1  2040 133 EPIGENETIC CHANGES WITH DIETARY SOY IN CYNOMOLGUS MONKEYS. NUTRITIONAL INTERVENTIONS ARE IMPORTANT ALTERNATIVES FOR REDUCING THE PREVALENCE OF MANY CHRONIC DISEASES. SOY IS A GOOD SOURCE OF PROTEIN THAT CONTAINS ISOFLAVONES, INCLUDING GENISTEIN AND DAIDZEIN, AND MAY ALTER THE RISK OF OBESITY, TYPE 2 DIABETES, OSTEOPOROSIS, CARDIOVASCULAR DISEASE, AND REPRODUCTIVE CANCERS. WE HAVE SHOWN PREVIOUSLY IN NONHUMAN PRIMATES THAT SOY PROTEIN CONTAINING ISOFLAVONES LEADS TO IMPROVED BODY WEIGHT, INSULIN SENSITIVITY, LIPID PROFILES, AND ATHEROSCLEROSIS COMPARED TO PROTEIN WITHOUT SOY ISOFLAVONES (CASEIN), AND DOES NOT INCREASE THE RISK OF CANCER. SINCE GENISTEIN HAS BEEN SHOWN TO ALTER DNA METHYLATION, WE COMPARED THE METHYLATION PROFILES OF CYNOMOLGUS MONKEYS, FROM MULTIPLE TISSUES, EATING TWO HIGH-FAT, TYPICAL AMERICAN DIETS (TAD) WITH SIMILAR MACRONUTRIENT CONTENTS, WITH OR WITHOUT SOY PROTEIN. DNA METHYLATION STATUS WAS SUCCESSFULLY DETERMINED FOR 80.6% OF THE PROBES IN AT LEAST ONE TISSUE USING ILLUMINA'S HUMANMETHYLATION27 BEADCHIP. OVERALL METHYLATION INCREASED IN LIVER AND MUSCLE TISSUE WHEN MONKEYS SWITCHED FROM THE TAD-SOY TO THE TAD-CASEIN DIETS. GENES INVOLVED IN EPIGENETIC PROCESSES, SPECIFICALLY HOMEOBOX GENES (HOXA5, HOXA11, AND HOXB1), AND ABCG5 WERE AMONG THOSE THAT CHANGED BETWEEN DIETS. THESE DATA SUPPORT THE USE OF THE HUMANMETHYLATION27 BEADCHIP IN CYNOMOLGUS MONKEYS AND IDENTIFY EPIGENETIC CHANGES ASSOCIATED WITH DIETARY INTERVENTIONS WITH SOY PROTEIN THAT MAY POTENTIALLY AFFECT THE ETIOLOGY OF COMPLEX DISEASES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  5535  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3   878  30 CHRONIC CADMIUM EXPOSURE AGGRAVATES MALIGNANT PHENOTYPES OF NASOPHARYNGEAL CARCINOMA BY ACTIVATING THE WNT/BETA-CATENIN SIGNALING PATHWAY VIA HYPERMETHYLATION OF THE CASEIN KINASE 1ALPHA PROMOTER. BACKGROUND: OUR PREVIOUS STUDY HAS SHOWN THAT CADMIUM (CD) EXPOSURE IS NOT ONLY A RISK FACTOR FOR NASOPHARYNGEAL CARCINOMA (NPC), BUT ALSO CORRELATED WITH THE CLINICAL STAGE AND LYMPH NODE METASTASIS. HOWEVER, THE UNDERLYING MOLECULAR EVENTS OF CD INVOLVED IN NPC PROGRESSION REMAIN TO BE ELUCIDATED. PURPOSE: THE OBJECTIVE OF THIS STUDY WAS TO DECIPHER HOW CD IMPACTS THE MALIGNANT PHENOTYPES OF NPC CELLS. METHODS: NPC CELL LINES CNE-1 AND CNE-2 WERE CONTINUOUSLY EXPOSED WITH 1 MUM CD CHLORIDE FOR 10 WEEKS, DESIGNATING AS CHRONIC CD TREATED NPC CELLS (CCT-NPC). MTT ASSAY, COLONY FORMATION ASSAY AND XENOGRAFT TUMOR GROWTH WERE USED TO ASSESS CELL VIABILITY IN VITRO AND IN VIVO. TRANSWELL ASSAYS