1  3203 139 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2  2826  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  4878  54 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	

4    69  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  3314  49 HIPPOCAMPAL CANNABINOID 1 RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN MALE RATS. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCING LONG-TERM NEUROPLASTIC CHANGES THAT, IN TURN, CONTRIBUTE TO MALADAPTIVE BEHAVIORS. THIS BEHAVIORAL DYSREGULATION IS ASSOCIATED WITH TRANSCRIPTIONAL REPROGRAMMING IN BRAIN REWARD CIRCUITRY, ALTHOUGH THE MECHANISMS UNDERLYING THIS MODULATION REMAIN POORLY UNDERSTOOD. THE ENDOGENOUS CANNABINOID SYSTEM MAY PLAY A ROLE IN THIS PROCESS IN THAT CANNABINOID MECHANISMS MODULATE DRUG REWARD AND CONTRIBUTE TO COCAINE-INDUCED NEURAL ADAPTATIONS. IN THIS STUDY, WE INVESTIGATED WHETHER COCAINE SELF-ADMINISTRATION INDUCES LONG-TERM ADAPTATIONS, INCLUDING TRANSCRIPTIONAL MODIFICATIONS AND ASSOCIATED EPIGENETIC PROCESSES. WE FIRST EXAMINED ENDOCANNABINOID GENE EXPRESSION IN REWARD-RELATED BRAIN REGIONS OF THE RAT FOLLOWING SELF-ADMINISTERED (0.33 MG/KG INTRAVENOUS, FR1, 10 DAYS) COCAINE INJECTIONS. INTERESTINGLY, WE FOUND INCREASED CNR1 EXPRESSION IN SEVERAL STRUCTURES, INCLUDING PREFRONTAL CORTEX, NUCLEUS ACCUMBENS, DORSAL STRIATUM, HIPPOCAMPUS, HABENULA, AMYGDALA, LATERAL HYPOTHALAMUS, VENTRAL TEGMENTAL AREA, AND ROSTROMEDIAL TEGMENTAL NUCLEUS, WITH MOST PRONOUNCED EFFECTS IN THE HIPPOCAMPUS. ENDOCANNABINOID LEVELS, MEASURED BY MASS SPECTROMETRY, WERE ALSO ALTERED IN THIS STRUCTURE. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR IN THE HIPPOCAMPUS REVEALED THAT TWO ACTIVATING HISTONE MARKS, H3K4ME3 AND H3K27AC, WERE ENRICHED AT SPECIFIC ENDOCANNABINOID GENES FOLLOWING COCAINE INTAKE. TARGETING CB1 RECEPTORS USING CHROMOSOME CONFORMATION CAPTURE, WE HIGHLIGHTED SPATIAL CHROMATIN RE-ORGANIZATION IN THE HIPPOCAMPUS, AS WELL AS IN THE NUCLEUS ACCUMBENS, SUGGESTING THAT DESTABILIZATION OF THE CHROMATIN MAY CONTRIBUTE TO NEURONAL RESPONSES TO COCAINE. OVERALL, OUR RESULTS HIGHLIGHT A KEY ROLE FOR THE HIPPOCAMPUS IN COCAINE-INDUCED PLASTICITY AND BROADEN THE UNDERSTANDING OF NEURONAL ALTERATIONS ASSOCIATED WITH ENDOCANNABINOID SIGNALING. THE LATTER SUGGESTS THAT EPIGENETIC MODIFICATIONS CONTRIBUTE TO MALADAPTIVE BEHAVIORS ASSOCIATED WITH CHRONIC DRUG USE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  5535  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  4218  41 METHYL SUPPLEMENTATION ATTENUATES COCAINE-SEEKING BEHAVIORS AND COCAINE-INDUCED C-FOS ACTIVATION IN A DNA METHYLATION-DEPENDENT