1 5535 101 ROLE OF BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS IN RELAPSE TO COCAINE-SEEKING BEHAVIOR IN MICE. COCAINE ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER CHARACTERIZED BY COMPULSIVE DRUG SEEKING. PRELIMINARY STUDY SUGGESTED THAT BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC READER PROTEIN, PARTICIPATES IN COCAINE-INDUCED REWARD AND NEUROPLASTICITY. HOWEVER, THE EXACT ROLE OF BRD4 IN COCAINE ADDICTION, PARTICULARLY COCAINE RELAPSE, REMAINS ELUSIVE. IN THIS STUDY, WE FOUND THAT BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS (NAC) WAS CLOSELY RELATED TO THE MAINTENANCE OF COCAINE REINFORCEMENT AND RELAPSE IN DIFFERENT COCAINE EXPOSURE PARADIGMS. COCAINE SIGNIFICANTLY INCREASED THE BINDING OF PHOSPHORYLATED BRD4 (PBRD4) AT THE PROMOTER OF GRIA2 AND BDNF GENES IN THE NAC. (+)JQ1, A SELECTIVE BRD4 INHIBITOR, MARKEDLY REDUCED THE REINFORCEMENT AND REINSTATEMENT OF COCAINE-SEEKING BEHAVIORS, WHICH WAS ACCOMPANIED BY THE DECREASED EXPRESSIONS OF GRIA2 AND BDNF. FURTHERMORE, CHROMATIN IMMUNOPRECIPITATION ASSAY SHOWED THAT (+)JQ1 CLEARLY ATTENUATED COCAINE-ENHANCED BINDING OF PBRD4 AT THE PROMOTOR OF GRIA2 AND BDNF GENES. BLOCKADE OF CASEIN KINASE II SIGNIFICANTLY ATTENUATED BRD4 PHOSPHORYLATION AND COCAINE RELAPSE-LIKE BEHAVIORS, SUGGESTING THE IMPORTANT ROLE OF PBRD4 IN MODULATING COCAINE EFFECT. TOGETHER, OUR FINDINGS SUGGEST THAT BRD4 PHOSPHORYLATION IN THE NAC MODULATES MULTIPLE ADDICTION-RELATED BEHAVIORS OF COCAINE AND PARTICULARLY RELAPSE TO COCAINE-SEEKING BEHAVIORS. INHIBITION OF BRD4 ACTIVITY MAY BE A NOVEL TARGET AGAINST COCAINE ADDICTION AND RELAPSE. 2020 2 6519 28 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF INTERLEUKIN-2 GENE IN ACTIVATED T CELLS BY MORPHINE. CHRONIC MORPHINE INHIBITS INTERLEUKIN-2 (IL-2) AT BOTH THE TRANSCRIPTIONAL AND PROTEIN SYNTHESIS LEVELS. THE MOLECULAR MECHANISMS BY WHICH MORPHINE DECREASES IL-2 ARE NOT FULLY UNDERSTOOD. THE PRODUCTION OF IL-2 IS TIGHTLY REGULATED BY SEVERAL TRANSCRIPTION FACTORS THAT BIND TO THE IL-2 PROMOTER. HEREIN, WE SHOW THAT CHRONIC MORPHINE TREATMENT RESULTS IN AN INCREASE IN CAMP LEVELS WITH A CONCURRENT UP-REGULATION OF THE CAMP INDUCIBLE REPRESSOR INDUCIBLE CAMP EARLY REPRESSOR (ICER)/CAMP RESPONSE ELEMENT MODULATOR (CREM) AND DOWN-REGULATION OF P-CAMP-RESPONSE ELEMENT-BINDING PROTEIN (CREB) IN ACTIVATED T CELLS. FURTHERMORE, ICER COMPETES FOR P-CREB BINDING TO THE CAMP-RESPONSIVE ELEMENTS (CRES) SITE. THIS LEADS TO THE UNCOUPLING OF CBP/P300 THEREBY ABROGATING IL-2 TRANSCRIPTION. OVEREXPRESSION OF EITHER ANTISENSE CREM OR CREB PLASMID RESCUED MORPHINE-INDUCED INHIBITION OF IL-2 PROMOTER ACTIVITY AND PROTEIN PRODUCTION. IN ADDITION, WE ALSO FOUND THAT CHRONIC MORPHINE TREATMENT INHIBITED THE ACETYLATION AND TRIMETHYLATION OF HISTONES AND DECREASED BOTH DNA DEMETHYLATION AND ACCESSIBILITY OF THE IL-2 PROMOTER. THESE FINDINGS SUGGEST THAT CHRONIC MORPHINE TREATMENT MAY FUNCTION THROUGH BOTH TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS TO INHIBIT IL-2 PRODUCTION. 2007 3 5014 29 PERSISTENCE OF CEREBELLAR ATAXIA DURING CHRONIC ETHANOL EXPOSURE IS ASSOCIATED WITH EPIGENETIC UP-REGULATION OF FMR1 GENE EXPRESSION IN RAT CEREBELLUM. BACKGROUND: ALCOHOL INTOXICATION PRODUCES ATAXIA BY AFFECTING THE CEREBELLUM, WHICH COORDINATES MOVEMENTS. FRAGILE X MENTAL RETARDATION (FMR) PROTEIN IS A COMPLEX REGULATOR OF RNA AND SYNAPTIC PLASTICITY IMPLICATED IN FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME, WHICH FEATURES ATAXIA AND INCREASED FMR1 MRNA EXPRESSION RESULTING FROM EPIGENETIC DYSREGULATION OF FMRP. WE RECENTLY DEMONSTRATED THAT ACUTE ETHANOL-INDUCED ATAXIA IS ASSOCIATED WITH INCREASED CEREBELLAR FMR1 GENE EXPRESSION VIA HISTONE MODIFICATIONS IN RATS, BUT IT IS UNKNOWN WHETHER SIMILAR BEHAVIORAL AND MOLECULAR CHANGES OCCUR FOLLOWING CHRONIC ETHANOL EXPOSURE. HERE, WE INVESTIGATED THE EFFECTS OF CHRONIC