1 2705 132 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2 4173  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 1808  38 EFFECTS OF ADOLESCENT SOCIAL STRESS AND ANTIDEPRESSANT TREATMENT ON COGNITIVE INFLEXIBILITY AND BDNF EPIGENETIC MODIFICATIONS IN THE MPFC OF ADULT MICE. ADOLESCENT SOCIAL STRESS (ASS) CAN INCREASE SUSCEPTIBILITY TO DEPRESSION IN ADULTHOOD. HOWEVER, THE UNDERLYING PSYCHOLOGICAL AND NEURAL MECHANISMS REMAIN UNCLEAR. CORTICALLY MEDIATED COGNITIVE DYSFUNCTIONS ARE INCREASINGLY RECOGNIZED AS AN INDEPENDENT AND IMPORTANT RISK FACTOR OF DEPRESSION. USING SOCIAL DEFEAT STRESS, A CLASSICAL ANIMAL MODEL OF DEPRESSION, OUR PREVIOUS STUDIES FOUND THAT MICE SUBJECTED TO THIS FORM OF STRESS DURING EARLY ADOLESCENCE DISPLAYED COGNITIVE INFLEXIBILITY (CI) IN ADULTHOOD. THIS CHANGE WAS ACCOMPANIED BY A DOWN-REGULATION OF BDNF GENE EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX (MPFC); THIS GENE ENCODES A KEY MOLECULE INVOLVED IN DEPRESSION AND ANTIDEPRESSANT ACTION. IN THE PRESENT PAPER, WE IDENTIFIED EPIGENETIC MODIFICATION OF BDNF AS A POSSIBLE MECHANISM UNDERLYING THE BEHAVIORAL AND MOLECULAR CHANGES. ASS INDUCED A SET OF DEPRESSIVE PHENOTYPES, INCLUDING INCREASED SOCIAL AVOIDANCE AND CI, AS WELL AS REDUCED LEVELS OF TOTAL BDNF AND ISOFORM IV BUT NOT ISOFORM I OR VI TRANSCRIPTS IN THE MPFC. IN PARALLEL WITH CHANGES IN BDNF GENE EXPRESSION, PREVIOUSLY STRESSED ADULT MICE SHOWED INCREASED LEVELS OF DIMETHYLATION OF HISTONE H3 AT LYSINE K9 (H3K9ME2) IMMEDIATELY DOWNSTREAM OF THE BDNF IV PROMOTER. ON THE OTHER HAND, NO DIFFERENCES WERE FOUND IN TRIMETHYLATION OF HISTONE H3 AT LYSINE K4 (H3K4ME3) OR IN ACETYLATION OF HISTONE H3 AT LYSINE K9 (H3K9AC) OR AT K4 (H3K4AC) IN THE BDNF IV PROMOTER. LIKEWISE, NO ALTERATIONS WERE FOUND IN DNA METHYLATION OF THE BDNF IV PROMOTER. ADDITIONALLY, TREATMENT WITH THE CHRONIC ANTIDEPRESSANT TRANYLCYPROMINE REVERSED BDNF EPIGENETIC CHANGES AND RELATED GENE TRANSCRIPTION WHILE ALSO REVERSING CI, BUT NOT SOCIAL AVOIDANCE, IN PREVIOUSLY STRESSED ADULT MICE. THESE RESULTS SUGGEST THAT EPIGENETIC CHANGES TO THE BDNF GENE IN THE MPFC AFTER ADOLESCENT SOCIAL ADVERSITY MAY BE INVOLVED IN THE REGULATION OF COGNITIVE DYSFUNCTION IN DEPRESSION AND ANTIDEPRESSANT ACTION IN ADULTHOOD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4 1004  43 CHRONIC TREATMENT WITH HORMONAL CONTRACEPTIVES ALTERS HIPPOCAMPAL BDNF AND HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS BUT NOT LEARNING AND MEMORY IN FEMALE RATS. HORMONAL CONTRACEPTIVES PREVENT OVULATION WITH SUBSEQUENT REDUCTION IN ENDOGENOUS LEVELS OF ESTRADIOL, PROGESTERONE AND ITS NEUROACTIVE METABOLITE ALLOPREGNANOLONE. THESE NEUROSTEROIDS MODULATE SEVERAL BRAIN FUNCTIONS, INCLUDING NEURONAL PLASTICITY, COGNITION AND MEMORY. WE HYPOTHESIZED THAT HORMONAL CONTRACEPTIVES MIGHT AFFECT SYNAPTIC PLASTICITY, LEARNING AND MEMORY, AS A CONSEQUENCE OF SUPPRESSED ENDOGENOUS HORMONES LEVELS. FEMALE RATS WERE ORALLY TREATED WITH A COMBINATION OF ETHINYL ESTRADIOL (EE, 0.020 MG) AND LEVONORGESTREL (LNG, 0.060 