1  113 181 A SELECTIVE HDAC 1/2 INHIBITOR MODULATES CHROMATIN AND GENE EXPRESSION IN BRAIN AND ALTERS MOUSE BEHAVIOR IN TWO MOOD-RELATED TESTS. PSYCHIATRIC DISEASES, INCLUDING SCHIZOPHRENIA, BIPOLAR DISORDER AND MAJOR DEPRESSION, ARE PROJECTED TO LEAD GLOBAL DISEASE BURDEN WITHIN THE NEXT DECADE. PHARMACOTHERAPY, THE PRIMARY--ALBEIT OFTEN INEFFECTIVE--TREATMENT METHOD, HAS REMAINED LARGELY UNCHANGED OVER THE PAST 50 YEARS, HIGHLIGHTING THE NEED FOR NOVEL TARGET DISCOVERY AND IMPROVED MECHANISM-BASED TREATMENTS. HERE, WE EXAMINED IN WILD TYPE MICE THE IMPACT OF CHRONIC, SYSTEMIC TREATMENT WITH COMPOUND 60 (CPD-60), A SLOW-BINDING, BENZAMIDE-BASED INHIBITOR OF THE CLASS I HISTONE DEACETYLASE (HDAC) FAMILY MEMBERS, HDAC1 AND HDAC2, IN MOOD-RELATED BEHAVIORAL ASSAYS RESPONSIVE TO CLINICALLY EFFECTIVE DRUGS. CPD-60 TREATMENT FOR ONE WEEK WAS ASSOCIATED WITH ATTENUATED LOCOMOTOR ACTIVITY FOLLOWING ACUTE AMPHETAMINE CHALLENGE. FURTHER, TREATED MICE DEMONSTRATED DECREASED IMMOBILITY IN THE FORCED SWIM TEST. THESE CHANGES ARE CONSISTENT WITH ESTABLISHED EFFECTS OF CLINICAL MOOD STABILIZERS AND ANTIDEPRESSANTS, RESPECTIVELY. WHOLE-GENOME EXPRESSION PROFILING OF SPECIFIC BRAIN REGIONS (PREFRONTAL CORTEX, NUCLEUS ACCUMBENS, HIPPOCAMPUS) FROM MICE TREATED WITH CPD-60 IDENTIFIED GENE EXPRESSION CHANGES, INCLUDING A SMALL SUBSET OF TRANSCRIPTS THAT SIGNIFICANTLY OVERLAPPED THOSE PREVIOUSLY REPORTED IN LITHIUM-TREATED MICE. HDAC INHIBITION IN BRAIN WAS CONFIRMED BY INCREASED HISTONE ACETYLATION BOTH GLOBALLY AND, USING CHROMATIN IMMUNOPRECIPITATION, AT THE PROMOTER REGIONS OF UPREGULATED TRANSCRIPTS, A FINDING CONSISTENT WITH IN VIVO ENGAGEMENT OF HDAC TARGETS. IN CONTRAST, TREATMENT WITH SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), A NON-SELECTIVE FAST-BINDING, HYDROXAMIC ACID HDAC 1/2/3/6 INHIBITOR, WAS SUFFICIENT TO INCREASE HISTONE ACETYLATION IN BRAIN, BUT DID NOT ALTER MOOD-RELATED BEHAVIORS AND HAD DISSIMILAR TRANSCRIPTIONAL REGULATORY EFFECTS COMPARED TO CPD-60. THESE RESULTS PROVIDE EVIDENCE THAT SELECTIVE INHIBITION OF HDAC1 AND HDAC2 IN BRAIN MAY PROVIDE AN EPIGENETIC-BASED TARGET FOR DEVELOPING IMPROVED TREATMENTS FOR MOOD DISORDERS AND OTHER BRAIN DISORDERS WITH ALTERED CHROMATIN-MEDIATED NEUROPLASTICITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2 6801  72 [EPIGENETIC MECHANISMS AND ALCOHOL USE DISORDERS: A POTENTIAL THERAPEUTIC TARGET]. ALCOHOL USE DISORDER IS A DEVASTATING ILLNESS WITH A PROFOUND HEALTH IMPACT, AND ITS DEVELOPMENT IS DEPENDENT ON BOTH GENETIC AND ENVIRONMENTAL FACTORS. THIS DISEASE OCCURS OVER TIME AND REQUIRES CHANGES IN BRAIN GENE EXPRESSION. THERE IS CONVERGING EVIDENCE SUGGESTING THAT THE EPIGENETIC PROCESSES MAY PLAY A ROLE IN THE ALCOHOL-INDUCED GENE REGULATIONS AND BEHAVIOR SUCH AS THE INTERVENTION OF DNA METHYLATION AND HISTONE ACETYLATION. HISTONE ACETYLATION, LIKE HISTONE METHYLATION, IS A HIGHLY DYNAMIC PROCESS REGULATED BY TWO CLASSES OF ENZYMES: HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES (HDACS). TO DATE, 18 HUMAN HDAC ISOFORMS HAVE BEEN CHARACTERIZED, AND BASED ON THEIR SEQUENCE HOMOLOGIES AND COFACTOR DEPENDENCIES, THEY HAVE BEEN PHYLOGENETICALLY CATEGORIZED INTO 4 MAIN CLASSES: CLASSES I, II (A AND B), III, AND IV. IN THE BRAIN, EXPRESSION OF THE DIFFERENT CLASSES OF HDACS VARIES BETWEEN CELL TYPES AND ALSO IN THEIR SUBCELLULAR LOCALIZATION (NUCLEUS AND/OR CYTOSOL). FURTHERMORE, WE RECENTLY SHOWED THAT A SINGLE ETHANOL EXPOSURE INHIBITS HDAC ACTIVITY AND INCREASES BOTH H3 AND H4 HISTONE ACETYLATION WITHIN THE AMYGDALA OF RATS. IN THE BRAIN OF ALCOHOLIC PATIENTS, ETHANOL HAS BEEN SHOWN TO INDUCE HISTONE-RELATED AND DNA METHYLATION EPIGENETIC CHANGES IN SEVERAL REWARD REGIONS INVOLVED IN REWARD PROCESSES SUCH AS HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA. WE RECENTLY