ETHANOL EXPOSURE ON ATAXIA AND EPIGENETICALLY REGULATED CHANGES IN FMR1 EXPRESSION IN THE CEREBELLUM. METHODS: MALE ADULT SPRAGUE-DAWLEY RATS WERE TRAINED ON THE ACCELERATING ROTAROD AND THEN FED WITH CHRONIC ETHANOL OR A CONTROL LIEBER-DECARLI DIET WHILE UNDERGOING PERIODIC BEHAVIORAL TESTING FOR ATAXIA DURING ETHANOL EXPOSURE AND WITHDRAWAL. CEREBELLAR TISSUES WERE ANALYZED FOR EXPRESSION OF THE FMR1 GENE AND ITS TARGETS USING A REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. THE EPIGENETIC REGULATION OF FMR1 WAS ALSO INVESTIGATED USING A CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: ATAXIC BEHAVIOR MEASURED BY THE ACCELERATING ROTAROD BEHAVIORAL TEST DEVELOPED DURING CHRONIC ETHANOL TREATMENT AND PERSISTED AT BOTH THE 8-H AND 24-H WITHDRAWAL TIME POINTS COMPARED TO CONTROL DIET-FED RATS. IN ADDITION, CHRONIC ETHANOL TREATMENT RESULTED IN UP-REGULATED EXPRESSION OF FMR1 MRNA AND INCREASED ACTIVATING EPIGENETIC MARKS H3K27 ACETYLATION AND H3K4 TRIMETHYLATION AT 2 SITES WITHIN THE FMR1 PROMOTER. FINALLY, MEASUREMENT OF THE EXPRESSION OF RELEVANT FMRP MRNA TARGETS IN THE CEREBELLUM SHOWED THAT CHRONIC ETHANOL UP-REGULATED CAMP RESPONSE ELEMENT BINDING (CREB) CREB1, PSD95, GRM5, AND GRIN2B MRNA EXPRESSION WITHOUT ALTERING GRIN2A, EAA1, OR HISTONE ACETYLTRANSFERASES CREB BINDING PROTEIN (CBP) OR P300 MRNA TRANSCRIPTS. CONCLUSIONS: THESE RESULTS SUGGEST THAT EPIGENETIC REGULATION OF FMR1 AND SUBSEQUENT FMRP REGULATION OF TARGET MRNA TRANSCRIPTS CONSTITUTE NEUROADAPTATIONS IN THE CEREBELLUM THAT MAY UNDERLIE THE PERSISTENCE OF ATAXIC BEHAVIOR DURING CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL. 2021 4 2012 29 EPIGENETIC BASIS OF OPIATE SUPPRESSION OF BDNF GENE EXPRESSION IN THE VENTRAL TEGMENTAL AREA. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS A CRUCIAL ROLE IN MODULATING NEURAL AND BEHAVIORAL PLASTICITY TO DRUGS OF ABUSE. WE FOUND A PERSISTENT DOWNREGULATION OF EXON-SPECIFIC BDNF EXPRESSION IN THE VENTRAL TEGMENTAL AREA (VTA) IN RESPONSE TO CHRONIC OPIATE EXPOSURE, WHICH WAS MEDIATED BY SPECIFIC EPIGENETIC MODIFICATIONS AT THE CORRESPONDING BDNF GENE PROMOTERS. EXPOSURE TO CHRONIC MORPHINE INCREASED STALLING OF RNA POLYMERASE II AT THESE BDNF PROMOTERS IN VTA AND ALTERED PERMISSIVE AND REPRESSIVE HISTONE MODIFICATIONS AND OCCUPANCY OF THEIR REGULATORY PROTEINS AT THE SPECIFIC PROMOTERS. FURTHERMORE, WE FOUND THAT MORPHINE SUPPRESSED BINDING OF PHOSPHO-CREB (CAMP RESPONSE ELEMENT BINDING PROTEIN) TO BDNF PROMOTERS IN VTA, WHICH RESULTED FROM ENRICHMENT OF TRIMETHYLATED H3K27 AT THE PROMOTERS, AND THAT DECREASED NURR1 (NUCLEAR RECEPTOR RELATED-1) EXPRESSION ALSO CONTRIBUTED TO BDNF REPRESSION AND ASSOCIATED BEHAVIORAL PLASTICITY TO MORPHINE. OUR FINDINGS SUGGEST PREVIOUSLY UNKNOWN EPIGENETIC MECHANISMS OF MORPHINE-INDUCED MOLECULAR AND BEHAVIORAL NEUROADAPTATIONS. 2015 5 4163 28 MECP2 REPRESSION OF G9A IN REGULATION OF PAIN AND MORPHINE REWARD. OPIOIDS ARE COMMONLY USED FOR PAIN RELIEF, BUT THEIR STRONG REWARDING EFFECTS DRIVE OPIOID MISUSE AND ABUSE. HOW PAIN AFFECTS THE LIABILITY OF OPIOID ABUSE IS UNKNOWN AT PRESENT. IN THIS STUDY, WE IDENTIFIED AN EPIGENETIC REGULATING CASCADE ACTIVATED BY BOTH PAIN AND THE OPIOID MORPHINE. BOTH PERSISTENT PAIN AND REPEATED MORPHINE UPREGULATED THE TRANSCRIPTIONAL REGULATOR MECP2 IN MOUSE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT MECP2 BOUND TO AND REPRESSED THE TRANSCRIPTIONAL REPRESSOR HISTONE DIMETHYLTRANSFERASE G9A, REDUCING G9A-CATALYZED REPRESSIVE MARK H3K9ME2 IN CEA. REPRESSION OF G9A ACTIVITY INCREASED EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF). BEHAVIORALLY, PERSISTENT INFLAMMATORY PAIN INCREASED THE SENSITIVITY TO ACQUIRING MORPHINE-INDUCED, REWARD-RELATED BEHAVIOR OF CONDITIONED PLACE PREFERENCE IN MICE. LOCAL VIRAL VECTOR-MEDIATED MECP2 OVEREXPRESSION, CRE-INDUCED G9A KNOCKDOWN, AND CEA APPLICATION OF BDNF MIMICKED, WHEREAS MECP2 KNOCKDOWN INHIBITED, THE PAIN EFFECT. THESE RESULTS SUGGEST THAT MECP2 DIRECTLY REPRESSES G9A AS A SHARED MECHANISM IN CENTRAL AMYGDALA FOR REGULATION OF EMOTIONAL RESPONSES TO PAIN AND OPIOID REWARD, AND FOR THEIR BEHAVIORAL INTERACTION. 