MG) ONCE DAILY FOR FOUR WEEKS. DECREASED HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND ALTERED HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS (PTMS) WERE OBSERVED 14 DAYS AFTER DISCONTINUATION FROM CHRONIC EE-LNG TREATMENT. THESE EFFECTS WERE NOT ACCOMPANIED BY ALTERATIONS IN LONG-TERM PLASTICITY AT GLUTAMATERGIC SYNAPSES, RECOGNITION MEMORY IN THE NOVEL OBJECT AND NOVEL PLACE LOCATION TESTS, OR SPATIAL LEARNING, MEMORY, AND BEHAVIORAL FLEXIBILITY IN THE MORRIS WATER MAZE TEST. THUS, DECREASED BDNF CONTENT DOES NOT AFFECT SYNAPTIC PLASTICITY AND COGNITIVE PERFORMANCE; RATHER IT MIGHT BE RELEVANT FOR THE OCCURRENCE OF CERTAIN PSYCHIATRIC SYMPTOMS, REPORTED BY SOME WOMEN USING HORMONAL CONTRACEPTIVES. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF HIPPOCAMPAL EPIGENETIC CHANGES INDUCED BY HORMONAL CONTRACEPTIVES AND COMPLEMENT PREVIOUS STUDIES ON THE NEUROBIOLOGICAL ACTIONS OF HORMONAL CONTRACEPTIVES; THE FINDING THAT EFFECTS OF CHRONIC EE-LNG TREATMENT ON BDNF CONTENT AND HISTONE PTMS ARE OBSERVED 14 DAYS AFTER DRUG DISCONTINUATION WARRANTS FURTHER INVESTIGATION TO BETTER UNDERSTAND THE IMPLICATIONS OF SUCH LONG-TERM CONSEQUENCES FOR WOMEN'S HEALTH.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 1809  35 EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR GENE EXPRESSION IN THE HIPPOCAMPI OF CHRONIC RESTRAINT STRESS RATS. RECENT STUDIES HAVE SHOWN THAT ANTIPSYCHOTIC DRUGS HAVE EPIGENETIC EFFECTS. HOWEVER, THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON HISTONE MODIFICATION REMAIN UNCLEAR. THEREFORE, WE INVESTIGATED THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF THE BDNF GENE IN THE RAT HIPPOCAMPUS. RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS (6 H/D FOR 21 D) AND THEN WERE ADMINISTERED WITH EITHER OLANZAPINE (2 MG/KG) OR HALOPERIDOL (1 MG/KG). THE LEVELS OF HISTONE H3 ACETYLATION AND MECP2 BINDING AT BDNF PROMOTER IV WERE ASSESSED WITH CHROMATIN IMMUNOPRECIPITATION ASSAYS. THE MRNA LEVELS OF TOTAL BDNF WITH EXON IV, HDAC5, DNMT1, AND DNMT3A WERE ASSESSED WITH A QUANTITATIVE RT-PCR PROCEDURE. CHRONIC RESTRAINT STRESS RESULTED IN THE DOWNREGULATION OF TOTAL AND EXON IV BDNF MRNA LEVELS AND A DECREASE IN HISTONE H3 ACETYLATION AND AN INCREASE IN MECP2 BINDING AT BDNF PROMOTER IV. FURTHERMORE, THERE WERE ROBUST INCREASES IN THE EXPRESSION OF HDAC5 AND DNMTS. OLANZAPINE ADMINISTRATION LARGELY PREVENTED THESE CHANGES. THE ADMINISTRATION OF HALOPERIDOL HAD NO EFFECT. THESE FINDINGS SUGGEST THAT THE ANTIPSYCHOTIC DRUG OLANZAPINE INDUCED HISTONE MODIFICATION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS AND THAT THESE EPIGENETIC ALTERATIONS MAY REPRESENT ONE OF THE MECHANISMS UNDERLYING THE ACTIONS OF ANTIPSYCHOTIC DRUGS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6 2740  26 EXPOSURE TO EARLY LIFE STRESS RESULTS IN EPIGENETIC CHANGES IN NEUROTROPHIC FACTOR GENE EXPRESSION IN A PARKINSONIAN RAT MODEL. EARLY LIFE ADVERSITY INCREASES THE RISK OF MENTAL DISORDERS LATER IN LIFE. CHRONIC EARLY LIFE STRESS MAY ALTER NEUROTROPHIC FACTOR