: THE RESULTS INDICATED THAT SYSTEMIC ADMINISTRATION OF TRICHOSTATIN A (2.5 MICROG/G) FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING, BUT SYSTEMIC ADMINISTRATION OF 5-AZACYTIDINE (2 MICROG/G) DID NOT CAUSE THE SAME EFFECT. HOWEVER, WHEN 5-AZACYTIDINE WAS ADMINISTERED BY INTRACEREBROVENTRICULAR INJECTION, IT FACILITATED CHRONIC INTERMITTENT ETHANOL-INDUCED ETHANOL DRINKING. FURTHERMORE, THE INCREASED DRINKING CAUSED BY CHRONIC INTERMITTENT ETHANOL WAS PREVENTED BY INJECTION OF A METHYL DONOR, S-ADENOSYL-L-METHIONINE. TO PROVIDE EVIDENCE THAT CHRONIC INTERMITTENT ETHANOL- OR TRICHOSTATIN A-INDUCED DNA DEMETHYLATION AND HISTONE MODIFICATIONS OF THE NR2B PROMOTER MAY UNDERLIE THE ALTERED ETHANOL CONSUMPTION, WE EXAMINED EPIGENETIC MODIFICATIONS AND NR2B EXPRESSION IN THE PREFRONTAL CORTEX OF THESE MICE. CHRONIC INTERMITTENT ETHANOL OR TRICHOSTATIN A DECREASED DNA METHYLATION AND INCREASED HISTONE ACETYLATION IN THE NR2B GENE PROMOTER, AS WELL AS MRNA LEVELS OF NR2B IN THESE MICE. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS INDICATE THAT EPIGENETIC MODIFICATIONS ARE INVOLVED IN REGULATING ETHANOL DRINKING BEHAVIOR, PARTIALLY THROUGH ALTERING NR2B EXPRESSION. 2014 6 6177 37 THE HISTONE METHYLTRANSFERASE G9A MEDIATES STRESS-REGULATED ALCOHOL DRINKING. THE EPIGENETIC ENZYME G9A IS A HISTONE METHYLTRANSFERASE THAT DIMETHYLATES LYSINE 9 ON HISTONE H3 (H3K9ME2), AND IN THE ADULT NUCLEUS ACCUMBENS (NAC), G9A REGULATES MULTIPLE BEHAVIORS ASSOCIATED WITH SUBSTANCE USE DISORDER. WE SHOW HERE THAT CHRONIC INTERMITTENT ETHANOL (CIE) EXPOSURE IN MALE MICE REDUCED BOTH G9A AND H3K9ME2 LEVELS IN THE ADULT NAC, BUT NOT DORSAL STRIATUM. VIRAL-MEDIATED REDUCTION OF G9A IN THE NAC HAD NO EFFECTS ON BASELINE VOLITIONAL ETHANOL DRINKING OR ESCALATED ALCOHOL DRINKING PRODUCED BY CIE EXPOSURE; HOWEVER, NAC G9A WAS REQUIRED FOR STRESS-REGULATED CHANGES IN ETHANOL DRINKING, INCLUDING POTENTIATED ALCOHOL DRINKING PRODUCED BY ACTIVATION OF THE KAPPA-OPIOID RECEPTOR. IN ADDITION, WE OBSERVED THAT CHRONIC SYSTEMIC ADMINISTRATION OF A G9A INHIBITOR, UNC0642, ALSO BLOCKED STRESS-POTENTIATED ALCOHOL DRINKING. TOGETHER, OUR FINDINGS SUGGEST THAT CHRONIC ALCOHOL USE, SIMILAR TO OTHER ABUSED SUBSTANCES, PRODUCES A NAC-SELECTIVE REDUCTION IN G9A LEVELS THAT SERVES TO LIMIT STRESS-REGULATED ALCOHOL DRINKING. MOREOVER, OUR FINDINGS SUGGEST THAT PHARMACOLOGICAL INHIBITION OF G9A MIGHT PROVIDE A NOVEL THERAPEUTIC APPROACH TO TREAT STRESS-INDUCED ALCOHOL DRINKING, WHICH IS A MAJOR TRIGGER OF RELAPSE IN INDIVIDUALS SUFFERING FROM AUD. 2022 7 863 46 