DEMONSTRATED ALTERATION OF HISTONE H3 ACETYLATION LEVELS IN SEVERAL BRAIN REGIONS FROM THE REWARD CIRCUIT OF RATS MADE DEPENDENT TO ALCOHOL AFTER CHRONIC AND INTERMITTENT EXPOSURE TO ETHANOL VAPOR. IN NEURONAL CELL LINE CULTURE, ETHANOL WAS SHOWN TO INDUCE HDAC EXPRESSION. IN MOUSE AND RAT BRAIN, NUMEROUS STUDIES REPORTED EPIGENETIC ALTERATIONS FOLLOWING ETHANOL EXPOSURE. WE ALSO DEMONSTRATED THAT BOTH THE EXPRESSION OF GENES AND THE ACTIVITY OF ENZYMES INVOLVED IN EPIGENETIC MECHANISMS ARE CHANGED AFTER REPEATED ADMINISTRATIONS OF ETHANOL IN MICE SENSITIZED TO THE MOTOR STIMULANT EFFECT OF ETHANOL (A MODEL OF DRUG-INDUCED NEUROPLASTICITY). NUMEROUS STUDIES HAVE SHOWN THAT HDAC INHIBITORS ARE ABLE TO COUNTER ETHANOL-INDUCED BEHAVIORS AND THE ETHANOL-INDUCED CHANGES IN THE LEVELS OF HDAC AND/OR LEVELS OF ACETYLATED HDAC. FOR EXAMPLE, TRICHOSTATIN A (TSA) TREATMENT CAUSED THE REVERSAL OF ETHANOL-INDUCED TOLERANCE, ANXIETY, AND ETHANOL DRINKING BY INHIBITING HDAC ACTIVITY, THEREBY INCREASING HISTONE ACETYLATION IN THE AMYGDALA OF RATS. ANOTHER STUDY DEMONSTRATED THAT TSA PREVENTED THE DEVELOPMENT OF ETHANOL WITHDRAWAL INDUCED ANXIETY IN RATS BY RESCUING DEFICITS IN HISTONE ACETYLATION INDUCED BY INCREASED HDAC ACTIVITY IN THE AMYGDALA. WE HAVE DEMONSTRATED THAT TREATMENT WITH THE HDAC INHIBITOR SODIUM BUTYRATE BLOCKS BOTH THE DEVELOPMENT AND THE EXPRESSION OF ETHANOL-INDUCED BEHAVIORAL SENSITIZATION IN MICE. IN THIS CONTEXT, CONVERGING EVIDENCE INDICATES THAT HDAC INHIBITORS COULD BE USEFUL IN COUNTERACTING ETHANOL-INDUCED GENE REGULATIONS VIA EPIGENETIC MECHANISMS, THAT IS, HDAC INHIBITORS COULD AFFECT DIFFERENT ACETYLATION SITES AND MAY ALSO ALTER THE EXPRESSION OF DIFFERENT GENES THAT COULD IN TURN COUNTERACT THE EFFECT OF ETHANOL. RECENT WORK IN RODENTS HAS SHOWN THAT SYSTEMIC ADMINISTRATION OF PAN HDAC CLASS I AND II INHIBITORS, TSA AND N-HYDROXY-N-PHENYL-OCTANEDIAMIDE [SUBEROYLANILIDE HYDROXAMIC ACID] (SAHA), AND OF THE MORE SELECTIVE INHIBITOR (MAINLY HDAC1 AND HDAC9) MS-275, DECREASE BINGE-LIKE ALCOHOL DRINKING IN MICE. SAHA SELECTIVELY REDUCED ETHANOL OPERANT SELF-ADMINISTRATION AND SEEKING IN RATS. OUR PREVIOUS STUDY REVEALED THAT MS-275 STRONGLY DECREASED OPERANT ETHANOL SELF-ADMINISTRATION IN ALCOHOL-DEPENDENT RATS WHEN ADMINISTERED 30 MINUTES BEFORE THE SESSION AT THE SECOND DAY OF INJECTION. WE ALSO DEMONSTRATED THAT INTRA-CEREBRO-VENTRICULAR INFUSION OF MS-275 INCREASES ACETYLATION OF HISTONE 4 WITHIN THE NUCLEUS ACCUMBENS AND THE DORSOLATERAL STRIATUM, ASSOCIATED TO A DECREASE IN ETHANOL SELF-ADMINISTRATION BY ABOUT 75%. MS-275 ALSO DIMINISHED BOTH THE MOTIVATION TO CONSUME ETHANOL (25% DECREASE), RELAPSE (BY ABOUT 50%) AND POSTPONED REACQUISITION AFTER ABSTINENCE. BOTH LITERATURE AND SEVERAL OF OUR STUDIES STRONGLY SUPPORT THE POTENTIAL THERAPEUTIC INTEREST OF TARGETING EPIGENETIC MECHANISMS IN EXCESSIVE ALCOHOL DRINKING AND STRENGTHEN THEINTEREST OF FOCUSING ON SPECIFIC ISOFORMS OF HISTONE DEACETYLASES.	2017	

3 5624  44 SELECTIVE BOOSTING OF TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES TO DRUGS OF ABUSE BY HISTONE DEACETYLASE INHIBITION. HISTONE ACETYLATION AND OTHER MODIFICATIONS OF THE CHROMATIN ARE IMPORTANT REGULATORS OF GENE EXPRESSION AND, CONSEQUENTLY, MAY CONTRIBUTE TO DRUG-INDUCED BEHAVIORS AND NEUROPLASTICITY. EARLIER STUDIES HAVE SHOWN THAT A REDUCTION IN HISTONE DEACETYLASE (HDAC) ACTIVITY RESULTS IN THE ENHANCEMENT OF SOME PSYCHOSTIMULANT-INDUCED BEHAVIORS. IN THIS STUDY, WE EXTEND THOSE SEMINAL FINDINGS BY SHOWING THAT THE ADMINISTRATION OF THE HDAC INHIBITOR SODIUM BUTYRATE ENHANCES MORPHINE-INDUCED LOCOMOTOR SENSITIZATION AND CONDITIONED PLACE PREFERENCE. IN CONTRAST, THIS COMPOUND HAS NO EFFECTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE. SIMILAR EFFECTS WERE OBSERVED FOR COCAINE AND ETHANOL-INDUCED BEHAVIORS. THESE BEHAVIORAL CHANGES WERE ACCOMPANIED BY A SELECTIVE BOOSTING OF A COMPONENT OF THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CHRONIC MORPHINE ADMINISTRATION THAT INCLUDED CIRCADIAN CLOCK GENES AND OTHER GENES RELEVANT TO ADDICTIVE BEHAVIOR. OUR RESULTS SUPPORT A SPECIFIC FUNCTION FOR HISTONE ACETYLATION AND THE EPIGENETIC MODULATION OF TRANSCRIPTION AT A REDUCED NUMBER OF BIOLOGICALLY RELEVANT LOCI ON NON-HOMEOSTATIC, LONG-LASTING, DRUG-INDUCED BEHAVIORAL PLASTICITY.