GENE EXPRESSION INCLUDING THOSE FOR BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND GLIAL CELL DERIVED NEUROTROPHIC FACTOR (GDNF) THAT ARE IMPORTANT IN NEURONAL GROWTH, SURVIVAL, AND MAINTENANCE. MATERNAL SEPARATION WAS USED IN THIS STUDY TO MODEL EARLY LIFE STRESS. FOLLOWING UNILATERAL INJECTION OF A MILD DOSE OF 6-HYDROXYDOPAMINE (6-OHDA), WE MEASURED CORTICOSTERONE (CORT) IN THE BLOOD AND STRIATUM OF STRESSED AND NONSTRESSED RATS; WE ALSO MEASURED DNA METHYLATION AND BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM USING REAL TIME PCR. IN THE PRESENCE OF STRESS, WE FOUND THAT THERE WAS INCREASED CORTICOSTERONE CONCENTRATION IN BOTH BLOOD AND STRIATAL TISSUE. FURTHER TO THIS, WE FOUND HIGHER DNA METHYLATION AND DECREASED NEUROTROPHIC FACTOR GENE EXPRESSION. 6-OHDA LESION INCREASED NEUROTROPHIC FACTOR GENE EXPRESSION IN BOTH STRESSED AND NONSTRESSED RATS BUT THIS INCREASE WAS HIGHER IN THE NONSTRESSED RATS. OUR RESULTS SUGGEST THAT EXPOSURE TO EARLY POSTNATAL STRESS INCREASES CORTICOSTERONE CONCENTRATION WHICH LEADS TO INCREASED DNA METHYLATION. THIS EFFECT RESULTS IN DECREASED BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM LEADING TO DECREASED PROTECTION AGAINST SUBSEQUENT INSULTS LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7 5019  33 PERSISTENT INFLAMMATORY PAIN IS LINKED WITH ANXIETY-LIKE BEHAVIORS, INCREASED BLOOD CORTICOSTERONE, AND REDUCED GLOBAL DNA METHYLATION IN THE RAT AMYGDALA. CHRONIC PAIN INCREASES THE RISK OF DEVELOPING ANXIETY, WITH LIMBIC AREAS BEING LIKELY NEUROLOGICAL SUBSTRATES. DESPITE HIGH CLINICAL RELEVANCE, LITTLE IS KNOWN ABOUT THE PRECISE BEHAVIORAL, HORMONAL, AND BRAIN NEUROPLASTIC CORRELATES OF ANXIETY IN THE CONTEXT OF PERSISTENT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT DECREASED NOCICEPTIVE THRESHOLDS IN CHRONIC PAIN MODELS ARE PARALLELED BY ANXIETY-LIKE BEHAVIOR IN RATS, BUT THERE ARE CONFLICTING IDEAS REGARDING ITS EFFECTS ON THE STRESS RESPONSE AND CIRCULATING CORTICOSTERONE LEVELS. EVEN LESS IS KNOWN ABOUT THE MOLECULAR MECHANISMS THROUGH WHICH THE BRAIN ENCODES PAIN-RELATED ANXIETY. THIS STUDY EXAMINES HOW PERSISTENT INFLAMMATORY PAIN IN A RAT MODEL WOULD IMPACT ANXIETY-LIKE BEHAVIORS AND CORTICOSTERONE RELEASE, AND WHETHER THESE CHANGES WOULD BE REFLECTED IN LEVELS OF GLOBAL DNA METHYLATION IN BRAIN AREAS INVOLVED IN STRESS REGULATION. COMPLETE FREUND'S ADJUVANT (CFA) OR SALINE WAS ADMINISTERED IN THE RIGHT HINDPAW OF ADULT MALE WISTAR RATS. BEHAVIORAL TESTING INCLUDED THE MEASUREMENT OF NOCICEPTIVE THRESHOLDS (DIGITAL ANESTHESIOMETER), MOTOR FUNCTION (OPEN FIELD TEST), AND ANXIETY-LIKE BEHAVIORS (ELEVATED PLUS MAZE AND THE DARK-LIGHT BOX TEST). CORTICOSTERONE WAS MEASURED VIA RADIOIMMUNOASSAY. GLOBAL DNA METHYLATION (ENZYME IMMUNOASSAY) AS WELL AS DNMT3A LEVELS (WESTERN BLOTTING) WERE QUANTIFIED IN THE AMYGDALA, PREFRONTAL CORTEX, AND VENTRAL HIPPOCAMPUS. CFA ADMINISTRATION RESULTED IN PERSISTENT REDUCTION IN NOCICEPTIVE THRESHOLD IN THE ABSENCE OF LOCOMOTOR ABNORMALITIES. INCREASED ANXIETY-LIKE BEHAVIORS WERE