CHROMODOMAIN Y-LIKE PROTEIN-MEDIATED HISTONE CROTONYLATION REGULATES STRESS-INDUCED DEPRESSIVE BEHAVIORS. BACKGROUND: MAJOR DEPRESSIVE DISORDER IS A PREVALENT AND LIFE-THREATENING ILLNESS IN MODERN SOCIETY. THE SUSCEPTIBILITY TO MAJOR DEPRESSIVE DISORDER IS PROFOUNDLY INFLUENCED BY ENVIRONMENTAL FACTORS, SUCH AS STRESSFUL LIFESTYLE OR TRAUMATIC EVENTS, WHICH COULD IMPOSE MALADAPTIVE TRANSCRIPTIONAL PROGRAM THROUGH EPIGENETIC REGULATION. HOWEVER, THE UNDERLYING MOLECULAR MECHANISMS REMAIN ELUSIVE. HERE, WE EXAMINED THE ROLE OF HISTONE CROTONYLATION, A NOVEL TYPE OF HISTONE MODIFICATION, AND CHROMODOMAIN Y-LIKE PROTEIN (CDYL), A CROTONYL-COENZYME A HYDRATASE AND HISTONE METHYLLYSINE READER, IN THIS PROCESS. METHODS: WE USED CHRONIC SOCIAL DEFEAT STRESS AND MICRODEFEAT STRESS TO EXAMINE THE DEPRESSIVE BEHAVIORS. IN ADDITION, WE COMBINED PROCEDURES THAT DIAGNOSE BEHAVIORAL STRATEGY IN MALE MICE WITH HISTONE EXTRACTION, VIRAL-MEDIATED CDYL MANIPULATIONS, RNA SEQUENCING, CHROMATIN IMMUNOPRECIPITATION, WESTERN BLOT, AND MESSENGER RNA QUANTIFICATION. RESULTS: THE RESULTS INDICATE THAT STRESS-SUSCEPTIBLE RODENTS EXHIBIT LOWER LEVELS OF HISTONE CROTONYLATION IN THE MEDIAL PREFRONTAL CORTEX CONCURRENT WITH SELECTIVE UPREGULATION OF CDYL. OVEREXPRESSION OF CDYL IN THE PRELIMBIC CORTEX, A SUBREGION OF THE MEDIAL PREFRONTAL CORTEX, INCREASES MICRODEFEAT-INDUCED SOCIAL AVOIDANCE BEHAVIORS AND ANHEDONIA IN MICE. CONVERSELY, KNOCKDOWN OF CDYL IN THE PRELIMBIC CORTEX PREVENTS CHRONIC SOCIAL DEFEAT STRESS-INDUCED DEPRESSION-LIKE BEHAVIORS. MECHANISTICALLY, WE SHOW THAT CDYL INHIBITS STRUCTURAL SYNAPTIC PLASTICITY MAINLY BY TRANSCRIPTIONAL REPRESSION OF NEUROPEPTIDE VGF NERVE GROWTH FACTOR INDUCIBLE, AND THIS ACTIVITY IS DEPENDENT ON ITS DUAL EFFECT ON HISTONE CROTONYLATION AND H3K27 TRIMETHYLATION ON THE VGF PROMOTER. CONCLUSIONS: OUR RESULTS DEMONSTRATE THAT CDYL-MEDIATED HISTONE CROTONYLATION PLAYS A CRITICAL ROLE IN REGULATING STRESS-INDUCED DEPRESSION, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR MAJOR DEPRESSIVE DISORDER. 2019 8 3331 45 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM. 2018 9 4581 31 N-METHYL-D-ASPARTATE 2B RECEPTOR SUBTYPE (NR2B) PROMOTER METHYLATION IN PATIENTS DURING ALCOHOL WITHDRAWAL. NMDA RECEPTORS AND ESPECIALLY THE NR2B RECEPTOR SUBTYPE PLAY A CRUCIAL ROLE DURING CHRONIC ETHANOL CONSUMPTION AND ALCOHOL WITHDRAWAL. THEREFORE, THE NR2B RECEPTOR SUBTYPE EXPRESSION IN PERIPHERAL BLOOD CELLS OF 32 MALE PATIENTS SUFFERING FROM ALCOHOL DEPENDENCY WERE ASSESSED THROUGH QUANTITATIVE RT-PCR AND TO EXPLORE REGULATING