MANNER. EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, REGULATE RESPONSIVENESS TO DRUGS OF ABUSE, SUCH AS COCAINE, BUT RELATIVELY LITTLE IS KNOWN ABOUT THE REGULATION OF ADDICTIVE-LIKE BEHAVIORS BY DNA METHYLATION. TO INVESTIGATE THE INFLUENCE OF DNA METHYLATION ON THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ON DRUG-SEEKING BEHAVIOR, RATS RECEIVING METHYL SUPPLEMENTATION VIA CHRONIC L-METHIONINE (MET) UNDERWENT EITHER A SENSITIZATION REGIMEN OF INTERMITTENT COCAINE INJECTIONS OR INTRAVENOUS SELF-ADMINISTRATION OF COCAINE, FOLLOWED BY CUE-INDUCED AND DRUG-PRIMED REINSTATEMENT. MET BLOCKED SENSITIZATION TO THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ATTENUATED DRUG-PRIMED REINSTATEMENT, WITH NO EFFECT ON CUE-INDUCED REINSTATEMENT OR SUCROSE SELF-ADMINISTRATION AND REINSTATEMENT. FURTHERMORE, UPREGULATION OF DNA METHYLTRANSFERASE 3A AND 3B AND GLOBAL DNA HYPOMETHYLATION WERE OBSERVED IN THE NUCLEUS ACCUMBENS CORE (NAC), BUT NOT IN THE MEDIAL PREFRONTAL CORTEX (MPFC), OF COCAINE-PRETREATED RATS. GLUTAMATERGIC PROJECTIONS FROM THE MPFC TO THE NAC ARE CRITICALLY INVOLVED IN THE REGULATION OF COCAINE-PRIMED REINSTATEMENT, AND ACTIVATION OF BOTH BRAIN REGIONS IS SEEN IN HUMAN ADDICTS WHEN REEXPOSED TO THE DRUG. WHEN COMPARED WITH VEHICLE-PRETREATED RATS, THE IMMEDIATE EARLY GENE C-FOS (A MARKER OF NEURONAL ACTIVATION) WAS UPREGULATED IN THE NAC AND MPFC OF COCAINE-PRETREATED RATS AFTER COCAINE-PRIMED REINSTATEMENT, AND CHRONIC MET TREATMENT BLOCKED ITS INDUCTION IN BOTH REGIONS. COCAINE-INDUCED C-FOS EXPRESSION IN THE NAC WAS ASSOCIATED WITH REDUCED METHYLATION AT CPG DINUCLEOTIDES IN THE C-FOS GENE PROMOTER, EFFECTS REVERSED BY MET TREATMENT. OVERALL, THESE DATA SUGGEST THAT DRUG-SEEKING BEHAVIORS ARE, IN PART, ATTRIBUTABLE TO A DNA METHYLATION-DEPENDENT PROCESS, LIKELY OCCURRING AT SPECIFIC GENE LOCI (E.G., C-FOS) IN THE REWARD PATHWAY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  4163  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9   882  45 CHRONIC COCAINE-INDUCED H3 ACETYLATION AND TRANSCRIPTIONAL ACTIVATION OF CAMKIIALPHA IN THE NUCLEUS ACCUMBENS IS CRITICAL FOR MOTIVATION FOR DRUG REINFORCEMENT. THE REGULATION OF GENE EXPRESSION IN THE BRAIN REWARD REGIONS IS KNOWN TO CONTRIBUTE TO THE PATHOGENESIS AND PERSISTENCE OF DRUG ADDICTION. INCREASING EVIDENCE SUGGESTS THAT THE REGULATION OF GENE TRANSCRIPTION IS MEDIATED BY EPIGENETIC MECHANISMS THAT ALTER THE CHROMATIN STRUCTURE AT SPECIFIC GENE PROMOTERS. TO BETTER UNDERSTAND THE INVOLVEMENT OF EPIGENETIC REGULATION IN DRUG REINFORCEMENT PROPERTIES, RATS WERE SUBJECTED TO COCAINE SELF-ADMINISTRATION