OBSERVED IN THE ELEVATED PLUS MAZE AND WERE ACCOMPANIED BY INCREASED BLOOD CORTICOSTERONE LEVELS 10 DAYS AFTER PAIN INDUCTION. GLOBAL DNA METHYLATION WAS DECREASED IN THE AMYGDALA, WITH NO CHANGES IN DNMT3A ABUNDANCE IN ANY OF THE REGIONS EXAMINED. PERSISTENT INFLAMMATORY PAIN PROMOTES ANXIETY -LIKE BEHAVIORS, HPA AXIS ACTIVATION, AND EPIGENETIC REGULATION THROUGH DNA METHYLATION IN THE AMYGDALA. THESE FINDINGS DESCRIBE A MOLECULAR MECHANISM THAT LINKS PAIN AND STRESS IN A WELL-CHARACTERIZED RODENT MODEL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8 6582  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 5874  34 SWIMMING EXERCISE REVERSES CUMS-INDUCED CHANGES IN DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL PLASTICITY-RELATED PROTEINS. BACKGROUND: STRESS-INDUCED FAILED RESILIENCE OF BRAIN PLASTICITY CAN CONTRIBUTE TO THE ONSET AND RECURRENCE OF DEPRESSION. CHRONIC STRESS HAS BEEN REPORTED TO OPEN WINDOWS OF EPIGENETIC PLASTICITY IN HIPPOCAMPUS. HOWEVER, HOW HIPPOCAMPAL PLASTICITY UNDERLIES DEPRESSION-LIKE BEHAVIORS AND HOW IT ADAPTS IN RESPONSE TO STRESS HAS NOT BEEN ADDRESSED. THE PRESENT STUDY AIMED TO INVESTIGATE THE SIGNALING MECHANISMS OF CUMS AFFECTING HIPPOCAMPAL PLASTICITY-RELATED PROTEINS EXPRESSION AND THE REGULATION OF SWIMMING EXERCISE IN MICE. METHODS: MALE C57BL/6 MICE WERE SUBJECTED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) FOR 7 WEEKS. FROM THE 4TH WEEK, CUMS MICE WERE TRAINED IN A MODERATE SWIMMING PROGRAM FOR A TOTAL OF 4 WEEKS. A VIDEOCOMPUTERIZED TRACKING SYSTEM WAS USED TO RECORD BEHAVIORS OF ANIMALS FOR A 5-MIN SESSION. REAL-TIME PCR AND WESTERN BLOTTING WERE USED TO EXAMINE GENE EXPRESSION IN MOUSE HIPPOCAMPUS. RESULTS: OUR RESULTS DEMONSTRATED THAT CUMS INDUCED DEPRESSION-LIKE BEHAVIORS, WHICH WERE REVERSED BY SWIMMING EXERCISE. MOREOVER, THE BEHAVIORAL CHANGES INDUCED BY CUMS AND EXERCISE WERE CORRELATED WITH HIPPOCAMPAL PLASTICITY-RELATED PROTEINS EXPRESSION OF GROWTH-ASSOCIATED PROTEIN-43 (GAP-43) AND SYNAPTOPHYSIN (SYN). THE MOLECULAR MECHANISMS REGULATING THIS PLASTICITY MAY INCLUDE SIRT1/MIRCORNA, CREB/BDNF, AND AKT/GSK-3BETA SIGNALING PATHWAYS. LIMITATIONS: WE DID NOT ESTABLISH A CORRELATION BETWEEN DEPRESSION-LIKE BEHAVIORS INDUCED BY CHRONIC STRESS AND EPIGENETIC CHANGES OF HIPPOCAMPAL PLASTICITY, EITHER A CAUSAL MOLECULAR SIGNALING UNDERLING THIS PLASTICITY. CONCLUSIONS: OUR FINDINGS HAVE IDENTIFIED SWIMMING EXERCISE EFFECTS ON CUMS-INDUCED CHANGES IN DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL PLASTICITY-RELATED PROTEINS, WHICH PROVIDE A FRAMEWORK FOR DEVELOPING NEW STRATEGIES TO TREAT STRESS-INDUCED DEPRESSION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10 6801  47 [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	