WERE PERFORMED TO DETECT CELL INVASION AND MIGRATION. THE PROTEIN LEVELS OF E-CADHERIN, N-CADHERIN, VIMENTIN AS WELL AS BETA-CATENIN AND CASEIN KINASE 1ALPHA(CK1ALPHA) WERE MEASURED BY WESTERN BLOT. IMMUNOFLUORESCENCE STAINING WAS USED TO OBSERVE THE DISTRIBUTION OF FILAMENT ACTIN (F-ACTIN), BETA-CATENIN AND CK1ALPHA. THE MRNA LEVELS OF DOWNSTREAM TARGET GENES OF BETA-CATENIN WERE DETECTED BY RT-PCR. WNT/BETA-CATENIN SIGNALING ACTIVITY WAS ASSESSED BY TOPFLASH/FOPFLASH DUAL LUCIFERASE REPORT SYSTEM. MS-PCR WAS USED TO DETECT THE METHYLATION STATUS OF CK1ALPHA. FINALLY, THE ACTIVATION OF WNT/BETA-CATENIN PATHWAY AND CELL BIOLOGICAL PROPERTIES WERE EXAMINED FOLLOWING TREATMENT OF CCT-NPC CELLS WITH 5-AZA-2-DEOXY-CYTIDINE(5-AZA-CDR). RESULTS: CCT-NPC CELLS SHOWED AN INCREASE IN CELL PROLIFERATION, COLONY FORMATION, INVASION AND MIGRATION COMPARED TO THE PARENTAL CELLS. CD ALSO INDUCED CYTOSKELETON REORGANIZATION AND EPITHELIAL-TO-MESENCHYMAL TRANSITION. UPREGULATION AND NUCLEAR TRANSLOCATION OF BETA-CATENIN AND INCREASED LUCIFERASE ACTIVITY ACCOMPANIED WITH TRANSCRIPTION OF DOWNSTREAM TARGET GENES WERE FOUND IN CCT-NPC CELLS. TREATMENT OF CCT-CNE1 CELLS WITH 5-AZA-CDR COULD REVERSE THE HYPERMETHYLATION OF CK1ALPHA AND ATTENUATE THE CELL MALIGNANCY. CONCLUSION: THESE RESULTS SUPPORT A ROLE FOR CHRONIC CD EXPOSURE AS A DRIVING FORCE FOR THE MALIGNANT PROGRESSION OF NPC VIA EPIGENETIC ACTIVATION OF THE WNT/BETA-CATENIN PATHWAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  1653  30 DOPAMINE TRANSPORTER KNOCKOUT RATS DISPLAY EPIGENETIC ALTERATIONS IN RESPONSE TO COCAINE EXPOSURE. (1) BACKGROUND: THERE IS AN URGENT NEED FOR EFFECTIVE TREATMENTS FOR COCAINE USE DISORDER (CUD), AND NEW PHARMACOLOGICAL APPROACHES TARGETING EPIGENETIC MECHANISMS APPEAR TO BE PROMISING OPTIONS FOR THE TREATMENT OF THIS DISEASE. DOPAMINE TRANSPORTER (DAT) TRANSGENIC RATS RECENTLY HAVE BEEN PROPOSED AS A NEW ANIMAL MODEL FOR STUDYING SUSCEPTIBILITY TO CUD. (2) METHODS: DAT TRANSGENIC RATS WERE TREATED CHRONICALLY WITH COCAINE (10 MG/KG) FOR 8 DAYS, AND THE EXPRESSION OF EPIGENETIC MODULATORS, LYSINE DEMETHYLASE 6B (KDM6B) AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), WAS EXAMINED IN THE PREFRONTAL CORTEX (PFC). (3) RESULTS: WE SHOW THAT ONLY FULL KNOCKOUT (KO) OF DAT IMPACTS BASAL LEVELS OF KDM6B IN FEMALES. ADDITIONALLY, COCAINE ALTERED THE EXPRESSION OF BOTH EPIGENETIC MARKERS IN A SEX- AND GENOTYPE-DEPENDENT MANNER. IN RESPONSE TO CHRONIC COCAINE, KDM6B EXPRESSION WAS DECREASED IN MALE RATS WITH PARTIAL DAT MUTATION (HET), WHILE NO CHANGES WERE