EPIGENETIC MECHANISMS, A METHYLATION ANALYSIS WAS CONDUCTED USING BISULFITE SEQUENCING OF A FRAGMENT OF THE NR2B PROMOTER REGION. THE EXPRESSION OF THE NR2B RECEPTOR INCREASED SIGNIFICANTLY DURING THE FIRST 24 H OF WITHDRAWAL TREATMENT (DAY 1; T = 4.1, P = 0.001), AND ALSO ON AND DAY 3 (T = 2.4; P = 0.029). THE SEVERITY OF ALCOHOL DRINKING PATTERN, MEASURED BY LIFETIME DRINKING AND DAILY ETHANOL INTAKE, WAS NEGATIVELY CORRELATED WITH THE METHYLATION OF A DEFINED CLUSTER OF FIVE CPG-SITES WITHIN THE NR2B PROMOTER (LIFETIME DRINKING: SPEARMAN'S RHO = -0.55; P = 0.013; DAILY ETHANOL INTAKE: RHO = -0.46; P = 0.043). THESE FINDINGS MIGHT EXPLAIN THE OBSERVATION OF AN IMPACT OF ALCOHOL CONSUMPTION PATTERNS ON THE GRAVITY OF WITHDRAWAL SYMPTOMS. 2009 10 6108 41 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS. 2019 11 5445 45 REPEATED VAPOR ETHANOL EXPOSURE INDUCES TRANSIENT HISTONE MODIFICATIONS IN THE BRAIN THAT ARE MODIFIED BY GENOTYPE AND BRAIN REGION. BACKGROUND: EMERGING RESEARCH IMPLICATES ETHANOL (ETOH)-INDUCED EPIGENETIC MODIFICATIONS IN REGULATING GENE EXPRESSION AND ETOH CONSUMPTION. HOWEVER, CONSENSUS ON SPECIFIC EPIGENETIC MODIFICATIONS INDUCED BY ETOH HAS NOT YET EMERGED, MAKING IT CHALLENGING TO IDENTIFY MECHANISMS AND DEVELOP TARGETED TREATMENTS. WE HYPOTHESIZED THAT CHRONIC INTERMITTENT ETOH (CIE) INDUCES PERSISTENT CHANGES IN HISTONE MODIFICATIONS ACROSS THE CEREBRAL CORTEX (CCX), NUCLEUS ACCUMBENS (NAC), AND PREFRONTAL CORTEX (PFC), AND THAT THESE HISTONE MODIFICATIONS ARE ALTERED IN A KNOCK-IN MOUSE STRAIN WITH ALTERED SENSITIVITY TO ETOH. METHODS: C57BL/6J (B6) MICE AND ALPHA1SHLA KNOCKIN MICE ON A B6 BACKGROUND WERE EXPOSED TO 16 H OF VAPOR ETOH OR ROOM AIR FOLLOWED BY 8 H OF ROOM AIR FOR 4 CONSECUTIVE DAYS AND SACRIFICED AT MULTIPLE TIME POINTS UP TO 72 H FOLLOWING EXPOSURE. HISTONE MODIFICATIONS WERE ASSESSED USING WESTERN BLOT AND DOT BLOT. RT-QPCR WAS USED TO STUDY EXPRESSION OF CHROMATIN MODIFYING ENZYMES IN NAC AND PFC. RESULTS: IN NAC, CIE SIGNIFICANTLY INCREASED ACETYLATION OF HISTONE SUBUNIT H3 AT LYSINE 9 (H3K9AC) BUT NOT LYSINE 14 (H3K14AC) OR LYSINE 27 (H3K27AC). IN PFC, CIE SIGNIFICANTLY INCREASED H3K9AC BUT NOT H3K14 OR H3K27AC. THERE WERE NO SIGNIFICANT CHANGES AT 8 OR 72 H AFTER ETOH EXPOSURE IN EITHER NAC OR PFC. CIE WAS ALSO ASSOCIATED WITH INCREASED EXPRESSION OF KAT2B, KAT5, AND TET1 IN NAC BUT NOT PFC. IN CCX, CIE HAD A SIGNIFICANT EFFECT ON LEVELS OF H3K18AC; THERE WAS ALSO A SIGNIFICANT EFFECT OF THE ALPHA1SHLA MUTATION ON LEVELS OF H3K27ME3, H3K14AC, AND H3K18AC AS WELL AS A TREND FOR H3S10PK14AC. CONCLUSIONS: THE ETOH-INDUCED HISTONE MODIFICATIONS OBSERVED WERE TRANSIENT AND VARIED SIGNIFICANTLY BETWEEN BRAIN REGIONS. A GENETIC MUTATION THAT ALTERED SENSITIVITY TO ETOH WAS ASSOCIATED WITH ALTERED INDUCTION OF HISTONE MODIFICATIONS DURING CIE. THESE RESULTS HAVE IMPLICATIONS FOR STUDYING ETOH-INDUCED HISTONE MODIFICATIONS AND ETOH SENSITIVITY. 