PARADIGM. DAILY HISTONE DEACETYLASE (HDAC) INHIBITOR INFUSIONS IN THE SHELL OF THE NUCLEUS ACCUMBENS (NAC) CAUSED AN UPWARD SHIFT IN THE DOSE-RESPONSE CURVE UNDER FIXED-RATIO SCHEDULE AND INCREASED THE BREAK POINT UNDER PROGRESSIVE-RATIO SCHEDULE, INDICATING ENHANCED MOTIVATION FOR SELF-ADMINISTERED DRUG. THE EFFECT OF THE HDAC INHIBITOR IS ATTRIBUTED TO THE INCREASED ELEVATION OF HISTONE ACETYLATION INDUCED BY CHRONIC, BUT NOT ACUTE, COCAINE EXPERIENCE. IN CONTRAST, NEUTRALIZING THE CHRONIC COCAINE-INDUCED INCREASE IN HISTONE MODIFICATION BY THE BILATERAL OVEREXPRESSION OF HDAC4 IN THE NAC SHELL REDUCED DRUG MOTIVATION. THE ASSOCIATION BETWEEN THE MOTIVATION FOR COCAINE AND THE TRANSCRIPTIONAL ACTIVATION OF ADDICTION-RELATED GENES BY H3 ACETYLATION IN THE NAC SHELL WAS ANALYZED. AMONG THE GENES ACTIVATED BY CHRONIC COCAINE EXPERIENCES, THE EXPRESSION OF CAMKIIALPHA, BUT NOT CAMKIIBETA, CORRELATED POSITIVELY WITH MOTIVATION FOR THE DRUG. LENTIVIRUS-MEDIATED SHRNA KNOCKDOWN EXPERIMENTS SHOWED THAT CAMKIIALPHA, BUT NOT CAMKIIBETA, IN THE NAC SHELL IS ESSENTIAL FOR THE MAINTENANCE OF MOTIVATION TO SELF-ADMINISTERED COCAINE. THESE FINDINGS SUGGEST THAT CHRONIC DRUG-USE-INDUCED TRANSCRIPTIONAL ACTIVATION OF GENES, SUCH AS CAMKIIALPHA, MODULATED BY H3 ACETYLATION IN THE NAC IS A CRITICAL REGULATORY MECHANISM UNDERLYING MOTIVATION FOR DRUG REINFORCEMENT.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10  5712  46 SIRT1 MEDIATES DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS. DEPRESSION IS A RECURRING AND LIFE-THREATENING ILLNESS THAT AFFECTS UP TO 120 MILLION PEOPLE WORLDWIDE. IN THE PRESENT STUDY, WE SHOW THAT CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MODEL OF DEPRESSION IN MICE, INCREASES SIRT1 LEVELS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. INCREASES IN SIRT1, A WELL CHARACTERIZED CLASS III HISTONE DEACETYLASE, AFTER CHRONIC SOCIAL DEFEAT SUGGEST A ROLE FOR THIS ENZYME IN MEDIATING DEPRESSION-LIKE BEHAVIORS. WHEN RESVERATROL, A PHARMACOLOGICAL ACTIVATOR OF SIRT1, WAS DIRECTLY INFUSED BILATERALLY INTO THE NAC, WE OBSERVED AN INCREASE IN DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. CONVERSELY, INTRA-NAC INFUSIONS OF EX-527, A SIRT1 ANTAGONIST, REDUCED THESE BEHAVIORS; EX-527 ALSO REDUCED ACUTE STRESS RESPONSES IN STRESS-NAIVE MICE. NEXT, WE INCREASED SIRT1 LEVELS DIRECTLY IN NAC BY USE OF VIRAL-MEDIATED GENE TRANSFER AND OBSERVED AN INCREASE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS WHEN MICE WERE ASSESSED IN THE OPEN-FIELD, ELEVATED-PLUS-MAZE, AND FORCED SWIM TESTS. USING A CRE-INDUCIBLE VIRAL VECTOR SYSTEM TO OVEREXPRESS