OBSERVED IN WILD-TYPE (WT) OR KO RATS. INDEED, WHILE HET MALE RATS HAVE REDUCED KDM6B AND BRD4 EXPRESSION, HET FEMALE RATS SHOWED INCREASED KDM6B AND BRD4 EXPRESSION LEVELS, HIGHLIGHTING THE IMPACT OF SEX ON EPIGENETIC MECHANISMS IN RESPONSE TO COCAINE. FINALLY, BOTH MALE AND FEMALE KO RATS SHOWED INCREASED EXPRESSION OF BRD4, BUT ONLY KO FEMALES EXHIBITED SIGNIFICANTLY INCREASED KDM6B EXPRESSION IN RESPONSE TO COCAINE. ADDITIONALLY, THE MAGNITUDE OF THESE EFFECTS WAS BIGGER IN FEMALES WHEN COMPARED TO MALES FOR BOTH EPIGENETIC ENZYMES. (4) CONCLUSIONS: THIS PRELIMINARY STUDY PROVIDES ADDITIONAL SUPPORT THAT TARGETING KDM6B AND/OR BRD4 MAY POTENTIALLY BE THERAPEUTIC IN TREATING ADDICTION-RELATED BEHAVIORS IN A SEX-DEPENDENT MANNER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  3410  42 HOXA5 UNDERGOES DYNAMIC DNA METHYLATION AND TRANSCRIPTIONAL REPRESSION IN THE ADIPOSE TISSUE OF MICE EXPOSED TO HIGH-FAT DIET. BACKGROUND/OBJECTIVES: THE GENOMIC BASES OF THE ADIPOSE TISSUE ABNORMALITIES INDUCED BY CHRONIC POSITIVE CALORIE EXCESS HAVE BEEN ONLY PARTIALLY ELUCIDATED. WE ADOPTED A GENOME-WIDE APPROACH TO DIRECTLY TEST WHETHER LONG-TERM HIGH-FAT DIET (HFD) EXPOSURE AFFECTS THE DNA METHYLATION PROFILE OF THE MOUSE ADIPOSE TISSUE AND TO IDENTIFY THE FUNCTIONAL CONSEQUENCES OF THESE CHANGES. SUBJECTS/METHODS: WE HAVE USED EPIDIDYMAL FAT OF MICE FED EITHER HIGH-FAT (HFD) OR REGULAR CHOW (STD) DIET FOR 5 MONTHS AND PERFORMED GENOME-WIDE DNA METHYLATION ANALYSES BY METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). MOUSE HOMEOBOX (HOX) GENE DNA METHYLATION PCR, RT-QPCR AND BISULPHITE SEQUENCING ANALYSES WERE THEN PERFORMED. RESULTS: MICE FED THE HFD PROGRESSIVELY EXPANDED THEIR ADIPOSE MASS ACCOMPANIED BY A SIGNIFICANT DECREASE IN GLUCOSE TOLERANCE (P<0.001) AND INSULIN SENSITIVITY (P<0.05). MEDIP-SEQ DATA ANALYSIS REVEALED A UNIFORM DISTRIBUTION OF DIFFERENTIALLY METHYLATED REGIONS (DMR) THROUGH THE ENTIRE ADIPOCYTE GENOME, WITH A HIGHER NUMBER OF HYPERMETHYLATED REGIONS IN HFD MICE (P<0.005). THIS DIFFERENT METHYLATION PROFILE WAS ACCOMPANIED BY INCREASED EXPRESSION OF THE DNMT3A DNA METHYLTRANSFERASE (DNMT; P<0.05) AND THE METHYL-CPG-BINDING DOMAIN PROTEIN MBD3 (P<0.05) GENES IN HFD MICE. GENE ONTOLOGY ANALYSIS REVEALED THAT, IN THE HFD-TREATED MICE, THE HOX FAMILY OF DEVELOPMENT GENES WAS HIGHLY ENRICHED IN DIFFERENTIALLY METHYLATED GENES (P=0.008). TO VALIDATE THIS FINDING, HOXA5, WHICH IS IMPLICATED IN FAT TISSUE DIFFERENTIATION AND REMODELING, HAS BEEN SELECTED AND ANALYZED BY BISULPHITE SEQUENCING, CONFIRMING HYPERMETHYLATION