2015 12 3177 43 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021 13 4935 30 PATERNAL COCAINE TAKING ELICITS EPIGENETIC REMODELING AND MEMORY DEFICITS IN MALE PROGENY. PATERNAL ENVIRONMENTAL PERTURBATIONS INCLUDING EXPOSURE TO DRUGS OF ABUSE CAN PRODUCE PROFOUND EFFECTS ON THE PHYSIOLOGY AND BEHAVIOR OF OFFSPRING VIA EPIGENETIC MODIFICATIONS. HERE WE SHOW THAT ADULT DRUG-NAIVE MALE OFFSPRING OF COCAINE-EXPOSED SIRES HAVE MEMORY FORMATION DEFICITS AND ASSOCIATED REDUCTIONS IN NMDA RECEPTOR-MEDIATED HIPPOCAMPAL SYNAPTIC PLASTICITY. REDUCED LEVELS OF THE ENDOGENOUS NMDA RECEPTOR CO-AGONIST D-SERINE WERE ACCOMPANIED BY INCREASED EXPRESSION OF THE D-SERINE DEGRADING ENZYME D-AMINO ACID OXIDASE (DAO1) IN THE HIPPOCAMPUS OF COCAINE-SIRED MALE PROGENY. INCREASED DAO1 TRANSCRIPTION WAS ASSOCIATED WITH ENRICHMENT OF PERMISSIVE EPIGENETIC MARKS ON HISTONE PROTEINS IN THE HIPPOCAMPUS OF MALE COCAINE-SIRED PROGENY, SOME OF WHICH WERE ENHANCED NEAR THE DAO1 LOCUS. FINALLY, HIPPOCAMPAL ADMINISTRATION OF D-SERINE REVERSED BOTH THE MEMORY FORMATION AND SYNAPTIC PLASTICITY DEFICITS. COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT PATERNAL COCAINE EXPOSURE PRODUCES EPIGENETIC REMODELING IN THE HIPPOCAMPUS LEADING TO NMDA RECEPTOR-DEPENDENT MEMORY FORMATION AND SYNAPTIC PLASTICITY IMPAIRMENTS ONLY IN MALE PROGENY, WHICH HAS SIGNIFICANT IMPLICATIONS FOR THE MALE DESCENDANTS OF CHRONIC COCAINE USERS. 2017 14 1808 54 EFFECTS OF ADOLESCENT SOCIAL STRESS AND ANTIDEPRESSANT TREATMENT ON COGNITIVE INFLEXIBILITY AND BDNF EPIGENETIC MODIFICATIONS IN THE MPFC OF ADULT MICE. ADOLESCENT SOCIAL STRESS (ASS) CAN INCREASE SUSCEPTIBILITY TO DEPRESSION IN ADULTHOOD. HOWEVER, THE UNDERLYING PSYCHOLOGICAL AND NEURAL MECHANISMS REMAIN UNCLEAR. CORTICALLY MEDIATED COGNITIVE DYSFUNCTIONS ARE INCREASINGLY RECOGNIZED AS AN INDEPENDENT AND IMPORTANT RISK FACTOR OF DEPRESSION. USING SOCIAL DEFEAT STRESS, A CLASSICAL ANIMAL MODEL OF DEPRESSION, OUR PREVIOUS STUDIES FOUND THAT MICE SUBJECTED TO THIS FORM OF STRESS DURING EARLY ADOLESCENCE DISPLAYED COGNITIVE INFLEXIBILITY (CI) IN ADULTHOOD. THIS CHANGE WAS ACCOMPANIED BY A DOWN-REGULATION OF BDNF GENE EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX (MPFC); THIS GENE ENCODES A KEY MOLECULE INVOLVED IN DEPRESSION AND ANTIDEPRESSANT ACTION. IN THE PRESENT PAPER, WE IDENTIFIED EPIGENETIC MODIFICATION OF BDNF AS A POSSIBLE MECHANISM UNDERLYING THE BEHAVIORAL AND MOLECULAR CHANGES. ASS INDUCED A SET OF DEPRESSIVE PHENOTYPES, INCLUDING INCREASED SOCIAL AVOIDANCE AND CI, AS WELL AS REDUCED LEVELS OF TOTAL BDNF AND ISOFORM IV BUT NOT ISOFORM I OR VI TRANSCRIPTS IN THE MPFC. IN PARALLEL WITH CHANGES IN BDNF GENE EXPRESSION, PREVIOUSLY STRESSED ADULT MICE SHOWED INCREASED LEVELS OF DIMETHYLATION OF HISTONE H3 AT LYSINE K9 (H3K9ME2) IMMEDIATELY DOWNSTREAM OF THE BDNF IV PROMOTER. ON THE OTHER HAND, NO DIFFERENCES WERE FOUND IN TRIMETHYLATION OF HISTONE H3 AT LYSINE K4 (H3K4ME3) OR IN ACETYLATION OF HISTONE H3 AT LYSINE K9 (H3K9AC) OR AT K4 (H3K4AC) IN THE BDNF IV PROMOTER. LIKEWISE, NO ALTERATIONS WERE FOUND IN DNA METHYLATION OF THE BDNF IV PROMOTER. ADDITIONALLY, TREATMENT WITH THE CHRONIC ANTIDEPRESSANT TRANYLCYPROMINE REVERSED BDNF EPIGENETIC CHANGES AND RELATED GENE TRANSCRIPTION WHILE ALSO REVERSING CI, BUT NOT SOCIAL AVOIDANCE, IN PREVIOUSLY STRESSED ADULT MICE. THESE RESULTS SUGGEST THAT EPIGENETIC CHANGES TO THE BDNF GENE IN THE MPFC AFTER ADOLESCENT SOCIAL ADVERSITY MAY BE INVOLVED IN THE REGULATION OF COGNITIVE DYSFUNCTION IN DEPRESSION AND ANTIDEPRESSANT ACTION IN ADULTHOOD. 2018 15 69 39 A MEDIAL PREFRONTAL CORTEX-NUCLEUS ACUMENS CORTICOTROPIN-RELEASING FACTOR CIRCUITRY FOR NEUROPATHIC PAIN-INCREASED SUSCEPTIBILITY TO OPIOID REWARD. RECENT STUDIES HAVE SHOWN THAT PERSISTENT PAIN FACILITATES THE RESPONSE TO MORPHINE REWARD. HOWEVER, THE CIRCUIT MECHANISM UNDERLYING THIS PROCESS REMAINS AMBIGUOUS. IN THIS STUDY, USING CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN MICE, WE FOUND THAT PERSISTENT NEUROPATHIC PAIN REDUCED THE MINIMUM NUMBER OF MORPHINE CONDITIONING SESSIONS REQUIRED TO INDUCE CONDITIONED PLACE PREFERENCE (CPP) BEHAVIOR. THIS DOSE OF MORPHINE HAD NO EFFECT ON THE PAIN THRESHOLD. IN THE MEDIAL PREFRONTAL CORTEX (MPFC), WHICH IS INVOLVED IN BOTH PAIN AND EMOTION PROCESSING, CORTICOTROPIN-RELEASING FACTOR (CRF) EXPRESSING NEURONAL ACTIVITY WAS INCREASED IN CCI MICE. CHEMOGENETIC INHIBITION OF MPFC CRF NEURONS REVERSED CCI-INDUCED MORPHINE CPP FACILITATION. FURTHERMORE, THE NUCLEUS ACUMENS (NAC) RECEIVED MPFC CRF FUNCTIONAL PROJECTIONS THAT EXERTED EXCITATORY EFFECTS ON NAC NEURONS. OPTOGENETIC INHIBITION OF MPCF NEURONAL TERMINALS OR LOCAL INFUSION OF THE CRF RECEPTOR 1 (CRFR1) ANTAGONIST IN THE NAC RESTORED THE EFFECTS OF NEUROPATHIC PAIN ON MORPHINE-INDUCED CPP BEHAVIOR, BUT NOT IN NORMAL MICE. ON A MOLECULAR LEVEL, IN CCI MICE, CRFR1 PROTEIN EXPRESSION WAS INCREASED IN THE NAC BY A HISTONE DIMETHYLTRANSFERASE G9A-MEDIATED EPIGENETIC MECHANISM. LOCAL G9A KNOCKDOWN INCREASED THE EXPRESSION OF CRFR1 AND MIMICKED CCI-INDUCED HYPERSENSITIVITY TO ACQUIRING MORPHINE CPP. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE A PREVIOUSLY UNKNOWN AND SPECIFIC MPFC CRF ENGAGEMENT OF NAC NEURONAL CIRCUITS, THE SENSITIZATION OF WHICH FACILITATES BEHAVIORAL RESPONSES TO MORPHINE REWARD IN NEUROPATHIC PAIN STATES VIA CRFR1S. 2018 16 2358 40 EPIGENETIC REGULATION OF RAC1 INDUCES SYNAPTIC REMODELING IN STRESS DISORDERS AND DEPRESSION. DEPRESSION INDUCES STRUCTURAL AND FUNCTIONAL SYNAPTIC PLASTICITY IN BRAIN REWARD CIRCUITS, ALTHOUGH THE MECHANISMS PROMOTING THESE CHANGES AND THEIR RELEVANCE TO BEHAVIORAL OUTCOMES ARE UNKNOWN. TRANSCRIPTIONAL PROFILING OF THE NUCLEUS ACCUMBENS (NAC) FOR RHO GTPASE-RELATED GENES, WHICH ARE KNOWN REGULATORS OF SYNAPTIC STRUCTURE, REVEALED A SUSTAINED REDUCTION IN RAS-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1 (RAC1) EXPRESSION AFTER CHRONIC SOCIAL DEFEAT STRESS. THIS WAS ASSOCIATED WITH A REPRESSIVE CHROMATIN STATE SURROUNDING THE PROXIMAL PROMOTER OF RAC1. INHIBITION OF CLASS 1 HISTONE DEACETYLASES (HDACS) WITH MS-275 RESCUED BOTH THE DECREASE IN RAC1 TRANSCRIPTION AFTER SOCIAL DEFEAT STRESS AND DEPRESSION-RELATED BEHAVIOR, SUCH AS SOCIAL AVOIDANCE. WE FOUND A SIMILAR REPRESSIVE CHROMATIN STATE SURROUNDING THE RAC1 PROMOTER IN THE NAC OF SUBJECTS WITH DEPRESSION, WHICH CORRESPONDED WITH REDUCED RAC1 TRANSCRIPTION. VIRAL-MEDIATED REDUCTION OF RAC1 EXPRESSION OR INHIBITION OF RAC1 ACTIVITY IN THE NAC INCREASES SOCIAL DEFEAT-INDUCED SOCIAL AVOIDANCE AND ANHEDONIA IN MICE. CHRONIC SOCIAL DEFEAT STRESS INDUCES THE FORMATION OF STUBBY EXCITATORY SPINES THROUGH A RAC1-DEPENDENT MECHANISM INVOLVING THE REDISTRIBUTION OF SYNAPTIC COFILIN, AN ACTIN-SEVERING PROTEIN DOWNSTREAM OF RAC1. OVEREXPRESSION OF CONSTITUTIVELY ACTIVE RAC1 IN THE NAC OF MICE AFTER CHRONIC SOCIAL DEFEAT STRESS REVERSES DEPRESSION-RELATED BEHAVIORS AND PRUNES STUBBY SPINES. TAKEN TOGETHER, OUR DATA IDENTIFY EPIGENETIC REGULATION OF RAC1 IN THE NAC AS A DISEASE MECHANISM IN DEPRESSION AND REVEAL A FUNCTIONAL ROLE FOR RAC1 IN RODENTS IN REGULATING STRESS-RELATED BEHAVIORS. 