2014 6 2826 40 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 7 4878 48 OVEREXPRESSION OF THE HISTONE DIMETHYLTRANSFERASE G9A IN NUCLEUS ACCUMBENS SHELL INCREASES COCAINE SELF-ADMINISTRATION, STRESS-INDUCED REINSTATEMENT, AND ANXIETY. REPEATED EXPOSURE TO COCAINE INDUCES LASTING EPIGENETIC CHANGES IN NEURONS THAT PROMOTE THE DEVELOPMENT AND PERSISTENCE OF ADDICTION. ONE EPIGENETIC ALTERATION INVOLVES REDUCTIONS IN LEVELS OF THE HISTONE DIMETHYLTRANSFERASE G9A IN NUCLEUS ACCUMBENS (NAC) AFTER CHRONIC COCAINE ADMINISTRATION. THIS REDUCTION IN G9A MAY ENHANCE COCAINE REWARD BECAUSE OVEREXPRESSING G9A IN THE NAC DECREASES COCAINE-CONDITIONED PLACE PREFERENCE. THEREFORE, WE HYPOTHESIZED THAT HSV-MEDIATED G9A OVEREXPRESSION IN THE NAC SHELL (NACSH) WOULD ATTENUATE COCAINE SELF-ADMINISTRATION (SA) AND COCAINE-SEEKING BEHAVIOR. INSTEAD, WE FOUND THAT G9A OVEREXPRESSION, AND THE RESULTING INCREASE IN HISTONE 3 LYSINE 9 DIMETHYLATION (H3K9ME2), INCREASES SENSITIVITY TO COCAINE REINFORCEMENT AND ENHANCES MOTIVATION FOR COCAINE IN SELF-ADMINISTERING MALE RATS. MOREOVER, WHEN G9A OVEREXPRESSION IS LIMITED TO THE INITIAL 15 D OF COCAINE SA TRAINING, IT PRODUCES AN ENDURING POSTEXPRESSION ENHANCEMENT IN COCAINE SA AND PROLONGED (OVER 5 WEEKS) INCREASES IN REINSTATEMENT OF COCAINE SEEKING INDUCED BY FOOT-SHOCK STRESS, BUT IN THE ABSENCE OF CONTINUED GLOBAL ELEVATIONS IN H3K9ME2. THE INCREASE IN STRESS-INDUCED REINSTATEMENT IS PARALLELED BY HEIGHTENED ANXIETY MEASURES, SUGGESTING THAT COUNTERING THE COCAINE-INDUCED DECREASES IN ENDOGENOUS G9A WITH ECTOPIC G9A OVEREXPRESSION LEADS TO LASTING ANXIOGENIC EFFECTS. FINALLY, WE FOUND AN ENDURING REDUCTION IN PHOSPHORYLATED CAMP-RESPONSE ELEMENT BINDING PROTEIN LEVELS IN THE NACSH THAT COULD ACCOUNT FOR THE INCREASED ANXIETY. THESE DATA DEMONSTRATE A NOVEL ROLE FOR G9A IN PROMOTING COMORBID COCAINE ADDICTION AND ANXIETY AND SUGGEST THAT INCREASED EPIGENETIC REPRESSION OF TRANSCRIPTION THROUGH H3K9 DURING COCAINE USE CAN HAVE LONG-LASTING AND UNEXPECTED NEGATIVE CONSEQUENCES ON BEHAVIOR.SIGNIFICANCE STATEMENT COCAINE ADDICTION IS A NEUROPSYCHIATRIC DISORDER THAT IS DETRIMENTAL TO SOCIETY AND CURRENTLY HAS NO EFFECTIVE TREATMENTS. THE DIFFICULTY IN TREATING DRUG ADDICTION IS COMPOUNDED BY THE HIGH COMORBIDITY WITH OTHER PSYCHIATRIC ILLNESSES, INCLUDING ANXIETY DISORDERS. HERE, WE DEMONSTRATE THAT G9A, AN EPIGENETIC REPRESSOR OF GENE EXPRESSION, ACTING IN THE NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, IS CAPABLE OF INCREASING BOTH ADDICTION- AND ANXIETY-LIKE BEHAVIORS IN RATS. THESE FINDINGS ARE INTRIGUING BECAUSE REPEATED COCAINE EXPOSURE DECREASES G9A IN THIS REGION AND THEREBY ENHANCES EXPRESSION OF CERTAIN ADDICTION-PROMOTING GENES. HOWEVER, OUR RESULTS SUGGEST THAT COUNTERING THIS COCAINE-INDUCED DECREASE IN G9A ACTIVITY ACTUALLY EXACERBATES ADDICTION AND SENSITIVITY TO RELAPSE UNDER STRESSFUL SITUATIONS. 2018 8 5021 31 PERSISTENT PAIN MAINTAINS MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL THROUGH REDUCED MECP2 REPRESSION OF GLUA1 IN RAT CENTRAL AMYGDALA. AS LONG-TERM OPIOIDS ARE INCREASINGLY USED FOR CONTROL OF CHRONIC PAIN, HOW PAIN AFFECTS THE REWARDING EFFECT OF OPIOIDS AND HENCE RISK OF PRESCRIPTION OPIOID MISUSE AND ABUSE REMAINS A HEALTHCARE CONCERN AND A CHALLENGING ISSUE IN CURRENT PAIN MANAGEMENT. IN THIS STUDY, USING A RAT MODEL OF MORPHINE SELF-ADMINISTRATION, WE INVESTIGATED THE MOLECULAR MECHANISMS UNDERLYING THE IMPACT OF PAIN ON OPERANT BEHAVIOR OF MORPHINE INTAKE AND MORPHINE SEEKING BEFORE AND AFTER MORPHINE WITHDRAWAL. WE FOUND THAT RATS WITH PERSISTENT PAIN CONSUMED A SIMILAR AMOUNT OF DAILY MORPHINE TO THAT IN CONTROL RATS WITHOUT PAIN, BUT MAINTAINED THEIR LEVEL-PRESSING BEHAVIOR OF MORPHINE SEEKING AFTER ABSTINENCE OF MORPHINE AT 0.2 MG/KG, WHEREAS THIS BEHAVIOR WAS GRADUALLY DIMINISHED IN CONTROL RATS. IN THE CENTRAL NUCLEUS OF AMYGDALA (CEA), A LIMBIC STRUCTURE CRITICALLY INVOLVED IN THE AFFECTIVE DIMENSION OF PAIN, PROTEINS OF GLUA1 SUBUNITS OF GLUTAMATE AMPA RECEPTORS WERE UPREGULATED DURING MORPHINE WITHDRAWAL, AND VIRAL KNOCKDOWN OF CEA GLUA1 ELIMINATED THE MORPHINE-SEEKING BEHAVIOR IN WITHDRAWN RATS OF THE PAIN GROUP. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT THE METHYL CPG-BINDING PROTEIN 2 (MECP2) WAS ENRICHED IN THE PROMOTER REGION OF GRIA1 ENCODING GLUA1 AND THIS ENRICHMENT WAS SIGNIFICANTLY ATTENUATED IN WITHDRAWN RATS OF THE PAIN GROUP. FURTHERMORE, VIRAL OVEREXPRESSION OF CEA MECP2 REPRESSED THE GLUA1 LEVEL AND ELIMINATED THE MAINTENANCE OF MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL. THESE RESULTS SUGGEST DIRECT MECP2 REPRESSION OF GLUA1 FUNCTION AS A LIKELY MECHANISM FOR MORPHINE-SEEKING BEHAVIOR MAINTAINED BY LONG-LASTING AFFECTIVE PAIN AFTER MORPHINE WITHDRAWAL. 2015 9 1829 33 EFFECTS OF INHIBITING ASTROCYTES AND BET/BRD4 CHROMATIN READER ON SPATIAL MEMORY AND SYNAPTIC PROTEINS IN RATS WITH ALZHEIMER'S DISEASE. COMMUNICATION BETWEEN ASTROCYTES AND NEURONS HAS A PROFOUND EFFECT ON THE PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE (AD). ASTROCYTES REGULATE HOMEOSTASIS AND INCREASE SYNAPTIC PLASTICITY IN PHYSIOLOGICAL SITUATIONS, HOWEVER, THEY BECOME ACTIVATED DURING THE PROGRESSION OF AD. WHETHER OR NOT THESE REACTIONS ARE SUPPORTIVE OR DETRIMENTAL FOR THE CENTRAL NERVOUS SYSTEM HAVE NOT BEEN UNDERSTOOD YET. CONSIDERING EPIGENETIC REGULATION OF NEUROINFLAMMATORY GENES BY CHROMATIN READERS, PARTICULARLY BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY, HERE WE EXAMINED THE EFFECT OF CHRONIC CO-INHIBITION OF ASTROCYTES METABOLISM (WITH FLUOROCITRATE) AND ALSO BRD4 (WITH JQ1) ON COGNITION DEFICIT AT EARLY STAGES OF AD. FORTY ADULT MALE WISTAR RATS UNDERWENT STEREOTAXIC CANNULATION FOR INDUCING AD BY INTRAHIPPOCAMPAL INJECTION OF ABETA(1-42) (4 MUG/8 MUL/RAT). THEN ANIMALS WERE DIVIDED INTO FIVE GROUPS OF SALINE+DMSO, ABETA + SALINE+DMSO, ABETA + JQ1, ABETA + FC (FLUOROCITRATE), AND ABETA + JQ1 + FC AND RECEIVED THE RELATED TREATMENTS. TWO WEEKS LATER, SPATIAL MEMORY WAS RECORDED BY MORRIS WATER MAZE (MWM), AND THE LEVELS OF PHOSPHORYLATED CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CREB), POSTSYNAPTIC DENSITY 95 (PSD95), SYNAPTOPHYSIN (SYP), AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE MEASURED IN THE HIPPOCAMPUS BY WESTERN BLOTTING AND RT-QPCR. ADMINISTRATION OF JQ1 SIGNIFICANTLY IMPROVED BOTH ACQUISITION AND RETRIEVAL OF SPATIAL MEMORY, WHICH WERE EVIDENT BY DECREASED ESCAPE LATENCY AND INCREASED TOTAL TIME SPENT (TTS) IN TARGET QUADRANT, AND SIGNIFICANT RISE IN P-CREB, PSD95, AND SYNAPTOPHYSIN COMPARED WITH ABETA + SALINE+DMSO GROUP. IN CONTRAST, BOTH GROUPS RECEIVING FC DEMONSTRATED MEMORY DECLINE, AND REDUCTION IN P-CREB, PSD95 AND SYNAPTOPHYSIN IN PARALLEL WITH INCREASE IN TNF-ALPHA. OUR DATA INDICATE THAT CHRONIC INHIBITION OF BRD4 SIGNIFICANTLY RESTORES MEMORY IMPAIRED BY AMYLOID BETA PARTLY VIA CREB SIGNALING AND UPREGULATING SYNAPTIC PROTEINS OF PSD95 AND SYNAPTOPHYSIN. HOWEVER, INHIBITION OF ASTROCYTES NULLIFIES THE MEMORY-BOOSTING EFFECTS OF JQ1 AND REDUCES CREB/PSD95/SYNAPTOPHYSIN LEVELS IN HIPPOCAMPUS. 