IN THE ADIPOSE TISSUE FROM THE HFD MICE. HOXA5 HYPERMETHYLATION WAS ASSOCIATED WITH DOWNREGULATION OF HOXA5 MRNA AND PROTEIN EXPRESSION. FEEDING ANIMALS PREVIOUSLY EXPOSED TO THE HFD WITH A STANDARD CHOW DIET FOR TWO FURTHER MONTHS IMPROVED THE METABOLIC PHENOTYPE OF THE ANIMALS, ACCOMPANIED BY RETURN OF HOXA5 METHYLATION AND EXPRESSION LEVELS (P<0.05) TO VALUES SIMILAR TO THOSE OF THE CONTROL MICE MAINTAINED UNDER STANDARD CHOW. CONCLUSIONS: HFD INDUCES ADIPOSE TISSUE ABNORMALITIES ACCOMPANIED BY EPIGENETIC CHANGES AT THE HOXA5 ADIPOSE TISSUE REMODELING GENE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  6108  24 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	

7  1829  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  4218  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9   695  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10   917  34 CHRONIC HIGH-FAT DIET DRIVES POSTNATAL EPIGENETIC REGULATION OF MU-OPIOID RECEPTOR IN THE BRAIN. OPIOID SYSTEM DYSREGULATION HAS BEEN OBSERVED IN BOTH GENETIC AND HIGH-FAT DIET (HFD)-INDUCED MODELS OF OBESITY. AN UNDERSTANDING OF THE MOLECULAR MECHANISMS OF MOR TRANSCRIPTIONAL REGULATION, PARTICULARLY WITHIN AN IN VIVO CONTEXT, IS LACKING. USING A DIET-INDUCED MODEL OF OBESITY (DIO), MICE WERE FED A HIGH-FAT DIET (60% CALORIES FROM FAT) FROM WEANING TO >18 WEEKS OF AGE. COMPARED WITH MICE FED THE CONTROL DIET, DIO MICE HAD A DECREASED PREFERENCE FOR SUCROSE. MOR MRNA EXPRESSION WAS DECREASED IN REWARD-RELATED CIRCUITRY (VENTRAL TEGMENTAL AREA (VTA), NUCLEUS ACCUMBENS (NAC), AND PREFRONTAL CORTEX (PFC)) BUT NOT THE HYPOTHALAMUS, IMPORTANT IN THE HOMEOSTATIC REGULATION OF FEEDING. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT LINKS ENVIRONMENTAL EXPOSURES TO ALTERED GENE EXPRESSION. WE FOUND A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE MOR PROMOTER REGION WITHIN THE REWARD-RELATED BRAIN REGIONS. METHYL CPG-BINDING PROTEIN 2 (MECP2) CAN BIND METHYLATED DNA AND REPRESS TRANSCRIPTION, AND DIO MICE SHOWED INCREASED BINDING OF MECP2 TO THE MOR PROMOTER IN REWARD-RELATED REGIONS OF THE BRAIN. FINALLY, USING CHIP ASSAYS WE EXAMINED H3K9 METHYLATION (INACTIVE CHROMATIN) AND H3 ACETYLATION (ACTIVE CHROMATIN) WITHIN THE MOR PROMOTER REGION AND FOUND INCREASED H3K9 METHYLATION AND DECREASED H3 ACETYLATION. THESE DATA ARE THE FIRST TO IDENTIFY DNA METHYLATION, MECP2 RECRUITMENT, AND CHROMATIN REMODELING AS MECHANISMS LEADING TO TRANSCRIPTIONAL REPRESSION OF MOR IN THE BRAINS OF MICE FED A HIGH-FAT DIET.