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4 5712  53 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 6175  50 THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ALLEVIATES DEPRESSION-LIKE BEHAVIOR AND NORMALIZES EPIGENETIC CHANGES IN THE HIPPOCAMPUS DURING ETHANOL WITHDRAWAL. WITHDRAWAL FROM CHRONIC ALCOHOL DRINKING CAN CAUSE DEPRESSION, LEADING TO AN INABILITY TO FUNCTION IN DAILY LIFE AND AN INCREASED RISK FOR RELAPSE TO HARMFUL DRINKING. UNDERSTANDING THE CAUSES OF ALCOHOL WITHDRAWAL-RELATED DEPRESSION MAY LEAD TO NEW THERAPEUTIC TARGETS FOR TREATMENT. EPIGENETIC FACTORS HAVE RECENTLY EMERGED AS IMPORTANT CONTRIBUTORS TO BOTH DEPRESSION AND ALCOHOL USE DISORDER (AUD). SPECIFICALLY, ACETYLATION OF THE N-TERMINAL TAILS OF HISTONE PROTEINS THAT PACKAGE DNA INTO NUCLEOSOMES IS ALTERED IN STRESS-INDUCED MODELS OF DEPRESSION AND DURING ALCOHOL WITHDRAWAL. THE GOAL OF THIS STUDY WAS TO EXAMINE DEPRESSION-LIKE BEHAVIOR DURING ALCOHOL WITHDRAWAL AND ASSOCIATED CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE DEACETYLASE 2 (HDAC2) IN THE HIPPOCAMPUS, A BRAIN REGION CRITICAL FOR MOOD REGULATION AND DEPRESSION. MALE SPRAGUE-DAWLEY RATS WERE TREATED WITH THE LIEBER-DECARLI ETHANOL LIQUID DIET FOR 15 DAYS AND THEN UNDERWENT WITHDRAWAL. RATS WERE TREATED WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), DURING WITHDRAWAL AND WERE TESTED FOR DEPRESSION-LIKE BEHAVIOR. IN A SEPARATE GROUP OF RATS, THE HIPPOCAMPUS WAS ANALYZED FOR MRNA AND PROTEIN EXPRESSION OF HDAC2 AND LEVELS OF HISTONE H3 LYSINE 9 ACETYLATION (H3K9AC) DURING CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL. RATS UNDERGOING ETHANOL WITHDRAWAL EXHIBITED DEPRESSION-LIKE BEHAVIOR AND HAD INCREASED HDAC2 AND DECREASED H3K9AC LEVELS IN SPECIFIC STRUCTURES OF THE HIPPOCAMPUS. TREATMENT WITH SAHA DURING WITHDRAWAL AMELIORATED DEPRESSION-LIKE BEHAVIOR AND NORMALIZED CHANGES IN HIPPOCAMPAL HDAC2 AND H3K9AC LEVELS. THESE RESULTS DEMONSTRATE THAT ETHANOL WITHDRAWAL CAUSES AN ALTERED EPIGENETIC STATE IN THE HIPPOCAMPUS. TREATMENT WITH AN HDAC INHIBITOR CAN CORRECT THIS STATE AND ALLEVIATE DEPRESSION-LIKE SYMPTOMS DEVELOPED DURING WITHDRAWAL. TARGETING HISTONE ACETYLATION MAY BE A NOVEL STRATEGY TO REDUCE ETHANOL WITHDRAWAL-INDUCED DEPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6 4173  40 MELATONIN INDUCES HISTONE HYPERACETYLATION IN THE RAT BRAIN. WE HAVE REPORTED THAT MELATONIN INDUCES HISTONE HYPERACETYLATION IN MOUSE NEURAL STEM CELLS, SUGGESTING AN EPIGENETIC ROLE FOR THIS PLEIOTROPIC HORMONE. TO SUPPORT SUCH A ROLE, IT IS NECESSARY TO DEMONSTRATE THAT MELATONIN PRODUCES SIMILAR EFFECTS IN VIVO. HISTONE ACETYLATION, FOLLOWING CHRONIC TREATMENT WITH MELATONIN (4MUG/ML IN DRINKING WATER FOR 17 DAYS), WAS EXAMINED BY WESTERN BLOTTING IN SELECTED RAT BRAIN REGIONS. MELATONIN INDUCED SIGNIFICANT INCREASES IN HISTONE H3 AND HISTONE H4 ACETYLATION IN THE HIPPOCAMPUS. HISTONE H4 WAS ALSO HYPERACETYLATED IN THE STRIATUM, BUT THERE WERE NO SIGNIFICANT CHANGES IN HISTONE H3 ACETYLATION IN THIS BRAIN REGION. NO SIGNIFICANT CHANGES IN THE ACETYLATION OF EITHER HISTONE H3 OR H4 WERE OBSERVED IN THE MIDBRAIN AND CEREBELLUM. AN EXAMINATION OF KINASE ACTIVATION, WHICH MAY BE RELATED TO THESE CHANGES, REVEALED THAT MELATONIN TREATMENT INCREASED THE LEVELS OF PHOSPHO-ERK (EXTRACELLULAR