SIRT1 SELECTIVELY IN DOPAMINE D1 OR D2 SUBPOPULATIONS OF MEDIUM SPINY NEURONS (MSNS) IN THE NAC, WE FOUND THAT SIRT1 PROMOTES DEPRESSIVE-LIKE BEHAVIORS ONLY WHEN OVEREXPRESSED IN D1 MSNS, WITH NO EFFECT SEEN IN D2 MSNS. CONVERSELY, SELECTIVE ABLATION OF SIRT1 IN THE NAC USING VIRAL-CRE IN FLOXED SIRT1 MICE RESULTED IN DECREASED DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. TOGETHER, THESE RESULTS DEMONSTRATE THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN THE NAC IN REGULATING MOOD-RELATED BEHAVIORAL ABNORMALITIES AND IDENTIFIES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT MAJOR DEPRESSIVE DISORDERS. SIGNIFICANCE STATEMENT: IN THIS STUDY, WE DEMONSTRATE A PIVOTAL ROLE FOR SIRT1 IN ANXIETY- AND DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW THAT STRESS STABLY INDUCES SIRT1 EXPRESSION IN THIS BRAIN REGION AND THAT ALTERING SIRT1 ACTIVITY USING A PHARMACOLOGICAL OR GENETIC APPROACH REGULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIORS. THESE RESULTS SUGGEST THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN REGULATING MOOD-RELATED BEHAVIORS AND INTRODUCES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT DEPRESSION AND OTHER STRESS-RELATED DISORDERS. A RECENT GROUNDBREAKING PUBLICATION BY THE CONVERGE CONSORTIUM (2015) IDENTIFIED A REPRODUCIBLE ASSOCIATION OF THE SIRT1 LOCUS WITH MAJOR DEPRESSION IN HUMANS. THEREFORE, OUR RESULTS ARE TIMELY AND HAVE SIGNIFICANT TRANSLATIONAL RELEVANCE.	2016	
                                                                                                                                                          
11  5749  36 SOCIAL DEFEAT INDUCES CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VENTRAL HIPPOCAMPUS, PREFRONTAL CORTEX, AND DORSAL RAPHE NUCLEUS. CHRONIC EXPOSURE TO STRESS IS ASSOCIATED WITH A NUMBER OF PSYCHIATRIC DISORDERS, BUT LITTLE IS KNOWN ABOUT THE EPIGENETIC MECHANISMS THAT UNDERLIE THE STRESS RESPONSE OR RESILIENCE TO CHRONIC STRESS. WE INVESTIGATED HISTONE ACETYLATION IN SEVEN DIFFERENT BRAIN REGIONS OF RATS EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS: THE DORSAL HIPPOCAMPUS (DHPC), VENTRAL HIPPOCAMPUS (VHPC), MEDIAL PREFRONTAL CORTEX (MPFC), BASOLATERAL AMYGDALA (BLA), LOCUS COERULEUS (LC), PARAVENTRICULAR THALAMUS (PVT), AND DORSAL RAPHE (DR) NUCLEUS. THIS STRESS PARADIGM WAS UNIQUE IN THAT IT ALLOWED RATS TO DISPLAY RESILIENCE IN THE FORM OF AN ACTIVE COPING MECHANISM. WE FOUND THAT THERE WAS AN INCREASE IN ACETYLATION OF H3K9/14 (H3K9/14AC) AND BULK ACETYLATION OF H4K5,8,12,16 (H4K5,8,12,16AC) IN THE DR NUCLEUS OF RATS THAT WERE LESS RESILIENT. LESS RESILIENT RATS