11 1907  43 ENRICHED ENVIRONMENT PRIORS TO TET1 HIPPOCAMPAL ADMINISTRATION FOR REGULATING PSYCHIATRIC BEHAVIORS VIA GLIAL REACTIVITY IN CHRONIC CEREBRAL HYPOPERFUSION MODELS. BACKGROUND: CHRONIC CEREBRAL HYPOPERFUSION (CCH) HAS BEEN GRADUALLY REGARDED AS A COMMON ETIOLOGIC MECHANISM FOR COGNITIVE AND PSYCHIATRIC DISTURBANCES. TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1) PLAYED AN IMPORTANT ROLE IN ADULT HIPPOCAMPAL NEUROGENESIS (AHN), NEURONAL CIRCUITS FORMATION, COGNITION AND PSYCHIATRIC DISORDERS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON COGNITION AND DEPRESSION VIA EFFECTIVELY REGULATING AHN AND GLIAL REACTIVITY. THIS STUDY AIMED TO ASSESS WHICH STRATEGY WAS FEASIBLE TO IMPROVE COGNITION AND PSYCHIATRIC DISTURBANCES BY COMPARING THE TET1 HIPPOCAMPAL MICROINJECTION AND EE IN CCH MODELS AND TO INVESTIGATE THE POSSIBLE MECHANISMS. METHOD: CCH RATS WERE ESTABLISHED VIA PERMANENT BILATERAL COMMON CAROTID ARTERY OCCLUSION (2-VO). RATS WERE STEREOTAXICALLY INJECTED WITH THE HUMAN CATALYTIC DOMAIN OF TET1 (HTET1) TO OVEREXPRESS THE HTET1 IN THE HIPPOCAMPUS 10 DAYS BEFORE 2-VO. 3 DAYS AFTER 2-VO, RATS WERE SUBJECTED TO STANDARD ENVIRONMENT OR EE WITH FREE ACCESS TO FOOD AND WATER. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION BEFORE SACRIFICE. EPIGENETIC MOLECULES, ADULT NEUROGENESIS, SYNAPTIC PROTEINS EXPRESSION, AND GLIAL ACTIVATION WERE ANALYZED USING IMMUNOFLUORESCENT STAINING, QRT-PCR AND WESTERN BLOT. RESULTS: IN THE PRESENT STUDY, WE FOUND BOTH EE AND GENETICAL TREATMENT WITH OVEREXPRESSING HTET1 WERE SUFFICIENT FOR STIMULATING AHN. HOWEVER, PROMOTING ANH COULD NOT DEAL WITH THE COGNITIVE DYSFUNCTION AND DEPRESSIVE-LIKE BEHAVIORS IN CCH RATS. NOTABLY, A HEALTHY LOCAL BRAIN ENVIRONMENT WITH ELEVATED BDNF AND ASTROCYTES WAS CONDUCIVE TO IMPROVING COGNITIVE DYSFUNCTION. MEANWHILE, ASTROCYTES WERE INVOLVED IN THE COGNITIVE REGULATING PROCESS OF NEURONS, PRESYNAPTIC FUNCTION AND MICROGLIA. IN GENERAL, WE HELD THAT DEPRESSIVE DISTURBANCES WERE DETERMINED BY BDNF LEVELS, NEURONAL AND PRESYNAPTIC FUNCTION, AS WELL AS GLIAL ACTIVATION CONTAINING ASTROCYTES AND MICROGLIA. TO FURTHER SUPPORT THIS POINT, WE INVESTIGATED SEVERE DEPRESSIVE SYMPTOMS THAT WERE STRONGLY CORRELATED WITH THE ACTIVATION OF ASTROGLIA AND MICROGLIA. IMPORTANTLY, CAUSAL MEDIATION ANALYSIS SHOWED SIGNIFICANT MEDIATION BY THE PRESENCE OF REACTIVE GLIAL CELLS IN THE RELATION BETWEEN NEURAL PLASTICITY AND DEPRESSIVE SYMPTOMS. FINALLY, WE SHOWED EE PERFORMED BETTER THAN HTET1 TREATMENT FOR COGNITIVE DEFICITS AND DEPRESSION. EE WITH LESS GLIAL REACTIVITY WAS MUCH MORE RESISTANT TO DEPRESSION, WHILE HTET1 WITH MORE GLIAL ACTIVATION WAS MORE VULNERABLE TO DEPRESSIVE DISORDERS. CONCLUSIONS: EE WAS LIKELY TO BE SUPERIOR TO TET1 HIPPOCAMPAL ADMINISTRATION FOR COGNITION AND PSYCHIATRIC BEHAVIORS IN CCH RATS. FURTHERMORE, A HEALTHY LOCAL BRAIN ENVIRONMENT WITH ELEVATED BDNF AND ASTROCYTES WAS CONDUCIVE TO IMPROVING COGNITIVE DYSFUNCTION. MORE GLIAL ACTIVATION, AND MORE VULNERABLE TO DEPRESSIVE DISORDERS. THESE RESULTS WERE IMPORTANT FOR OUR UNDERSTANDING OF DISEASE MECHANISMS AND PROVIDED VALUABLE TOOLS FOR THE OVERALL MANAGEMENT OF CCH PATIENTS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12 1903  39 ENHANCED NEUROINFLAMMATION MEDIATED BY DNA METHYLATION OF THE GLUCOCORTICOID RECEPTOR TRIGGERS COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS SUBJECTED TO MATERNAL SEPARATION DURING THE NEONATAL PERIOD. BACKGROUND: MOUNTING EVIDENCE INDICATES THAT CHILDREN WHO EXPERIENCE ABUSE AND NEGLECT ARE PRONE TO CHRONIC DISEASES AND PREMATURE MORTALITY LATER IN LIFE. ONE MECHANISTIC HYPOTHESIS FOR THIS PHENOMENON IS THAT EARLY LIFE ADVERSITY ALTERS THE EXPRESSION OR FUNCTIONING OF THE GLUCOCORTICOID RECEPTOR (GR) THROUGHOUT THE COURSE OF LIFE AND THEREBY INCREASES SENSITIVITY TO INFLAMMATORY STIMULATION. AN EXAGGERATED PRO-INFLAMMATORY RESPONSE IS GENERALLY CONSIDERED TO BE A KEY CAUSE OF POSTOPERATIVE COGNITIVE DYSFUNCTION (POCD). THE AIM OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF EARLY LIFE ADVERSITY ON COGNITIVE FUNCTION AND NEUROINFLAMMATION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS AND TO DETERMINE WHETHER SUCH EFFECTS ARE ASSOCIATED WITH THE EPIGENETIC REGULATION OF GR. METHODS: WISTAR RAT PUPS WERE REPEATEDLY SUBJECTED TO INFANT MATERNAL SEPARATION (EARLY LIFE STRESS) FROM POSTNATAL DAYS 2-21. IN ADULTHOOD, THEIR BEHAVIOR AND THE SIGNALING OF HIPPOCAMPAL PRO-INFLAMMATORY FACTORS AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AFTER SEVOFLURANE ANESTHESIA WERE EVALUATED. WE ALSO EXAMINED THE EFFECTS OF MATERNAL SEPARATION (MS) ON THE EXPRESSION OF GR AND THE DNA METHYLATION STATUS OF THE PROMOTER REGION OF EXON 1(7) OF GR AND WHETHER BEHAVIORAL CHANGES AND NEUROINFLAMMATION AFTER ANESTHESIA WERE REVERSIBLE WHEN THE EXPRESSION OF GR WAS INCREASED BY ALTERING DNA METHYLATION. RESULTS: MS INDUCED COGNITIVE DECLINE AFTER SEVOFLURANE INHALATION IN THE MORRIS WATER MAZE AND CONTEXT FEAR CONDITIONING TESTS AND ENHANCED THE RELEASE OF CYTOKINES AND THE ACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING INDUCED BY SEVOFLURANE IN THE HIPPOCAMPUS OF ADULT RATS. BLOCKING NF-KAPPAB SIGNALING BY PYRROLIDINE DITHIOCARBAMATE (PDTC) INHIBITED THE RELEASE OF CYTOKINES. MS ALSO REDUCED THE EXPRESSION OF GR AND UPREGULATED THE METHYLATION LEVELS OF THE PROMOTER REGION OF GR EXON 1(7), AND SUCH EFFECTS WERE REVERSED BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) IN ADULT RATS. MOREOVER, TSA TREATMENT IN ADULT MS RATS INHIBITED THE OVERACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING AND THE RELEASE OF CYTOKINES AND ALLEVIATED COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA. CONCLUSIONS: EARLY LIFE STRESS INDUCES COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA, PERHAPS DUE TO THE ABERRANT METHYLATION OF THE GR GENE PROMOTER, WHICH REDUCES THE EXPRESSION OF THE GR GENE AND FACILITATES EXAGGERATED INFLAMMATORY RESPONSES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13  213  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  531  41 ASTROCYTE REACTIVITY FOLLOWING BLAST EXPOSURE INVOLVES ABERRANT HISTONE ACETYLATION. BLAST INDUCED NEUROTRAUMA (BINT) IS A PREVALENT INJURY WITHIN MILITARY AND CIVILIAN POPULATIONS. THE INJURY IS CHARACTERIZED BY PERSISTENT INFLAMMATION AT THE CELLULAR LEVEL WHICH MANIFESTS AS A MULTITUDE OF COGNITIVE