SIGNAL-REGULATED KINASE) IN THE HIPPOCAMPUS AND STRIATUM, BUT PHOSPHO-AKT (PROTEIN KINASE B) LEVELS WERE UNCHANGED. THESE FINDINGS SUGGEST THAT CHROMATIN REMODELING AND ASSOCIATED CHANGES IN THE EPIGENETIC REGULATION OF GENE EXPRESSION UNDERLIE THE MULTIPLE PHYSIOLOGICAL EFFECTS OF MELATONIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 4150  54 MECHANISTIC INSIGHTS INTO EPIGENETIC MODULATION OF ETHANOL CONSUMPTION. THERE IS GROWING EVIDENCE THAT SMALL-MOLECULE INHIBITORS OF EPIGENETIC MODULATORS, SUCH AS HISTONE DEACETYLASES (HDAC) AND DNA METHYLTRANSFERASES (DNMT), CAN REDUCE VOLUNTARY ETHANOL CONSUMPTION IN ANIMAL MODELS, BUT MOLECULAR AND CELLULAR PROCESSES UNDERLYING THIS BEHAVIORAL EFFECT ARE POORLY UNDERSTOOD. WE USED C57BL/6J MALE MICE TO INVESTIGATE THE EFFECTS OF TWO FDA-APPROVED DRUGS, DECITABINE (A DNMT INHIBITOR) AND SAHA (AN HDAC INHIBITOR), ON ETHANOL CONSUMPTION USING TWO TESTS: BINGE-LIKE DRINKING IN THE DARK (DID) AND CHRONIC INTERMITTENT EVERY OTHER DAY (EOD) DRINKING. DECITABINE BUT NOT SAHA REDUCED ETHANOL CONSUMPTION IN BOTH TESTS. WE FURTHER INVESTIGATED DECITABINE'S EFFECTS ON THE BRAIN'S REWARD PATHWAY BY GENE EXPRESSION PROFILING IN THE VENTRAL TEGMENTAL AREA (VTA), USING RNA SEQUENCING AND ELECTROPHYSIOLOGICAL RECORDINGS FROM VTA DOPAMINERGIC NEURONS. DECITABINE-INDUCED DECREASES IN EOD DRINKING WERE ASSOCIATED WITH GLOBAL CHANGES IN GENE EXPRESSION, IMPLICATING REGULATION OF CEREBRAL BLOOD FLOW, EXTRACELLULAR MATRIX ORGANIZATION, AND NEUROIMMUNE FUNCTIONS IN DECITABINE ACTIONS. IN ADDITION, AN IN VIVO ADMINISTRATION OF DECITABINE SHORTENED ETHANOL-INDUCED EXCITATION OF VTA DOPAMINERGIC NEURONS IN VITRO, SUGGESTING THAT DECITABINE REDUCES ETHANOL DRINKING VIA CHANGES IN THE REWARD PATHWAY. TAKEN TOGETHER, OUR DATA SUGGEST A CONTRIBUTION OF BOTH NEURONAL AND NON-NEURONAL MECHANISMS IN THE VTA IN THE REGULATION OF ETHANOL CONSUMPTION. DECITABINE AND OTHER EPIGENETIC COMPOUNDS HAVE BEEN APPROVED FOR CANCER TREATMENT, AND UNDERSTANDING THEIR MECHANISMS OF ACTIONS IN THE BRAIN MAY ASSIST IN REPURPOSING THESE DRUGS AND DEVELOPING NOVEL THERAPIES FOR CENTRAL DISORDERS, INCLUDING DRUG ADDICTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8 3341  28 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9 1331  37 DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS ARE ASSOCIATED WITH HDAC7 REDUCTION IN THE NUCLEUS ACCUMBENS. PERSISTENT SYMPTOMS OF DEPRESSION INDICATE THE ADAPTIVE INVOLVEMENT OF STABLE MOLECULES IN THE BRAIN THAT MAY BE MANIFESTED AT THE LEVEL OF CHROMATIN REMODELING, SUCH AS HISTONE ACETYLATION. FORMER STUDIES HAVE IDENTIFIED ALTERATIONS IN HISTONE ACETYLATION AND DEACETYLATION IN SEVERAL ANIMAL MODELS ABOUT DEPRESSION. HOWEVER, THE SPECIFIC HISTONE DEACETYLASES RELATED WITH DEPRESSION ARE NEEDED TO BE EXPLORED. HERE, SOCIAL AVOIDANCE BEHAVIORS, ANXIETY-, AND DEPRESSION-LIKE BEHAVIORS WERE ALL FOUND IN MICE SUFFERED FROM CHRONIC SOCIAL DEFEAT STRESS. MOREOVER, WE ALSO DISCOVERED THAT THE AMOUNT OF THE CLASS II HISTONE DEACETYLASE, HDAC7 RATHER THAN HDAC2, WAS SIGNIFICANTLY DECREASED IN THE NUCLEUS ACCUMBENS OF DEFEATED MICE, WHICH SUGGESTED THAT HDAC7 MIGHT BE A CRUCIAL HISTONE DEACETYLASE IN A CHRONIC SOCIAL DEFEAT STRESS MODEL. OUR DATA SHOWED THAT THE DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS WERE ASSOCIATED WITH HDAC7 REDUCTION IN NUCLEUS ACCUMBENS. HDAC7 MIGHT BE A PROMISING THERAPEUTIC TARGET FOR DEPRESSION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 2705  39 EXERCISE AND LOW-LEVEL GABA(A) RECEPTOR INHIBITION MODULATE LOCOMOTOR ACTIVITY AND THE EXPRESSION OF BDNF ACCOMPANIED BY CHANGES IN EPIGENETIC REGULATION IN THE HIPPOCAMPUS. AEROBIC EXERCISE IS KNOWN TO INCREASE EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN THE HIPPOCAMPUS AND TO IMPROVE COGNITIVE