2022 10 4500 35 MORPHINE-WITHDRAWAL AVERSIVE MEMORIES AND THEIR EXTINCTION MODULATE H4K5 ACETYLATION AND BRD4 ACTIVATION IN THE RAT HIPPOCAMPUS AND BASOLATERAL AMYGDALA. CHROMATIN MODIFICATION IS A CRUCIAL MECHANISM IN SEVERAL IMPORTANT PHENOMENA IN THE BRAIN, INCLUDING DRUG ADDICTION. PERSISTENCE OF DRUG CRAVING AND RISK OF RELAPSE COULD BE ATTRIBUTED TO DRUG-INDUCED EPIGENETIC MECHANISMS THAT SEEM TO BE CANDIDATES EXPLAINING LONG-LASTING DRUG-INDUCED BEHAVIOUR AND MOLECULAR ALTERATIONS. HISTONE ACETYLATION HAS BEEN PROPOSED TO REGULATE DRUG-SEEKING BEHAVIOURS AND THE EXTINCTION OF REWARDING MEMORY OF DRUG TAKING. IN THIS WORK, WE STUDIED THE EPIGENETIC REGULATION DURING CONDITIONED PLACE AVERSION AND AFTER EXTINCTION OF AVERSIVE MEMORY OF OPIATE WITHDRAWAL. THROUGH IMMUNOFLUORESCENCE ASSAYS, WE ASSESSED SOME EPIGENETIC MARKS (H4K5AC AND P-BRD4) IN CRUCIAL AREAS RELATED TO MEMORY RETRIEVAL -BASOLATERAL AMYGDALA (BLA) AND HIPPOCAMPUS-. ADDITIONALLY, TO TEST THE DEGREE OF TRANSCRIPTIONAL ACTIVATION, WE EVALUATED THE IMMEDIATE EARLY GENES (IEGS) RESPONSE (ARC, BDNF, CREB, EGR-1, FOS AND NFKB) AND SMARCC1 (CHROMATIN REMODELER) THROUGH RT-QPCR IN THESE NUCLEI. OUR RESULTS SHOWED INCREASED P-BRD4 AND H4K5AC LEVELS DURING AVERSIVE MEMORY RETRIEVAL, SUGGESTING A MORE OPEN CHROMATIN STATE. HOWEVER, TRANSCRIPTIONAL ACTIVATION OF THESE IEGS WAS NOT FOUND, THEREFORE SUGGESTING THAT OTHER SECONDARY RESPONSE MAY ALREADY BE HAPPENING. ADDITIONALLY, SMARCC1 LEVELS WERE REDUCED DUE TO MORPHINE CHRONIC ADMINISTRATION IN BLA AND DENTATE GYRUS. THE ACTIVATION MARKERS RETURNED TO CONTROL LEVELS AFTER THE RETRIEVAL OF AVERSIVE MEMORIES, REVEALING A MORE REPRESSED CHROMATIN STATE. TAKEN TOGETHER, OUR RESULTS SHOW A MAJOR ROLE OF THE TANDEM H4K5AC/P-BRD4 DURING THE RETRIEVAL OF AVERSIVE MEMORIES. THESE RESULTS MIGHT BE USEFUL TO ELUCIDATE NEW MOLECULAR TARGETS TO IMPROVE AND DEVELOP PHARMACOLOGICAL TREATMENTS TO ADDRESS ADDICTION AND TO AVOID DRUG RELAPSE. 2023 11 2477 29 EPIGENETIC UPREGULATION OF CDK5 IN THE DORSAL HORN CONTRIBUTES TO NEUROPATHIC PAIN IN RATS. NUMEROUS REPORTS HAVE SHOWN THAT CYCLIN-DEPENDENT KINASE 5 (CDK5), A PROLINE-DIRECTED SERINE/THREONINE KINASE, CRITICALLY CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF CHRONIC PAIN INDUCED BY PERIPHERAL INFLAMMATION AND NERVE INJURY. RECENT EVIDENCE HAS ALSO SUGGESTED THE CRITICAL ROLE OF AN EPIGENETIC MECHANISM IN THE SETTING OF CHRONIC PAIN. THE PRESENT STUDY AIMS TO ELUCIDATE THE CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN (CREB)-MEDIATED UPREGULATION OF CDK5 AND ITS FUNCTIONAL SIGNIFICANCE IN RATS WITH NEUROPATHIC PAIN INDUCED BY CHRONIC CONSTRICTION INJURY (CCI) IN THE SCIATIC NERVE. SIGNIFICANTLY INCREASED EXPRESSION OF CDK5 WAS OBSERVED IN THE DORSAL HORN OF RATS WITH CCI, AND INTRATHECAL DELIVERY OF CDK5 INHIBITOR ROSCOVITINE SIGNIFICANTLY ATTENUATED THE MECHANICAL ALLODYNIA IN THESE RATS. PHOSPHORYLATION OF CREB AND ITS OCCUPANCY IN THE CDK5 PROMOTER REGION WAS ALSO INCREASED IN THE DORSAL HORN, WHICH LED TO INCREASED HISTONE H4 ACETYLATION IN THE CDK5 PROMOTER REGION AND THE UPREGULATED TRANSCRIPTION OF CDK5. INHIBITION OF CREB ACTIVITY ATTENUATED THE UPREGULATION OF CDK5 AND ALLEVIATED THE MECHANICAL ALLODYNIA IN RATS WITH CCI. THESE RESULTS DEMONSTRATED A CREB-MEDIATED EPIGENETIC UPREGULATION OF CDK5 IN THE DORSAL HORN, WHICH CRITICALLY CONTRIBUTED TO THE MAINTENANCE OF PAINFUL BEHAVIOR IN THE RATS WITH NEUROPATHIC PAIN. 2014 12 3203 36 HDAC3 ACTIVITY WITHIN THE NUCLEUS ACCUMBENS REGULATES COCAINE-INDUCED PLASTICITY AND BEHAVIOR IN A CELL-TYPE-SPECIFIC MANNER. EPIGENETIC MECHANISMS REGULATE PROCESSES OF NEUROPLASTICITY CRITICAL TO COCAINE-INDUCED BEHAVIORS. THIS INCLUDES THE CLASS I HISTONE DEACETYLASE (HDAC) HDAC3, KNOWN TO ACT AS A NEGATIVE REGULATOR OF COCAINE-ASSOCIATED MEMORY FORMATION WITHIN THE NUCLEUS ACCUMBENS (NAC). DESPITE THIS, IT REMAINS UNKNOWN HOW COCAINE ALTERS HDAC3-DEPENDENT MECHANISMS. HERE, WE PROFILED HDAC3 EXPRESSION AND ACTIVITY IN TOTAL NAC MOUSE TISSUE FOLLOWING COCAINE EXPOSURE. ALTHOUGH CHRONIC COCAINE DID NOT AFFECT EXPRESSION OF HDAC3 WITHIN THE NAC, CHRONIC COCAINE DID AFFECT PROMOTER-SPECIFIC CHANGES IN HDAC3 AND H4K8AC OCCUPANCY. THESE CHANGES IN PROMOTER OCCUPANCY CORRELATED WITH COCAINE-INDUCED CHANGES IN EXPRESSION OF PLASTICITY-RELATED GENES. TO CAUSALLY DETERMINE