2013 17 1783 39 EFFECT OF AGOMELATINE ON MEMORY DEFICITS AND HIPPOCAMPAL GENE EXPRESSION INDUCED BY CHRONIC SOCIAL DEFEAT STRESS IN MICE. CHRONIC STRESS IS KNOWN TO INDUCE NOT ONLY ANXIETY AND DEPRESSIVE-LIKE PHENOTYPES IN MICE BUT ALSO COGNITIVE IMPAIRMENTS, FOR WHICH THE ACTION OF CLASSICAL ANTIDEPRESSANT COMPOUNDS REMAINS UNSATISFACTORY. IN THIS CONTEXT, WE INVESTIGATED THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS (CSDS) ON ANXIETY-, SOCIAL- AND COGNITIVE-RELATED BEHAVIORS, AS WELL AS HIPPOCAMPAL BDNF, SYNAPTIC PLASTICITY MARKERS (PSD-95, SYNAPTOPHYSIN, SPINOPHILIN, SYNAPSIN I AND MAP-2), AND EPIGENETIC MODIFYING ENZYMES (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) GENE EXPRESSION IN C57BL/6J MICE. CSDS FOR 10 DAYS PROVOKED LONG-LASTING ANXIOUS-LIKE PHENOTYPE IN THE OPEN FIELD AND EPISODIC MEMORY DEFICITS IN THE NOVEL OBJECT RECOGNITION TEST. WHILE TOTAL BDNF MRNA LEVEL WAS UNCHANGED, BDNF EXON IV, MAP-2, HDAC2, HDAC6 AND MLL3 GENE EXPRESSION WAS SIGNIFICANTLY DECREASED IN THE CSDS MOUSE HIPPOCAMPUS. IN CSDS MICE TREATED 3 WEEKS WITH 50 MG/KG/D AGOMELATINE, AN ANTIDEPRESSANT WITH MELATONERGIC RECEPTOR AGONIST AND 5-HT(2C) RECEPTOR ANTAGONIST PROPERTIES, THE ANXIOUS-LIKE PHENOTYPE WAS NOT REVERSED, BUT THE TREATMENT SUCCESSFULLY PREVENTED THE COGNITIVE IMPAIRMENTS AND HIPPOCAMPAL GENE EXPRESSION MODIFICATIONS. ALTOGETHER, THESE DATA EVIDENCED THAT, IN MICE, AGOMELATINE WAS EFFECTIVE IN ALLEVIATING STRESS-INDUCED ALTERED COGNITIVE FUNCTIONS, POSSIBLY THROUGH A MECHANISM INVOLVING BDNF SIGNALING, SYNAPTIC PLASTICITY AND EPIGENETIC REMODELING. 2017 18 2826 45 FLUOXETINE EPIGENETICALLY ALTERS THE CAMKIIALPHA PROMOTER IN NUCLEUS ACCUMBENS TO REGULATE DELTAFOSB BINDING AND ANTIDEPRESSANT EFFECTS. CHRONIC SOCIAL DEFEAT STRESS IN MICE PRODUCES A SUSCEPTIBLE PHENOTYPE CHARACTERIZED BY SEVERAL BEHAVIORAL ABNORMALITIES CONSISTENT WITH HUMAN DEPRESSION THAT ARE REVERSED BY CHRONIC BUT NOT ACUTE EXPOSURE TO ANTIDEPRESSANT MEDICATIONS. RECENT WORK IN ADDICTION MODELS DEMONSTRATES THAT THE TRANSCRIPTION FACTOR DELTAFOSB AND PROTEIN KINASE CALMODULIN-DEPENDENT PROTEIN KINASE II (CAMKII) ARE CO-REGULATED IN NUCLEUS ACCUMBENS (NAC), A BRAIN REWARD REGION IMPLICATED IN BOTH ADDICTION AND DEPRESSION MODELS INCLUDING SOCIAL DEFEAT. PREVIOUS WORK HAS ALSO DEMONSTRATED THAT DELTAFOSB IS INDUCED IN NAC AFTER CHRONIC SOCIAL DEFEAT STRESS OR AFTER CHRONIC ANTIDEPRESSANT TREATMENT, WHEREIN IT MEDIATES A PRO-RESILIENCE OR ANTIDEPRESSANT-LIKE PHENOTYPE. HERE, USING CHROMATIN IMMUNOPRECIPITATION ASSAYS, WE FOUND THAT DELTAFOSB BINDS THE CAMKIIALPHA GENE PROMOTER IN NAC AND THAT THIS BINDING INCREASES AFTER MICE ARE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS. PARADOXICALLY, CHRONIC EXPOSURE TO THE ANTIDEPRESSANT FLUOXETINE REDUCES