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  3600  33 IMPORTANCE OF EPIGENETIC MECHANISMS IN VISCERAL PAIN INDUCED BY CHRONIC WATER AVOIDANCE STRESS. EPIGENETIC MOLECULAR MECHANISMS, WHICH INCLUDE DNA METHYLATION AND HISTONE DEACETYLATION, ARE IMPLICATED IN THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. PREVIOUSLY, WE DEMONSTRATED THAT REPEATED WATER AVOIDANCE STRESS (WAS), A VALIDATED MODEL OF CHRONIC PSYCHOLOGICAL STRESS, INDUCES HEIGHTENED VISCERAL PAIN BEHAVIORS IN RODENTS THAT RESEMBLE IRRITABLE BOWEL SYNDROME (IBS) SEQUELAE. HOWEVER, THE INVOLVEMENT OF EPIGENETIC MOLECULAR MECHANISMS IN THE PATHOPHYSIOLOGY OF STRESS-INDUCED VISCERAL PAIN HAS NOT BEEN EXPLORED. OUR HYPOTHESIS IS THAT EPIGENETIC MECHANISMS WITHIN THE CENTRAL NERVOUS SYSTEM (CNS) ARE IMPORTANT TO CHRONIC STRESS-INDUCED VISCERAL HYPERSENSITIVITY. ADULT MALE F-344 RATS WITH INTRACEREBROVENTRICULAR (I.C.V.) CANNULAE WERE EXPOSED TO 7 DAYS OF REPEATED WAS. CONTROLS RECEIVED A SHAM STRESS. FOLLOWING THE DAILY 1H STRESSOR, TRICHOSTATIN A (TSA; 100 NG/ML), A POTENT HISTONE DEACETYLASE INHIBITOR, OR VEHICLE (VEH; 0.1% DMSO/SALINE,) AS CONTROL WAS ADMINISTERED VIA THE I.C.V. CANNULA. VISCERAL SENSITIVITY WAS ASSESSED 24H AFTER THE FINAL WAS AND QUANTIFIED THE VISCEROMOTOR RESPONSE (VMR) BY RECORDING THE NUMBER OF ABDOMINAL CONTRACTIONS IN RESPONSE TO GRADED PRESSURES (20-60 MMHG) OF COLORECTAL DISTENSIONS (CRD). FROM A SEPARATE GROUP OF RATS THAT WERE EXPOSED TO REPEATED WAS OR SHAM STRESS, THE AMYGDALA WAS ISOLATED TO ASSESS THE METHYLATION STATUS OF GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPIN RELEASING-FACTOR (CRF) GENES VIA BISULFITE SEQUENCING AND VERIFIED BY PYROSEQUENCING. GR AND CRF GENE EXPRESSION WAS QUANTIFIED VIA QRT-PCR. STRESSED RATS EXHIBITED VISCERAL HYPERSENSITIVITY THAT WAS SIGNIFICANTLY ATTENUATED BY TSA. COMPARED TO SHAM CONTROLS, METHYLATION OF THE GR GENE WAS INCREASED FOLLOWING WAS WHILE EXPRESSION OF THE GR GENE WAS DECREASED. METHYLATION OF THE CRF PROMOTER WAS DECREASED WITH WAS WITH A CONCOMITANT INCREASE IN CRF EXPRESSION. THIS STUDY DEMONSTRATES THE INVOLVEMENT OF CENTRAL EPIGENETIC MECHANISMS IN REGULATING STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND PROVIDES A FOUNDATION FOR EXPLORING THE EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO IBS-LIKE SYMPTOMATOLOGY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  3331  25 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  1009  35 CHRONIC VOLUNTARY ETHANOL DRINKING IN CYNOMOLGUS MACAQUES ELICITS GENE EXPRESSION CHANGES IN PREFRONTAL CORTICAL AREA 46. BACKGROUND: GENOME-WIDE PROFILING TO EXAMINE