ALSO DISPLAYED INCREASED LEVELS OF H3K18 ACETYLATION (H3K18AC) IN THE MPFC WHEN COMPARED TO NON-STRESSED CONTROLS. IN THE VHPC, THERE WAS AN INCREASE IN H3K18AC AND H4K12 (H4K12AC) IN RATS THAT WERE LESS RESILIENT WHEN COMPARED TO NON-STRESSED CONTROL RATS. IN ADDITION, THERE WAS A DECREASE IN LEVELS OF H4K8 ACETYLATION (H4K8AC) IN BOTH RESILIENT AND NON-RESILIENT RATS AS COMPARED TO CONTROLS. WE ASSESSED EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VHPC AND THE MPFC USING QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (PCR) AND FOUND CHANGES IN EXPRESSION OF A NUMBER OF TARGETS. THESE INCLUDED CHANGES IN SIRT1 AND SIRT2 IN THE VHPC AND CHANGES IN KAT5 IN THE MPFC. OVERALL, THESE RESULTS SUGGEST THAT CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THESE REGIONS CORRELATE WITH THE BEHAVIORAL RESPONSE TO STRESS IN SOCIALLY DEFEATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  3315  39 HIPPOCAMPAL MU OPIOID RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN RAT. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCED BY LONG-TERM BRAIN CHANGES. UNDERSTANDING THE NEUROCHEMICAL CHANGES UNDERLYING THE REINFORCING EFFECTS OF THIS DRUG OF ABUSE IS CRITICAL FOR REDUCING THE SOCIETAL BURDEN OF DRUG ADDICTION. THE MU OPIOID RECEPTOR PLAYS A MAJOR ROLE IN DRUG REWARD. THIS RECEPTOR IS MODULATED BY CHRONIC COCAINE TREATMENT IN SPECIFIC BRAIN STRUCTURES, BUT FEW STUDIES INVESTIGATED NEUROCHEMICAL ADAPTATIONS INDUCED BY VOLUNTARY COCAINE INTAKE. IN THIS STUDY, WE INVESTIGATED WHETHER INTRAVENOUS COCAINE-SELF ADMINISTRATION (0.33 MG/KG/INJECTION, FIXED-RATIO 1 [FR1], 10 DAYS) IN RATS INDUCES TRANSCRIPTIONAL AND FUNCTIONAL CHANGES OF THE MU OPIOID RECEPTOR IN REWARD-RELATED BRAIN REGIONS. EPIGENETIC PROCESSES WITH HISTONE MODIFICATIONS WERE EXAMINED FOR TWO ACTIVATING MARKS, H3K4ME3, AND H3K27AC. WE FOUND AN INCREASE OF MU OPIOID RECEPTOR GENE EXPRESSION ALONG WITH A POTENTIATION OF ITS FUNCTIONALITY IN HIPPOCAMPUS OF COCAINE SELF-ADMINISTERING ANIMALS COMPARED TO SALINE CONTROLS. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR REVEALED NO MODIFICATIONS OF THE HISTONE MARK H3K4ME3 AND H3K27AC LEVELS AT MU OPIOID RECEPTOR PROMOTER. OUR STUDY HIGHLIGHTS THE HIPPOCAMPUS AS AN IMPORTANT TARGET TO FURTHER INVESTIGATE NEUROADAPTIVE PROCESSES LEADING TO COCAINE ADDICTION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  6177  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  5021  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  5651  30 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16   775  41 CELL TYPE-SPECIFIC WHOLE-GENOME LANDSCAPE OF DELTAFOSB