BINDING OF DELTAFOSB TO THE CAMKIIALPHA PROMOTER AND REDUCES CAMKII EXPRESSION IN NAC, DESPITE THE FACT THAT DELTAFOSB IS INDUCED UNDER THESE CONDITIONS. THESE DATA SUGGEST A NOVEL EPIGENETIC MECHANISM OF ANTIDEPRESSANT ACTION, WHEREBY FLUOXETINE INDUCES SOME CHROMATIN CHANGE AT THE CAMKIIALPHA PROMOTER, WHICH BLOCKS THE DELTAFOSB BINDING. INDEED, CHRONIC FLUOXETINE REDUCES ACETYLATION AND INCREASES LYSINE-9 DIMETHYLATION OF HISTONE H3 AT THE CAMKIIALPHA PROMOTER IN NAC, EFFECTS ALSO SEEN IN DEPRESSED HUMANS EXPOSED TO ANTIDEPRESSANTS. OVEREXPRESSION OF CAMKII IN NAC BLOCKS FLUOXETINE'S ANTIDEPRESSANT EFFECTS IN THE CHRONIC SOCIAL DEFEAT PARADIGM, WHEREAS INHIBITION OF CAMKII ACTIVITY IN NAC MIMICS FLUOXETINE EXPOSURE. THESE FINDINGS SUGGEST THAT EPIGENETIC SUPPRESSION OF CAMKIIALPHA EXPRESSION IN NAC IS BEHAVIORALLY RELEVANT AND OFFER A NOVEL PATHWAY FOR POSSIBLE THERAPEUTIC INTERVENTION IN DEPRESSION AND RELATED SYNDROMES. 2014 19 910 36 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS. 2014 20 6352 34 THE ROLE OF GABA(A) RECEPTORS IN THE DEVELOPMENT OF ALCOHOLISM. ALCOHOLISM IS A COMMON, HERITABLE, CHRONIC RELAPSING DISORDER. GABA(A) RECEPTORS UNDERGO ALLOSTERIC MODULATION BY ETHANOL, ANESTHETICS, BENZODIAZEPINES AND NEUROSTEROIDS AND HAVE BEEN IMPLICATED IN THE ACUTE AS WELL AS THE CHRONIC EFFECTS OF ETHANOL INCLUDING TOLERANCE, DEPENDENCE AND WITHDRAWAL. MEDICATIONS TARGETING GABA(A) RECEPTORS AMELIORATE THE SYMPTOMS OF ACUTE WITHDRAWAL. ETHANOL INDUCES PLASTICITY IN GABA(A) RECEPTORS: TOLERANCE IS ASSOCIATED WITH GENERALLY DECREASED GABA(A) RECEPTOR ACTIVATION AND DIFFERENTIALLY ALTERED SUBUNIT EXPRESSION. THE DOPAMINE (DA) MESOLIMBIC REWARD PATHWAY ORIGINATING IN THE VENTRAL TEGMENTAL AREA (VTA), AND INTERACTING STRESS CIRCUITRY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ADDICTION. VTA GABAERGIC INTERNEURONS ARE THE PRIMARY INHIBITORY REGULATORS OF DA NEURONS AND A SUBSET OF VTA GABA(A) RECEPTORS MAY BE IMPLICATED IN THE SWITCH FROM HEAVY DRINKING TO DEPENDENCE. GABA(A) RECEPTORS MODULATE ANXIETY AND RESPONSE TO STRESS; IMPORTANT ELEMENTS OF SUSTAINED DRINKING AND RELAPSE. THE GABA(A) RECEPTOR SUBUNIT GENES CLUSTERED ON CHROMOSOME 4 ARE HIGHLY EXPRESSED IN THE REWARD PATHWAY. SEVERAL RECENT STUDIES HAVE PROVIDED STRONG EVIDENCE THAT ONE OF THESE GENES, GABRA2, IS IMPLICATED IN ALCOHOLISM IN HUMANS. THE INFLUENCE OF THE INTERACTION BETWEEN ETHANOL AND GABA(A) RECEPTORS IN THE REWARD PATHWAY ON THE DEVELOPMENT OF ALCOHOLISM TOGETHER WITH GENETIC AND EPIGENETIC VULNERABILITIES WILL BE EXPLORED IN THIS REVIEW. 2008