WHETHER COCAINE-INDUCED PLASTICITY IS MEDIATED BY HDAC3'S DEACETYLASE ACTIVITY, WE OVEREXPRESSED A DEACETYLASE-DEAD HDAC3 POINT MUTANT (HDAC3-Y298H-V5) WITHIN THE NAC OF ADULT MALE MICE. WE FOUND THAT DISRUPTING HDAC3'S ENZYMATIC ACTIVITY ALTERED SELECTIVE CHANGES IN GENE EXPRESSION AND SYNAPTIC PLASTICITY FOLLOWING COCAINE EXPOSURE, DESPITE HAVING NO EFFECTS ON COCAINE-INDUCED BEHAVIORS. IN FURTHER ASSESSING HDAC3'S ROLE WITHIN THE NAC, WE OBSERVED THAT CHRONIC COCAINE INCREASES HDAC3 EXPRESSION IN DRD1 BUT NOT DRD2-CELLS OF THE NAC. MOREOVER, WE DISCOVERED THAT HDAC3 ACTS SELECTIVELY WITHIN D1R CELL-TYPES TO REGULATE COCAINE-ASSOCIATED MEMORY FORMATION AND COCAINE-SEEKING. OVERALL, THESE RESULTS SUGGEST THAT COCAINE INDUCES CELL-TYPE-SPECIFIC CHANGES IN EPIGENETIC MECHANISMS TO PROMOTE PLASTICITY IMPORTANT FOR DRIVING COCAINE-RELATED BEHAVIORS.SIGNIFICANCE STATEMENT DRUGS OF ABUSE ALTER MOLECULAR MECHANISMS THROUGHOUT THE REWARD CIRCUITRY THAT CAN LEAD TO PERSISTENT DRUG-ASSOCIATED BEHAVIORS. EPIGENETIC REGULATORS ARE CRITICAL DRIVERS OF DRUG-INDUCED CHANGES IN GENE EXPRESSION. HERE, WE DEMONSTRATE THAT THE ACTIVITY OF AN EPIGENETIC ENZYME PROMOTES NEUROPLASTICITY WITHIN THE NUCLEUS ACCUMBENS (NAC) CRITICAL TO COCAINE ACTION. IN ADDITION, WE DEMONSTRATE THAT THESE CHANGES IN EPIGENETIC ACTIVITY DRIVE COCAINE-SEEKING BEHAVIORS IN A CELL-TYPE-SPECIFIC MANNER. THESE FINDINGS ARE KEY IN UNDERSTANDING AND TARGETING COCAINE'S IMPACT OF NEURAL CIRCUITRY AND BEHAVIOR. 2021 13 695 40 BRG1 IN THE NUCLEUS ACCUMBENS REGULATES COCAINE-SEEKING BEHAVIOR. BACKGROUND: DRUG ADDICTION IS DEFINED AS A CHRONIC DISEASE CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND EPISODES OF RELAPSE DESPITE PROLONGED PERIODS OF DRUG ABSTINENCE. NEUROBIOLOGICAL ADAPTATIONS, INCLUDING TRANSCRIPTIONAL AND EPIGENETIC ALTERATIONS IN THE NUCLEUS ACCUMBENS, ARE THOUGHT TO CONTRIBUTE TO THIS LIFE-LONG DISEASE STATE. WE PREVIOUSLY DEMONSTRATED THAT THE TRANSCRIPTION FACTOR SMAD3 IS INCREASED AFTER 7 DAYS OF WITHDRAWAL FROM COCAINE SELF-ADMINISTRATION. HOWEVER, IT IS STILL UNKNOWN WHICH ADDITIONAL FACTORS PARTICIPATE IN THE PROCESS OF CHROMATIN REMODELING AND FACILITATE THE BINDING OF SMAD3 TO PROMOTER REGIONS OF TARGET GENES. HERE, WE EXAMINED THE POSSIBLE INTERACTION OF BRG1-ALSO KNOWN AS SMARCA4, AN ADENOSINE TRIPHOSPHATASE-CONTAINING CHROMATIN REMODELER-AND SMAD3 IN RESPONSE TO COCAINE EXPOSURE. METHODS: THE EXPRESSION OF BRG1, AS WELL AS ITS BINDING TO SMAD3 AND TARGET GENE PROMOTER REGIONS, WAS EVALUATED IN THE NUCLEUS ACCUMBENS AND DORSAL STRIATUM OF RATS USING WESTERN BLOTTING, CO-IMMUNOPRECIPITATION, AND CHROMATIN IMMUNOPRECIPITATION FOLLOWING ABSTINENCE FROM COCAINE SELF-ADMINISTRATION. RATS WERE ASSESSED FOR COCAINE-SEEKING BEHAVIORS AFTER EITHER INTRA-ACCUMBAL INJECTIONS OF THE BRG1 INHIBITOR PFI3 OR VIRAL-MEDIATED OVEREXPRESSION OF BRG1. RESULTS: AFTER WITHDRAWAL FROM COCAINE SELF-ADMINISTRATION, BRG1 EXPRESSION AND COMPLEX FORMATION WITH SMAD3 ARE INCREASED IN THE NUCLEUS ACCUMBENS, RESULTING IN INCREASED BINDING OF BRG1 TO THE PROMOTER REGIONS OF CTNNB1, MEF2D, AND DBN1. INTRA-ACCUMBAL INFUSION OF PFI3 ATTENUATED, WHEREAS VIRAL OVEREXPRESSION OF BRG1 ENHANCED, COCAINE-REINSTATEMENT BEHAVIOR. CONCLUSIONS: BRG1 IS A KEY MEDIATOR OF THE SMAD3-DEPENDENT REGULATION OF CELLULAR AND BEHAVIORAL PLASTICITY THAT MEDIATES COCAINE SEEKING AFTER A PERIOD OF WITHDRAWAL. 