AND FUNCTIONAL IMPAIRMENTS. EPIGENETIC REGULATION OF TRANSCRIPTION OFFERS AN IMPORTANT CONTROL MECHANISM FOR GENE EXPRESSION AND CELLULAR FUNCTION WHICH MAY UNDERLIE CHRONIC INFLAMMATION AND RESULT IN NEURODEGENERATION. WE HYPOTHESIZE THAT ALTERED HISTONE ACETYLATION PATTERNS MAY BE INVOLVED IN BLAST INDUCED INFLAMMATION AND THE CHRONIC ACTIVATION OF GLIAL CELLS. THIS STUDY AIMED TO ELUCIDATE CHANGES TO HISTONE ACETYLATION OCCURRING FOLLOWING INJURY AND THE ROLES THESE CHANGES MAY HAVE WITHIN THE PATHOLOGY. SPRAGUE DAWLEY RATS WERE SUBJECTED TO EITHER A 10 OR 17 PSI BLAST OVERPRESSURE WITHIN AN ADVANCED BLAST SIMULATOR (ABS). SHAM ANIMALS UNDERWENT THE SAME PROCEDURES WITHOUT BLAST EXPOSURE. MEMORY IMPAIRMENTS WERE MEASURED USING THE NOVEL OBJECT RECOGNITION (NOR) TEST AT 2 AND 7 DAYS POST-INJURY. TISSUES WERE COLLECTED AT 7 DAYS FOR WESTERN BLOT AND IMMUNOHISTOCHEMISTRY (IHC) ANALYSIS. SHAM ANIMALS SHOWED INTACT MEMORY AT EACH TIME POINT. THE NOVEL OBJECT DISCRIMINATION DECREASED SIGNIFICANTLY BETWEEN TWO AND 7 DAYS FOR EACH INJURY GROUP (P < 0.05). THIS IS INDICATIVE OF THE ONSET OF MEMORY IMPAIRMENT. WESTERN BLOT ANALYSIS SHOWED GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), A KNOWN MARKER OF ACTIVATED ASTROCYTES, WAS ELEVATED IN THE PREFRONTAL CORTEX (PFC) FOLLOWING BLAST EXPOSURE FOR BOTH INJURY GROUPS. ANALYSIS OF HISTONE PROTEIN EXTRACT SHOWED NO CHANGES IN THE LEVEL OF ANY TOTAL HISTONE PROTEINS WITHIN THE PFC. HOWEVER, ACETYLATION LEVELS OF HISTONE H2B, H3, AND H4 WERE DECREASED IN BOTH GROUPS (P < 0.05). CO-LOCALIZATION IMMUNOFLUORESCENCE WAS USED TO FURTHER INVESTIGATE ANY POTENTIAL CORRELATION BETWEEN DECREASED HISTONE ACETYLATION AND ASTROCYTE ACTIVATION. THESE EXPERIMENTS SHOWED A SIMILAR DECREASE IN H3 ACETYLATION IN ASTROCYTES EXPOSED TO A 17 PSI BLAST BUT NOT A 10 PSI BLAST. FURTHER INVESTIGATION OF GENE EXPRESSION BY POLYMERASE CHAIN REACTION (PCR) ARRAY, SHOWED DYSREGULATION OF SEVERAL CYTOKINE AND CYTOKINE RECEPTORS THAT ARE INVOLVED IN NEUROINFLAMMATORY PROCESSES. WE HAVE SHOWN ABERRANT HISTONE ACETYLATION PATTERNS INVOLVED IN BLAST INDUCED ASTROGLIOSIS AND COGNITIVE IMPAIRMENTS. FURTHER UNDERSTANDING OF THEIR ROLE IN THE INJURY PROGRESSION MAY LEAD TO NOVEL THERAPEUTIC TARGETS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15 3969  33 LONG-LASTING DEPRESSION-LIKE BEHAVIOR AND EPIGENETIC CHANGES OF BDNF GENE EXPRESSION INDUCED BY PERINATAL EXPOSURE TO METHYLMERCURY. SUBSTANTIAL EVIDENCE INDICATES THAT PREDISPOSITION TO DISEASES CAN BE ACQUIRED DURING EARLY STAGES OF DEVELOPMENT AND INTERACTIONS BETWEEN ENVIRONMENTAL AND GENETIC FACTORS MAY BE IMPLICATED IN THE ONSET OF MANY PATHOLOGICAL CONDITIONS. DATA COLLECTED OVER SEVERAL DECADES HAVE SHOWN THAT CHEMICALS ARE AMONG THE RELEVANT FACTORS THAT CAN ENDANGER CNS. WE PREVIOUSLY SHOWED THAT PERINATAL EXPOSURE TO METHYLMERCURY (MEHG) CAUSES PERSISTENT CHANGES IN LEARNING AND MOTIVATIONAL BEHAVIOR IN MICE. IN THIS STUDY, WE REPORT THAT THE DEPRESSION-LIKE BEHAVIOR IN MEHG-EXPOSED MALE MICE IS REVERSED BY CHRONIC TREATMENT