FUNCTION. THE INHIBITION OF GABAERGIC SYNAPSES ENHANCES HIPPOCAMPAL PLASTICITY AS WELL AS LEARNING AND MEMORY. THE OBJECTIVE OF THE PRESENT STUDY WAS TO EXAMINE THE INTERACTIVE EFFECT OF LOW-LEVEL GABA(A) RECEPTOR INHIBITION AND EXERCISE ON BEHAVIOR TESTS (COGNITIVE FUNCTION AND LOCOMOTOR ACTIVITY), EXPRESSION OF BDNF AND EPIGENETIC REGULATIONS INCLUDING THE ACTIVITY LEVELS OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS) IN THE HIPPOCAMPUS. ICR MICE WERE DIVIDED INTO TWO GROUPS: THOSE WHO DID NOT PARTICIPATE IN EXERCISE AND THOSE WHO PARTICIPATED IN EXERCISE. EACH GROUP WAS SUBDIVIDED INTO TWO OTHER GROUPS: THE ONE WHO RECEIVED VEHICLE AND THE ONE WHO RECEIVED GABA(A) RECEPTOR ANTAGONIST, BICUCULLIN. WE ADMINISTERED SALINE OR BICUCULLINE INTRAPERITONEALLY TO THE MICE AT A NON-EPILEPTIC DOSE OF 0.25 MG/KG, WHEREAS THE MICE WERE EXERCISED ON A TREADMILL FOR APPROXIMATELY 1 H A DAY, 5 DAYS A WEEK FOR 4 WEEKS. NOVEL-OBJECT RECOGNITION TEST AND LOCOMOTOR ACTIVITY WERE ASSESSED AT A REST DAY APPROXIMATELY 4 DAYS BEFORE THE EUTHANASIA. THE MICE WERE EUTHANIZED 4 H AFTER THE LAST EXERCISE SESSION. AEROBIC EXERCISE FOR 4 WEEKS INCREASED MRNA AND PROTEIN EXPRESSION OF BDNF IN THE HIPPOCAMPUS, ACCOMPANIED BY ENHANCED HAT ACTIVITY. ALTERNATIVELY, BICUCULLINE ADMINISTRATION INCREASED HDAC ACTIVITY IN THE HIPPOCAMPUS. FURTHERMORE, EXERCISE IN THE PRESENCE OF BICUCULLINE ADMINISTRATION INCREASED LOCOMOTOR ACTIVITY, INDICATING THAT EXERCISE COMBINED WITH LOW-LEVEL GABA(A) RECEPTOR INHIBITION POTENTIATED THE ACTIVITY OF THE MICE. ALTOGETHER, THE PRESENT STUDY SUGGESTED THAT EXERCISE BENEFICIALLY CONTRIBUTES TO NEUROPROTECTION IN THE HIPPOCAMPUS ACCOMPANIED BY THE UP-REGULATION OF BDNF EXPRESSION AND EPIGENETIC REGULATION, WHEREAS THE CHRONIC INHIBITION OF GABA(A) RECEPTOR POTENTIATES EXERCISE-INDUCED BEHAVIORAL ACTIVITY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 4401  50 MODULATION OF NEURONAL PLASTICITY FOLLOWING CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE WITH THE MOOD STABILIZER VALPROIC ACID. RATIONALE: COMBINATORY THERAPY IS WIDELY USED IN PSYCHIATRY OWING TO THE POSSIBILITY THAT DRUGS WITH DIFFERENT MECHANISMS OF ACTION MAY SYNERGIZE TO IMPROVE FUNCTIONS DETERIORATED IN SCHIZOPHRENIA, BIPOLAR DISORDERS, AND MAJOR DEPRESSION. WHILE COMBINATORY STRATEGIES RELY ON RECEPTOR AND SYNAPTIC MECHANISMS, IT SHOULD ALSO BE CONSIDERED THAT TWO DRUGS MAY ALSO "INTERACT" ON THE LONG-TERM TO DETERMINE MORE ROBUST CHANGES IN NEURONAL PLASTICITY, WHICH REPRESENTS A DOWNSTREAM TARGET IMPORTANT FOR FUNCTIONAL RECOVERY. OBJECTIVE: THE AIM OF THE STUDY IS TO INVESTIGATE NEUROADAPTIVE CHANGES SET IN MOTION BY CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE AND THE MOOD STABILIZER VALPROATE. METHODS: ANIMALS WERE CHRONICALLY TREATED WITH LURASIDONE, VALPROATE, OR THE COMBINATION OF THE TWO DRUGS AND KILLED 24 H AFTER THE LAST INJECTION TO EVALUATE ALTERATIONS OF DIFFERENT MEASURES OF NEURONAL PLASTICITY SUCH AS THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), THE IMMEDIATE EARLY GENE ACTIVITY-REGULATED CYTOSKELETAL ASSOCIATED PROTEIN, AND THE EPIGENETIC REGULATORS HDAC 1, 2, AND 5 IN DORSAL AND VENTRAL HIPPOCAMPUS. RESULTS: THE RESULTS SUGGEST THAT COADMINISTRATION OF LURASIDONE AND VALPROATE PRODUCES, WHEN COMPARED TO THE SINGLE DRUGS, A LARGER INCREASE IN THE EXPRESSION OF BDNF IN THE VENTRAL HIPPOCAMPUS, THROUGH THE REGULATION OF SPECIFIC NEUROTROPHIN TRANSCRIPTS. WE ALSO FOUND THAT THE HISTONE DEACETYLASES WERE REGULATED BY THE DRUG COMBINATION, SUGGESTING THAT SOME OF THE TRANSCRIPTIONAL CHANGES MAY BE SUSTAINED BY EPIGENETIC MECHANISMS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE BENEFICIAL EFFECTS ASSOCIATED WITH COMBINATORY TREATMENT BETWEEN A SECOND-GENERATION ANTIPSYCHOTIC AND A MOOD STABILIZER COULD RESULT FROM THE ABILITY