2016 14 69 35 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 15 683 26 BRAIN PLASTICITY AND COGNITIVE FUNCTIONS AFTER ETHANOL CONSUMPTION IN C57BL/6J MICE. ACUTE OR CHRONIC ADMINISTRATIONS OF HIGH DOSES OF ETHANOL IN MICE ARE KNOWN TO PRODUCE SEVERE COGNITIVE DEFICITS LINKED TO HIPPOCAMPAL DAMAGE. HOWEVER, WE RECENTLY REPORTED THAT CHRONIC AND MODERATE ETHANOL INTAKE IN C57BL/6J MICE INDUCED CHROMATIN REMODELING WITHIN THE BDNF PROMOTERS, LEADING TO BOTH ENHANCED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND HIPPOCAMPAL NEUROGENESIS UNDER FREE-CHOICE PROTOCOL. WE PERFORMED HERE A SERIES OF CELLULAR AND BEHAVIORAL STUDIES TO ANALYZE THE CONSEQUENCES OF THESE MODIFICATIONS. WE SHOWED THAT A 3-WEEK CHRONIC FREE-CHOICE ETHANOL CONSUMPTION IN C57BL/6J MICE LED TO A DECREASE IN DNA METHYLATION OF THE BDNF GENE WITHIN THE CA1 AND CA3 SUBFIELDS OF THE HIPPOCAMPUS, AND UPREGULATED HIPPOCAMPAL BDNF SIGNALING PATHWAYS MEDIATED BY ERK, AKT AND CREB. HOWEVER, THIS ACTIVATION DID NOT AFFECT LONG-TERM POTENTIATION IN THE CA1. CONVERSELY, ETHANOL INTAKE IMPAIRED LEARNING AND MEMORY CAPACITIES ANALYZED IN THE CONTEXTUAL FEAR CONDITIONING TEST AND THE NOVEL OBJECT RECOGNITION TASK. IN ADDITION, ETHANOL INCREASED BEHAVIORAL PERSEVERATION IN THE BARNES MAZE TEST BUT DID NOT ALTER THE MOUSE OVERALL SPATIAL CAPACITIES. THESE DATA SUGGESTED THAT IN CONDITIONS OF CHRONIC AND MODERATE ETHANOL INTAKE, THE CHROMATIN REMODELING LEADING TO BDNF SIGNALING UPREGULATION IS PROBABLY AN ADAPTIVE PROCESS, ENGAGED VIA EPIGENETIC REGULATIONS, TO COUNTERACT THE COGNITIVE DEFICITS INDUCED BY ETHANOL. 2015 16 6108 34 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 17 6602 27 TWO KINDS OF TRANSCRIPTION FACTORS MEDIATE CHRONIC MORPHINE-INDUCED DECREASE IN MIR-105 IN MEDIAL PREFRONTAL CORTEX OF RATS. CHRONIC MORPHINE ADMINISTRATION ALTERS GENE EXPRESSION IN DIFFERENT BRAIN REGIONS, AN EFFECT WHICH MAY CONTRIBUTE TO PLASTIC CHANGES ASSOCIATED WITH ADDICTIVE BEHAVIOR. THIS CHANGE IN GENE EXPRESSION IS MOST POSSIBLY MEDIATED BY ADDICTIVE DRUG-INDUCED EPIGENETIC REMODELING OF GENE EXPRESSION PROGRAMS. OUR PREVIOUS STUDIES SHOWED THAT CHRONIC MORPHINE-INDUCED DECREASE OF MIR-105 IN THE MEDIAL PREFRONTAL CORTEX (MPFC) CONTRIBUTED TO CONTEXT-INDUCED RETRIEVAL OF MORPHINE WITHDRAWAL MEMORY. HOWEVER, HOW CHRONIC MORPHINE TREATMENT DECREASES MIR-105 IN THE MPFC STILL REMAINS UNKNOWN. THE PRESENT STUDY SHOWS THAT CHRONIC MORPHINE INDUCES ADDICTION-RELATED CHANGE IN MIR-105 IN THE MPFC VIA TWO KINDS OF TRANSCRIPTION FACTORS: THE FIRST TRANSCRIPTION FACTOR IS CREB ACTIVATED BY MU RECEPTORS-ERK-P90RSK SIGNALING PATHWAY AND THE SECOND TRANSCRIPTION FACTOR IS GLUCOCORTICOID RECEPTOR (GR), WHICH AS A NEGATIVE TRANSCRIPTION FACTOR, MEDIATES CHRONIC MORPHINE-INDUCED DECREASE IN MIR-105 IN THE MPFC OF RATS. 2022 18 1315 31 DELTA FOSB MEDIATES EPIGENETIC DESENSITIZATION OF THE C-FOS GENE AFTER CHRONIC AMPHETAMINE EXPOSURE. THE MOLECULAR MECHANISMS UNDERLYING THE TRANSITION FROM RECREATIONAL DRUG USE TO CHRONIC ADDICTION REMAIN POORLY UNDERSTOOD. ONE MOLECULE IMPLICATED IN THIS PROCESS IS DELTAFOSB, A TRANSCRIPTION FACTOR THAT ACCUMULATES IN STRIATUM AFTER REPEATED DRUG EXPOSURE AND MEDIATES SENSITIZED BEHAVIORAL RESPONSES TO PSYCHOSTIMULANTS AND OTHER DRUGS OF ABUSE. THE DOWNSTREAM TRANSCRIPTIONAL MECHANISMS BY WHICH DELTAFOSB REGULATES DRUG-INDUCED BEHAVIORS ARE INCOMPLETELY UNDERSTOOD. WE REPORTED PREVIOUSLY THE CHROMATIN REMODELING MECHANISMS BY WHICH DELTAFOSB ACTIVATES THE EXPRESSION OF CERTAIN GENES; HOWEVER, THE MECHANISMS UNDERLYING DELTAFOSB-MEDIATED GENE REPRESSION REMAIN UNKNOWN. HERE, WE IDENTIFY C-FOS, AN IMMEDIATE EARLY GENE RAPIDLY INDUCED IN STRIATUM AFTER ACUTE PSYCHOSTIMULANT EXPOSURE, AS A NOVEL DOWNSTREAM TARGET THAT IS REPRESSED CHRONICALLY BY DELTAFOSB. WE SHOW THAT ACCUMULATION OF DELTAFOSB IN STRIATUM AFTER CHRONIC AMPHETAMINE TREATMENT DESENSITIZES C-FOS MRNA INDUCTION TO A SUBSEQUENT DRUG DOSE. DELTAFOSB DESENSITIZES C-FOS EXPRESSION BY RECRUITING HISTONE DEACETYLASE 1 (HDAC1) TO THE C-FOS GENE PROMOTER, WHICH, IN TURN, DEACETYLATES SURROUNDING HISTONES AND ATTENUATES GENE ACTIVITY. ACCORDINGLY, LOCAL KNOCK-OUT OF HDAC1 IN STRIATUM ABOLISHES AMPHETAMINE-INDUCED DESENSITIZATION OF THE C-FOS GENE. IN CONCERT, CHRONIC AMPHETAMINE INCREASES HISTONE H3 METHYLATION ON THE C-FOS PROMOTER, A CHROMATIN MODIFICATION ALSO KNOWN TO REPRESS GENE ACTIVITY, AS WELL AS EXPRESSION LEVELS OF THE H3 HISTONE METHYLTRANSFERASE, KMT1A (LYSINE METHYLTRANSFERASE 1A, FORMERLY SUV39H1). THIS STUDY REVEALS A NOVEL EPIGENETIC PATHWAY THROUGH WHICH DELTAFOSB MEDIATES DISTINCT TRANSCRIPTIONAL PROGRAMS THAT MAY ULTIMATELY ALTER BEHAVIORAL PLASTICITY TO CHRONIC AMPHETAMINE EXPOSURE. 