BRAIN TRANSCRIPTIONAL FEATURES ASSOCIATED WITH EXCESSIVE ETHANOL (ETOH) CONSUMPTION HAS BEEN APPLIED TO A VARIETY OF SPECIES INCLUDING RODENTS, NONHUMAN PRIMATES (NHPS), AND HUMANS. HOWEVER, THESE DATA WERE OBTAINED FROM CROSS-SECTIONAL SAMPLES WHICH ARE PARTICULARLY VULNERABLE TO INDIVIDUAL VARIATION WHEN OBTAINED FROM SMALL OUTBRED POPULATIONS TYPICAL OF HUMAN AND NHP STUDIES. IN THE CURRENT STUDY, A NOVEL WITHIN-SUBJECT DESIGN WAS USED TO EXAMINE THE EFFECTS OF VOLUNTARY ETOH CONSUMPTION ON PREFRONTAL CORTEX (PFC) GENE EXPRESSION IN A NHP MODEL. METHODS: TWO COHORTS OF CYNOMOLGUS MACAQUES (N = 23) UNDERWENT A SCHEDULE-INDUCED POLYDIPSIA PROCEDURE TO ESTABLISH ETOH SELF-ADMINISTRATION FOLLOWED BY 6 MONTHS OF DAILY OPEN ACCESS TO ETOH (4% W/V) AND WATER. INDIVIDUAL DAILY ETOH INTAKES RANGED FROM AN AVERAGE OF 0.7 TO 3.7 G/KG/D. DORSAL LATERAL PFC AREA 46 (A46) BRAIN BIOPSIES WERE COLLECTED IN ETOH-NAIVE AND CONTROL MONKEYS; CONTRALATERAL A46 BIOPSIES WERE COLLECTED FROM THE SAME MONKEYS FOLLOWING THE 6 MONTHS OF FLUID CONSUMPTION. GENE EXPRESSION CHANGES WERE ASSESSED USING RNA-SEQ PAIRED ANALYSIS, WHICH ALLOWED FOR CORRECTION OF INDIVIDUAL BASELINE DIFFERENCES IN GENE EXPRESSION. RESULTS: A TOTAL OF 675 GENES WERE SIGNIFICANTLY DOWN-REGULATED FOLLOWING ETOH CONSUMPTION; THESE WERE FUNCTIONALLY ENRICHED FOR IMMUNE RESPONSE, CELL ADHESION, PLASMA MEMBRANE, AND EXTRACELLULAR MATRIX. A TOTAL OF 567 GENES THAT WERE UP-REGULATED FOLLOWING ETOH CONSUMPTION WERE ENRICHED IN MICRORNA TARGET SITES AND INCLUDED TARGET SITES ASSOCIATED WITH TOLL-LIKE RECEPTOR PATHWAYS. THE DIFFERENTIALLY EXPRESSED GENES WERE ALSO SIGNIFICANTLY ENRICHED IN TRANSCRIPTION FACTOR BINDING SITES. CONCLUSIONS: THE DATA PRESENTED HERE ARE THE FIRST TO USE A LONGITUDINAL BIOPSY STRATEGY TO EXAMINE HOW CHRONIC ETOH CONSUMPTION AFFECTS GENE EXPRESSION IN THE PRIMATE PFC. PROMINENT EFFECTS WERE SEEN IN BOTH CELL ADHESION AND NEUROIMMUNE PATHWAYS; THE LATTER CONTAINED BOTH PRO- AND ANTIINFLAMMATORY GENES. THE DATA ALSO INDICATE THAT CHANGES IN MIRNAS AND TRANSCRIPTION FACTORS MAY BE IMPORTANT EPIGENETIC REGULATORS OF ETOH CONSUMPTION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  4878  31 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	
                                                                                                                                        