TO MODULATE NEUROPLASTIC MOLECULES, WHOSE EXPRESSION AND FUNCTION IS DETERIORATED IN DIFFERENT PSYCHIATRIC CONDITIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  213  43 ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURES (ECS) DIFFERENTIALLY REGULATE THE EXPRESSION OF EPIGENETIC MACHINERY IN THE ADULT RAT HIPPOCAMPUS. BACKGROUND: ELECTROCONVULSIVE SEIZURE TREATMENT IS A FAST-ACTING ANTIDEPRESSANT THERAPY THAT EVOKES RAPID TRANSCRIPTIONAL, NEUROGENIC, AND BEHAVIORAL CHANGES. EPIGENETIC MECHANISMS CONTRIBUTE TO ALTERED GENE REGULATION, WHICH UNDERLIES THE NEUROGENIC AND BEHAVIORAL EFFECTS OF ELECTROCONVULSIVE SEIZURE. WE HYPOTHESIZED THAT ELECTROCONVULSIVE SEIZURE MAY MODULATE THE EXPRESSION OF EPIGENETIC MACHINERY, THUS ESTABLISHING POTENTIAL ALTERATIONS IN THE EPIGENETIC LANDSCAPE. METHODS: WE EXAMINED THE INFLUENCE OF ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE ON THE GENE EXPRESSION OF HISTONE MODIFIERS, NAMELY HISTONE ACETYLTRANSFERASES, HISTONE DEACETYLASES, HISTONE METHYLTRANSFERASES, AND HISTONE (LYSINE) DEMETHYLASES AS WELL AS DNA MODIFYING ENZYMES, INCLUDING DNA METHYLTRANSFERASES, DNA DEMETHYLASES, AND METHYL-CPG-BINDING PROTEINS IN THE HIPPOCAMPI OF ADULT MALE WISTAR RATS USING QUANTITATIVE REAL TIME-PCR ANALYSIS. FURTHER, WE EXAMINED THE INFLUENCE OF ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE ON GLOBAL AND RESIDUE-SPECIFIC HISTONE ACETYLATION AND METHYLATION LEVELS WITHIN THE HIPPOCAMPUS, A BRAIN REGION IMPLICATED IN THE CELLULAR AND BEHAVIORAL EFFECTS OF ELECTROCONVULSIVE SEIZURE. RESULTS: ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE INDUCED A PRIMARILY UNIQUE, AND IN CERTAIN CASES BIDIRECTIONAL, REGULATION OF HISTONE AND DNA MODIFIERS, AND METHYL-CPG-BINDING PROTEINS, WITH AN OVERLAPPING PATTERN OF GENE REGULATION RESTRICTED TO SIRT4, MLL3, JMJD3, GADD45B, TET2, AND TET3. GLOBAL HISTONE ACETYLATION AND METHYLATION LEVELS WERE PREDOMINANTLY UNCHANGED, WITH THE EXCEPTION OF A SIGNIFICANT DECLINE IN H3K9 ACETYLATION IN THE HIPPOCAMPUS FOLLOWING CHRONIC ELECTROCONVULSIVE SEIZURE. CONCLUSIONS: ELECTROCONVULSIVE SEIZURE TREATMENT EVOKES THE TRANSCRIPTIONAL REGULATION OF SEVERAL HISTONE AND DNA MODIFIERS, AND METHYL-CPG-BINDING PROTEINS WITHIN THE HIPPOCAMPUS, WITH A PREDOMINANTLY DISTINCT PATTERN OF REGULATION INDUCED BY ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13 3194  36 HDAC INHIBITORS ATTENUATE THE DEVELOPMENT OF HYPERSENSITIVITY IN MODELS OF NEUROPATHIC PAIN. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER THESE COMPOUNDS COULD ALSO AFFECT NEUROPATHIC PAIN. DIFFERENT CLASS I HDACIS WERE DELIVERED INTRATHECALLY INTO RAT SPINAL CORD IN MODELS OF TRAUMATIC NERVE INJURY AND ANTIRETROVIRAL DRUG-INDUCED PERIPHERAL NEUROPATHY (STAVUDINE, D4T). MECHANICAL AND THERMAL HYPERSENSITIVITY WAS ATTENUATED BY 40% TO 50% AS A RESULT OF HDACI TREATMENT, BUT ONLY IF STARTED BEFORE ANY INSULT. THE DRUGS GLOBALLY INCREASED HISTONE ACETYLATION IN THE SPINAL CORD, BUT APPEARED TO HAVE NO MEASURABLE EFFECTS IN RELEVANT DORSAL ROOT GANGLIA IN THIS TREATMENT PARADIGM, SUGGESTING THAT ANY POTENTIAL MECHANISM SHOULD BE SOUGHT IN THE CENTRAL NERVOUS SYSTEM. MICROARRAY ANALYSIS OF DORSAL CORD RNA REVEALED THE SIGNATURE OF THE SPECIFIC COMPOUND USED (MS-275) AND SUGGESTED THAT ITS MAIN EFFECT WAS MEDIATED THROUGH HDAC1. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE ACETYLATION IN THE EMERGENCE OF NEUROPATHIC PAIN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14 6207  40 THE INHIBITION OF HISTONE DEACETYLASES REDUCES THE REINSTATEMENT OF COCAINE-SEEKING BEHAVIOR IN RATS. DRUG ADDICTION IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY A PERSISTENT RISK OF RELAPSE, EVEN AFTER A LONG PERIOD OF ABSTINENCE. A CURRENT HYPOTHESIS STATES THAT RELAPSE RESULTS FROM LASTING NEUROADAPTATIONS THAT ARE INDUCED IN RESPONSE TO REPEATED DRUG ADMINISTRATION. THE ADAPTATIONS REQUIRE GENE EXPRESSION, SOME OF WHICH BEING UNDER THE CONTROL OF STABLE EPIGENETIC REGULATIONS. WE HAVE PREVIOUSLY DEMONSTRATED THAT PRETREATMENT WITH HISTONE DEACETYLASE (HDAC) INHIBITORS REDUCES THE COCAINE REINFORCING PROPERTIES AS WELL AS THE MOTIVATION OF RATS FOR COCAINE. WE SHOW HERE THAT THE SAME HDAC INHIBITORS, TRICHOSTATIN A AND PHENYLBUTYRATE, SIGNIFICANTLY REDUCED THE COCAINE-SEEKING BEHAVIOR INDUCED BY THE COMBINATION OF A COCAINE INJECTION TOGETHER WITH THE EXPOSURE TO A LIGHT CUE PREVIOUSLY ASSOCIATED WITH COCAINE TAKING. REINSTATEMENT OF DRUG-SEEKING BEHAVIOR WAS CARRIED OUT AFTER A 3-WEEK WITHDRAWAL PERIOD, WHICH CAME AFTER TEN DAILY SESSIONS OF COCAINE INTRAVENOUS SELF-ADMINISTRATION. OUR RESULTS SUGGEST THAT PHARMACOLOGICAL TREATMENT AIMED AT MODULATING EPIGENETIC REGULATION, AND PARTICULARLY TREATMENT THAT WOULD INHIBIT HDAC ACTIVITY, COULD REDUCE THE RISK OF RELAPSE, A MAJOR DRAWBACK IN THE TREATMENT OF DRUG ADDICTION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15 5974  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 4299  40 MICRORNA-15B CONTRIBUTES TO DEPRESSION-LIKE BEHAVIOR IN MICE BY AFFECTING SYNAPTIC PROTEIN LEVELS AND FUNCTION IN THE NUCLEUS ACCUMBENS. MAJOR DEPRESSION IS A PREVALENT AFFECTIVE DISORDER CHARACTERIZED BY RECURRENT LOW MOOD. IT PRESUMABLY RESULTS FROM STRESS-INDUCED DETERIORATIONS OF MOLECULAR NETWORKS AND SYNAPTIC FUNCTIONS IN BRAIN REWARD CIRCUITS OF GENETICALLY-SUSCEPTIBLE INDIVIDUALS THROUGH EPIGENETIC PROCESSES. EPIGENETIC REGULATOR MICRORNA-15B INHIBITS NEURONAL PROGENITOR PROLIFERATION AND IS UP-REGULATED IN THE MEDIAL PREFRONTAL CORTEX OF MICE THAT DEMONSTRATE DEPRESSION-LIKE BEHAVIOR, INDICATING THE CONTRIBUTION OF MICRORNA-15 TO MAJOR DEPRESSION. USING A MOUSE MODEL OF MAJOR DEPRESSION INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS), HERE WE EXAMINED THE EFFECTS OF MICRORNA-15B ON SYNAPSES AND SYNAPTIC PROTEINS IN THE NUCLEUS ACCUMBENS OF THESE MICE. THE APPLICATION OF A MICRORNA-15B ANTAGOMIR INTO THE NUCLEUS ACCUMBENS SIGNIFICANTLY REDUCED THE INCIDENCE OF CUMS-INDUCED DEPRESSION AND REVERSED THE ATTENUATIONS OF EXCITATORY SYNAPSE AND SYNTAXIN-BINDING PROTEIN 3 (STXBP3A)/VESICLE-ASSOCIATED PROTEIN 1 (VAMP1) EXPRESSION. IN CONTRAST, THE INJECTION OF A MICRORNA-15B ANALOG INTO THE NUCLEUS ACCUMBENS INDUCED DEPRESSION-LIKE BEHAVIOR AS WELL AS ATTENUATED EXCITATORY SYNAPSES AND STXBP3A/VAMP1 EXPRESSION SIMILAR TO THE DOWN-REGULATION OF THESE PROCESSES INDUCED BY THE CUMS. WE CONCLUDE THAT MICRORNA-15B-5P MAY PLAY A CRITICAL ROLE IN CHRONIC STRESS-INDUCED DEPRESSION BY DECREASING SYNAPTIC PROTEINS, INNERVATIONS, AND ACTIVITIES IN THE NUCLEUS ACCUMBENS. WE PROPOSE THAT THE TREATMENT OF ANTI-MICRORNA-15B-5P MAY CONVERT STRESS-INDUCED DEPRESSION INTO RESILIENCE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17 6582  39 TRICHOSTATIN A, A HISTONE DEACETYLASE INHIBITOR, ALLEVIATES THE EMOTIONAL ABNORMALITY INDUCED BY MALADAPTATION TO STRESS IN MICE. RECENT REPORTS HAVE IMPLIED THAT ABERRANT BIOCHEMICAL PROCESSES IN THE BRAIN ARE FREQUENTLY ACCOMPANIED BY SUBTLE SHIFTS IN THE CELLULAR EPIGENETIC PROFILE THAT MIGHT UNDERLIE THE PATHOGENIC PROGRESSION OF PSYCHIATRIC DISORDERS. THE AIM OF THE PRESENT STUDY WAS TO EXAMINE THE EFFECT OF TRICHOSTATIN A (TSA), A HISTONE DEACETYLASE (HDAC) INHIBITOR, ON THE EMOTIONAL ABNORMALITY INDUCED BY MALADAPTATION TO STRESS IN MICE. MICE WERE EXPOSED TO REPEATED RESTRAINT STRESS FOR 240 MIN/DAY FOR 14 DAYS. WE APPLIED DOSING SCHEDULES. IN ONE SCHEDULE, FROM THE 3RD DAY OF STRESS EXPOSURE, MICE WERE TREATED WITH TSA (1650 MUM/4 MUL, I.C.V.) IMMEDIATELY AFTER THE DAILY EXPOSURE TO RESTRAINT STRESS. IN THE OTHER SCHEDULE, FROM THE 1ST DAY OF STRESS EXPOSURE, MICE WERE