2008 19 598 21 BETA-ADRENERGIC SIGNALING PROMOTES TUMOR ANGIOGENESIS AND PROSTATE CANCER PROGRESSION THROUGH HDAC2-MEDIATED SUPPRESSION OF THROMBOSPONDIN-1. CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING HAVE BEEN SHOWN TO PROMOTE CANCER PROGRESSION, WHOSE UNDERLYING MECHANISMS ARE LARGELY UNCLEAR, ESPECIALLY THE INVOLVEMENT OF EPIGENETIC REGULATION. HISTONE DEACETYLASE-2 (HDAC2), AN EPIGENETIC REGULATOR, IS CRITICAL FOR STRESS-INDUCED CARDIAC HYPERTROPHY. IT IS UNKNOWN WHETHER IT IS NECESSARY FOR BETA-ADRENERGIC SIGNALING-PROMOTED CANCER PROGRESSION. USING XENOGRAFT MODELS, WE SHOWED THAT CHRONIC BEHAVIORAL STRESS AND BETA-ADRENERGIC SIGNALING PROMOTE ANGIOGENESIS AND PROSTATE CANCER PROGRESSION. HDAC2 WAS INDUCED BY BETA-ADRENERGIC SIGNALING IN VITRO AND IN MOUSE XENOGRAFTS. WE NEXT UNCOVERED THAT HDAC2 IS A DIRECT TARGET OF CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB) THAT IS ACTIVATED BY BETA-ADRENERGIC SIGNALING. NOTABLY, HDAC2 IS NECESSARY FOR BETA-ADRENERGIC SIGNALING TO INDUCE ANGIOGENESIS. WE FURTHER DEMONSTRATED THAT, UPON CREB ACTIVATION, HDAC2 REPRESSES THROMBOSPONDIN-1 (TSP1), A POTENT ANGIOGENESIS INHIBITOR, THROUGH EPIGENETIC REGULATION. TOGETHER, THESE DATA ESTABLISH A NOVEL PATHWAY THAT HDAC2 AND TSP1 ACT DOWNSTREAM OF CREB ACTIVATION IN BETA-ADRENERGIC SIGNALING TO PROMOTE CANCER PROGRESSION. 2017 20 6525 34 TRANSCRIPTIONAL AND EPIGENETIC SUBSTRATES OF METHAMPHETAMINE ADDICTION AND WITHDRAWAL: EVIDENCE FROM A LONG-ACCESS SELF-ADMINISTRATION MODEL IN THE RAT. METHAMPHETAMINE USE DISORDER IS A CHRONIC NEUROPSYCHIATRIC DISORDER CHARACTERIZED BY RECURRENT BINGE EPISODES, INTERVALS OF ABSTINENCE, AND RELAPSES TO DRUG USE. HUMANS ADDICTED TO METHAMPHETAMINE EXPERIENCE VARIOUS DEGREES OF COGNITIVE DEFICITS AND OTHER NEUROLOGICAL ABNORMALITIES THAT COMPLICATE THEIR ACTIVITIES OF DAILY LIVING AND THEIR PARTICIPATION IN TREATMENT PROGRAMS. IMPORTANTLY, MODELS OF METHAMPHETAMINE ADDICTION IN RODENTS HAVE SHOWN THAT ANIMALS WILL READILY LEARN TO GIVE THEMSELVES METHAMPHETAMINE. RATS ALSO ACCELERATE THEIR INTAKE OVER TIME. MICROARRAY STUDIES HAVE ALSO SHOWN THAT METHAMPHETAMINE TAKING IS ASSOCIATED WITH MAJOR TRANSCRIPTIONAL CHANGES IN THE STRIATUM MEASURED WITHIN A SHORT OR LONGER TIME AFTER CESSATION OF DRUG TAKING. AFTER A 2-H WITHDRAWAL TIME, THERE WAS INCREASED EXPRESSION OF GENES THAT PARTICIPATE IN TRANSCRIPTION REGULATION. THESE INCLUDED CYCLIC AMP RESPONSE ELEMENT BINDING (CREB), ETS DOMAIN-CONTAINING PROTEIN (ELK1), AND MEMBERS OF THE FOS FAMILY OF TRANSCRIPTION FACTORS. OTHER GENES OF INTEREST INCLUDE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), TYROSINE KINASE RECEPTOR, TYPE 2 (TRKB), AND SYNAPTOPHYSIN. METHAMPHETAMINE-INDUCED TRANSCRIPTION WAS FOUND TO BE REGULATED VIA PHOSPHORYLATED CREB-DEPENDENT EVENTS. AFTER A 30-DAY WITHDRAWAL FROM METHAMPHETAMINE SELF-ADMINISTRATION, HOWEVER, THERE WAS MOSTLY DECREASED EXPRESSION OF TRANSCRIPTION FACTORS INCLUDING JUND. THERE WAS ALSO DOWNREGULATION OF GENES WHOSE PROTEIN PRODUCTS ARE CONSTITUENTS OF CHROMATIN-REMODELING COMPLEXES. ALTOGETHER, THESE GENOME-WIDE RESULTS SHOW THAT METHAMPHETAMINE ABUSE MIGHT BE ASSOCIATED WITH ALTERED REGULATION OF A DIVERSITY OF GENE NETWORKS THAT IMPACT CELLULAR AND SYNAPTIC FUNCTIONS. THESE TRANSCRIPTIONAL CHANGES MIGHT SERVE AS TRIGGERS FOR THE NEUROPSYCHIATRIC PRESENTATIONS OF HUMANS WHO ABUSE THIS DRUG. BETTER UNDERSTANDING OF THE WAY THAT GENE PRODUCTS INTERACT TO CAUSE METHAMPHETAMINE ADDICTION WILL HELP TO DEVELOP BETTER PHARMACOLOGICAL TREATMENT OF METHAMPHETAMINE ADDICTS. 2015