15  3203  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16   219  19 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  2827  27 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  1875  33 EMERGING ROLE OF ONE-CARBON METABOLISM AND DNA METHYLATION ENRICHMENT ON DELTA-CONTAINING GABAA RECEPTOR EXPRESSION IN THE CEREBELLUM OF SUBJECTS WITH ALCOHOL USE DISORDERS (AUD). BACKGROUND: CEREBELLUM IS AN AREA OF THE BRAIN PARTICULARLY SENSITIVE TO THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL CONSUMPTION. ALCOHOL EXPOSURE DECREASES CEREBELLAR PURKINJE CELL OUTPUT BY INCREASING GABA RELEASE FROM GOLGI CELLS ONTO EXTRASYNAPTIC ALPHA6/DELTA-CONTAINING GABAA RECEPTORS LOCATED ON GLUTAMATERGIC GRANULE CELLS. HERE, WE STUDIED WHETHER CHRONIC ALCOHOL CONSUMPTION INDUCES CHANGES IN GABAA RECEPTOR SUBUNIT EXPRESSION AND WHETHER THESE CHANGES ARE ASSOCIATED WITH ALTERATIONS IN EPIGENETIC MECHANISMS VIA DNA METHYLATION. METHODS: WE USED A COHORT OF POSTMORTEM CEREBELLUM FROM CONTROL AND CHRONIC ALCOHOLICS, HERE DEFINED AS ALCOHOL USE DISORDERS SUBJECTS (N=25/GROUP). S-ADENOSYL-METHIONINE/S-ADENOSYL-HOMOCYSTEINE WERE MEASURED BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. MRNA LEVELS OF VARIOUS GENES WERE ASSESSED BY REVERSE TRANSCRIPTASE-QUANTITATIVE POLYMERASE CHAIN REACTION. PROMOTER METHYLATION ENRICHMENT WAS ASSESSED USING METHYLATED DNA IMMUNOPRECIPITATION AND HYDROXY-METHYLATED DNA IMMUNOPRECIPITATION ASSAYS. RESULTS: MRNAS ENCODING KEY ENZYMES OF 1-CARBON METABOLISM THAT DETERMINE THE S-ADENOSYL-METHIONINE/S-ADENOSYL-HOMOCYSTEINE RATIO WERE INCREASED, INDICATING HIGHER "METHYLATION INDEX" IN ALCOHOL USE DISORDER SUBJECTS. WE FOUND THAT INCREASED METHYLATION OF THE PROMOTER OF THE DELTA SUBUNIT GABAA RECEPTOR WAS ASSOCIATED WITH REDUCED MRNA AND PROTEIN LEVELS IN THE CEREBELLUM OF ALCOHOL USE DISORDER SUBJECTS. NO CHANGES WERE OBSERVED IN ALPHA1- OR ALPHA6-CONTAINING GABAA RECEPTOR SUBUNITS. THE EXPRESSION OF DNA-METHYLTRANSFERASES (1, 3A, AND 3B) WAS UNALTERED, WHEREAS THE MRNA LEVEL OF TET1, WHICH PARTICIPATES IN THE DNA DEMETHYLATION PATHWAY, WAS DECREASED. HENCE, INCREASED METHYLATION OF THE DELTA SUBUNIT GABAA RECEPTOR PROMOTER MAY RESULT FROM ALCOHOL-INDUCED REDUCTION OF DNA DEMETHYLATION. CONCLUSION: TOGETHER, THESE RESULTS SUPPORT THE HYPOTHESIS THAT ABERRANT DNA METHYLATION PATHWAYS MAY BE INVOLVED IN CEREBELLAR PATHOPHYSIOLOGY OF ALCOHOLISM. FURTHERMORE, THIS WORK PROVIDES NOVEL EVIDENCE FOR A CENTRAL ROLE OF DNA METHYLATION MECHANISMS IN THE ALCOHOL-INDUCED NEUROADAPTIVE CHANGES OF HUMAN CEREBELLAR GABAA RECEPTOR FUNCTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19  3314  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3315  24 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