BINDING IN THE NUCLEUS ACCUMBENS AFTER CHRONIC COCAINE EXPOSURE. BACKGROUND: THE ABILITY OF NEURONS TO RESPOND TO EXTERNAL STIMULI INVOLVES ADAPTATIONS OF GENE EXPRESSION. INDUCTION OF THE TRANSCRIPTION FACTOR DELTAFOSB IN THE NUCLEUS ACCUMBENS, A KEY BRAIN REWARD REGION, IS IMPORTANT FOR THE DEVELOPMENT OF DRUG ADDICTION. HOWEVER, A COMPREHENSIVE MAP OF DELTAFOSB'S GENE TARGETS HAS NOT YET BEEN GENERATED. METHODS: WE USED CUT&RUN (CLEAVAGE UNDER TARGETS AND RELEASE USING NUCLEASE) TO MAP THE GENOME-WIDE CHANGES IN DELTAFOSB BINDING IN THE 2 MAIN TYPES OF NUCLEUS ACCUMBENS NEURONS-D1 OR D2 MEDIUM SPINY NEURONS-AFTER CHRONIC COCAINE EXPOSURE. TO ANNOTATE GENOMIC REGIONS OF DELTAFOSB BINDING SITES, WE ALSO EXAMINED THE DISTRIBUTIONS OF SEVERAL HISTONE MODIFICATIONS. RESULTING DATASETS WERE LEVERAGED FOR MULTIPLE BIOINFORMATIC ANALYSES. RESULTS: THE MAJORITY OF DELTAFOSB PEAKS OCCUR OUTSIDE PROMOTER REGIONS, INCLUDING INTERGENIC REGIONS, AND ARE SURROUNDED BY EPIGENETIC MARKS INDICATIVE OF ACTIVE ENHANCERS. BRG1, THE CORE SUBUNIT OF THE SWI/SNF CHROMATIN REMODELING COMPLEX, OVERLAPS WITH DELTAFOSB PEAKS, A FINDING CONSISTENT WITH EARLIER STUDIES OF DELTAFOSB'S INTERACTING PROTEINS. CHRONIC COCAINE USE INDUCES BROAD CHANGES IN DELTAFOSB BINDING IN BOTH D1 AND D2 NUCLEUS ACCUMBENS MEDIUM SPINY NEURONS OF MALE AND FEMALE MICE. IN ADDITION, IN SILICO ANALYSES PREDICT THAT DELTAFOSB COOPERATIVELY REGULATES GENE EXPRESSION WITH HOMEOBOX AND T-BOX TRANSCRIPTION FACTORS. CONCLUSIONS: THESE NOVEL FINDINGS UNCOVER KEY ELEMENTS OF DELTAFOSB'S MOLECULAR MECHANISMS IN TRANSCRIPTIONAL REGULATION AT BASELINE AND IN RESPONSE TO CHRONIC COCAINE EXPOSURE. FURTHER CHARACTERIZATION OF DELTAFOSB'S COLLABORATIVE TRANSCRIPTIONAL AND CHROMATIN PARTNERS SPECIFICALLY IN D1 AND D2 MEDIUM SPINY NEURONS WILL REVEAL A BROADER PICTURE OF THE FUNCTION OF DELTAFOSB AND THE MOLECULAR BASIS OF DRUG ADDICTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17   695  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  5974  46 TET1 IN NUCLEUS ACCUMBENS OPPOSES DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. DEPRESSION IS A LEADING CAUSE OF DISEASE BURDEN, YET CURRENT THERAPIES FULLY TREAT <50% OF AFFECTED INDIVIDUALS. INCREASING EVIDENCE IMPLICATES EPIGENETIC MECHANISMS IN DEPRESSION AND ANTIDEPRESSANT ACTION. HERE WE EXAMINED A POSSIBLE ROLE FOR THE DNA DIOXYGENASE, TEN-ELEVEN TRANSLOCATION PROTEIN 1 (TET1), IN DEPRESSION-RELATED BEHAVIORAL ABNORMALITIES. WE APPLIED CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MOUSE MODEL OF DEPRESSION-LIKE BEHAVIORS, AND EXAMINED TET1 EXPRESSION CHANGES IN NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW DECREASED TET1 EXPRESSION IN NAC IN STRESS-SUSCEPTIBLE MICE ONLY. SURPRISINGLY, SELECTIVE KNOCKOUT OF TET1 IN NAC NEURONS OF ADULT MICE PRODUCED ANTIDEPRESSANT-LIKE EFFECTS IN SEVERAL BEHAVIORAL ASSAYS. TO IDENTIFY TET1 TARGETS THAT MEDIATE THESE ACTIONS, WE PERFORMED RNASEQ ON NAC AFTER CONDITIONAL DELETION OF TET1 AND FOUND THAT IMMUNE-RELATED GENES ARE THE MOST HIGHLY DYSREGULATED. MOREOVER, MANY OF THESE GENES ARE ALSO UPREGULATED IN THE NAC OF RESILIENT MICE AFTER CHRONIC SOCIAL DEFEAT STRESS. THESE FINDINGS REVEAL A NOVEL ROLE FOR TET1, AN ENZYME IMPORTANT FOR DNA HYDROXYMETHYLATION, IN THE BRAIN'S REWARD CIRCUITRY IN MODULATING STRESS RESPONSES IN MICE. WE ALSO IDENTIFY A SUBSET OF GENES THAT ARE REGULATED BY TET1 IN THIS CIRCUITRY. THESE FINDINGS PROVIDE NEW INSIGHT INTO THE PATHOPHYSIOLOGY OF DEPRESSION, WHICH CAN AID IN FUTURE ANTIDEPRESSANT DRUG DISCOVERY EFFORTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  4643  42 NEUROPATHIC PAIN AS A TRIGGER FOR HISTONE MODIFICATIONS IN LIMBIC CIRCUITRY. CHRONIC PAIN INVOLVES BOTH CENTRAL AND PERIPHERAL NEURONAL PLASTICITY THAT ENCOMPASSES CHANGES IN THE BRAIN, SPINAL CORD, AND PERIPHERAL NOCICEPTORS. WITHIN THE FOREBRAIN, MESOCORTICOLIMBIC REGIONS ASSOCIATED WITH EMOTIONAL REGULATION HAVE RECENTLY BEEN SHOWN TO EXHIBIT LASTING GENE EXPRESSION CHANGES IN MODELS OF CHRONIC PAIN. TO BETTER UNDERSTAND HOW SUCH ENDURING TRANSCRIPTIONAL CHANGES MIGHT BE REGULATED WITHIN BRAIN STRUCTURES ASSOCIATED WITH PROCESSING OF PAIN OR AFFECT, WE EXAMINED EPIGENETIC MODIFICATIONS INVOLVED WITH ACTIVE OR PERMISSIVE TRANSCRIPTIONAL STATES (HISTONE H3 LYSINE 4 MONO AND TRIMETHYLATION, AND HISTONE H3 LYSINE 27 ACETYLATION) IN PERIAQUEDUCTAL GRAY (PAG), LATERAL HYPOTHALAMUS (LH), NUCLEUS ACCUMBENS (NAC), AND VENTRAL TEGMENTAL AREA (VTA) 5 WEEKS AFTER SCIATIC NERVE INJURY IN MICE TO MODEL CHRONIC PAIN. FOR BOTH MALE AND FEMALE MICE IN CHRONIC PAIN, WE OBSERVED AN OVERALL TREND FOR A REDUCTION OF THESE EPIGENETIC MARKERS IN PERIAQUEDUCTAL GRAY, LH, AND NAC, BUT NOT VTA. MOREOVER, WE DISCOVERED THAT SOME EPIGENETIC MODIFICATIONS EXHIBITED CHANGES ASSOCIATED WITH PAIN HISTORY, WHILE OTHERS WERE ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY. WHEN TAKEN TOGETHER, THESE RESULTS SUGGEST THAT NERVE INJURY LEADS TO CHRONIC CHROMATIN-MEDIATED SUPPRESSION OF TRANSCRIPTION IN KEY LIMBIC BRAIN STRUCTURES AND CIRCUITS, WHICH MAY UNDERLIE ENDURING CHANGES IN PAIN PROCESSING AND SENSITIVITY WITHIN THESE SYSTEMS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  2012  35 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