TREATED WITH TSA 2 H BEFORE EXPOSURE TO RESTRAINT STRESS. AFTER THE FINAL EXPOSURE TO RESTRAINT STRESS, THE EMOTIONALITY OF MICE WAS EVALUATED USING THE HOLE-BOARD TEST. MICE THAT WERE EXPOSED TO RESTRAINT STRESS FOR 240 MIN/DAY FOR 14 DAYS SHOWED A DECREASE IN HEAD-DIPPING BEHAVIOR. THIS DECREASED EMOTIONALITY OBSERVED IN STRESS-MALADAPTIVE MICE WAS SIGNIFICANTLY RECOVERED BY CHRONIC TREATMENT WITH TSA 2 H BEFORE DAILY EXPOSURE TO RESTRAINT STRESS, WHICH CONFIRMED THE DEVELOPMENT OF STRESS ADAPTATION. ON THE OTHER HAND, NO SUCH STRESS ADAPTATION WAS OBSERVED UNDER CHRONIC TREATMENT WITH TSA IMMEDIATELY AFTER DAILY STRESS EXPOSURE. A BIOCHEMICAL STUDY SHOWED THAT TRYPTOPHAN HYDROXYLASE, THE RATE-LIMITING ENZYME IN SEROTONIN (5-HT) SYNTHESIS, WAS INCREASED IN MIDBRAIN CONTAINING RAPHE NUCLEI OBTAINED FROM STRESS-ADAPTED MICE THAT WERE CHRONICALLY TREATED WITH TSA 2 H BEFORE DAILY STRESS EXPOSURE. THESE FINDINGS SUGGEST THAT AN HDAC INHIBITOR MAY HAVE A BENEFICIAL EFFECT ON STRESS ADAPTATION BY AFFECTING 5-HT NEURAL FUNCTION IN THE BRAIN AND ALLEVIATE THE EMOTIONAL ABNORMALITY UNDER CONDITIONS OF EXCESSIVE STRESS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  882  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19 1614  37 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20 5709  44 SIRT1 DECREASES EMOTIONAL PAIN VULNERABILITY WITH ASSOCIATED CAMKIIALPHA DEACETYLATION IN CENTRAL AMYGDALA. EMOTIONAL DISORDERS ARE COMMON COMORBID CONDITIONS THAT FURTHER EXACERBATE THE SEVERITY AND CHRONICITY OF CHRONIC PAIN. HOWEVER, INDIVIDUALS SHOW CONSIDERABLE VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN UNDER SIMILAR PAIN CONDITIONS. IN THIS STUDY ON MALE RAT AND MOUSE MODELS OF CHRONIC NEUROPATHIC PAIN, WE IDENTIFY THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) IN CENTRAL AMYGDALA AS A KEY EPIGENETIC REGULATOR THAT CONTROLS THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDERLYING THE INDIVIDUAL VULNERABILITY TO CHRONIC PAIN. WE FOUND THAT ANIMALS THAT WERE VULNERABLE TO DEVELOPING BEHAVIORS OF ANXIETY AND DEPRESSION UNDER THE PAIN CONDITION DISPLAYED REDUCED SIRT1 PROTEIN LEVELS IN CENTRAL AMYGDALA, BUT NOT THOSE ANIMALS RESISTANT TO THE EMOTIONAL DISORDERS. VIRAL OVEREXPRESSION OF LOCAL SIRT1 REVERSED THIS VULNERABILITY, BUT VIRAL KNOCKDOWN OF LOCAL SIRT1 MIMICKED THE PAIN EFFECT, ELICITING THE PAIN VULNERABILITY IN PAIN-FREE ANIMALS. THE SIRT1 ACTION WAS ASSOCIATED WITH CAMKIIALPHA DOWNREGULATION AND DEACETYLATION OF HISTONE H3 LYSINE 9 AT THE CAMKIIALPHA PROMOTER. THESE RESULTS SUGGEST THAT, BY TRANSCRIPTIONAL REPRESSION OF CAMKIIALPHA IN CENTRAL AMYGDALA, SIRT1 FUNCTIONS TO GUARD AGAINST THE EMOTIONAL PAIN VULNERABILITY UNDER CHRONIC PAIN CONDITIONS. THIS STUDY INDICATES THAT SIRT1 MAY SERVE AS A POTENTIAL THERAPEUTIC MOLECULE FOR INDIVIDUALIZED TREATMENT OF CHRONIC PAIN WITH VULNERABLE EMOTIONAL DISORDERS.SIGNIFICANCE STATEMENT CHRONIC PAIN IS A PREVALENT NEUROLOGICAL DISEASE WITH NO EFFECTIVE TREATMENT AT PRESENT. PAIN PATIENTS DISPLAY CONSIDERABLY VARIABLE VULNERABILITY TO DEVELOPING CHRONIC PAIN, INDICATING INDIVIDUAL-BASED MOLECULAR MECHANISMS UNDERLYING THE PAIN VULNERABILITY, WHICH IS HARDLY ADDRESSED IN CURRENT PRECLINICAL RESEARCH. IN THIS STUDY, WE HAVE IDENTIFIED THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) AS A KEY REGULATOR THAT CONTROLS THIS PAIN VULNERABILITY. THIS STUDY REVEALS THAT THE SIRT1-CAMKIIAALPHA PATHWAY IN CENTRAL AMYGDALA ACTS AS AN EPIGENETIC MECHANISM THAT GUARDS AGAINST THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDER CHRONIC PAIN, AND THAT ITS DYSFUNCTION CAUSES INCREASED VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN. THESE FINDINGS SUGGEST THAT SIRT1 ACTIVATORS MAY BE USED IN A NOVEL THERAPEUTIC APPROACH FOR INDIVIDUAL-BASED TREATMENT OF CHRONIC PAIN.	2020