WITH THE ANTIDEPRESSANT FLUOXETINE. BEHAVIORAL ALTERATIONS ARE ASSOCIATED WITH A DECREASE IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPAL DENTATE GYRUS AND FLUOXETINE TREATMENT RESTORES BDNF MRNA EXPRESSION. WE ALSO SHOW THAT MEHG-EXPOSURE INDUCES LONG-LASTING REPRESSIVE STATE OF THE CHROMATIN STRUCTURE AT THE BDNF PROMOTER REGION, IN PARTICULAR DNA HYPERMETHYLATION, AN INCREASE IN HISTONE H3-K27 TRI-METHYLATION AND A DECREASE IN H3 ACETYLATION AT THE PROMOTER IV. WHILE FLUOXETINE TREATMENT DOES NOT ALTER HYPERMETHYLATION OF H3-K27, IT SIGNIFICANTLY UP-REGULATES H3 ACETYLATION AT THE BDNF PROMOTER IV IN MEHG-EXPOSED MICE. OUR STUDY SHOWS THAT DEVELOPMENTAL EXPOSURE TO LOW LEVELS OF MEHG PREDISPOSES MICE TO DEPRESSION AND INDUCES EPIGENETIC SUPPRESSION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16 6175  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17 1418  25 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18 2318  28 EPIGENETIC REGULATION OF GABAERGIC DIFFERENTIATION IN THE DEVELOPING BRAIN. IN THE VERTEBRATE BRAIN, GABAERGIC CELL DEVELOPMENT AND NEUROTRANSMISSION ARE IMPORTANT FOR THE ESTABLISHMENT OF NEURAL CIRCUITS. VARIOUS INTRINSIC AND EXTRINSIC FACTORS HAVE BEEN IDENTIFIED TO AFFECT GABAERGIC NEUROGENESIS. HOWEVER, LITTLE IS KNOWN ABOUT THE EPIGENETIC CONTROL OF GABAERGIC DIFFERENTIATION IN THE DEVELOPING BRAIN. HERE, WE REPORT THAT THE NUMBER OF GABAERGIC NEURONS DYNAMICALLY CHANGES DURING THE EARLY TECTAL DEVELOPMENT IN THE XENOPUS BRAIN. THE PERCENTAGE OF GABAERGIC NEURONS IS RELATIVELY UNCHANGED DURING THE EARLY STAGES FROM STAGE 40 TO 46 BUT SIGNIFICANTLY DECREASED FROM STAGE 46 TO 48 TADPOLES. INTERESTINGLY, THE HISTONE ACETYLATION OF H3K9 IS DEVELOPMENTALLY DECREASED FROM STAGE 42 TO 48 (ABOUT 3.5 DAYS). CHRONIC APPLICATION OF VALPROATE ACID (VPA), A BROAD-SPECTRUM HISTONE DEACETYLASE (HDAC) INHIBITOR, AT STAGE 46 FOR 48 H INCREASES THE ACETYLATION OF H3K9 AND THE NUMBER OF GABAERGIC CELLS IN THE OPTIC TECTUM. VPA TREATMENT ALSO REDUCES APOPTOTIC CELLS. ELECTROPHYSIOLOGICAL RECORDINGS SHOW THAT A VPA INDUCES AN INCREASE IN THE FREQUENCY OF MIPSCS AND NO CHANGES IN THE AMPLITUDE. BEHAVIORAL STUDIES REVEAL THAT VPA DECREASES SWIMMING ACTIVITY AND VISUALLY GUIDED AVOIDANCE BEHAVIOR. THESE FINDINGS EXTEND OUR UNDERSTANDING OF HISTONE MODIFICATION IN THE GABAERGIC DIFFERENTIATION AND NEUROTRANSMISSION DURING EARLY BRAIN DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 5624  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 1238  30 CURCUMIN BLOCKS CHRONIC MORPHINE ANALGESIC TOLERANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR UPREGULATION. THIS STUDY WAS CARRIED OUT BASED ON THE ASSUMPTION THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MAY COUNTERBALANCE THE ACTION OF MORPHINE IN THE BRAIN. MORPHINE ANALGESIC TOLERANCE AFTER DAILY ADMINISTRATIONS FOR SIX DAYS WAS BLOCKED BY INTRACEREBROVENTRICULAR INJECTION OF ANTI-BDNF IGG ON DAY 5, BUT NOT BY ADMINISTRATIONS ON DAYS 1-4. CHRONIC MORPHINE TREATMENT SIGNIFICANTLY INCREASED THE EXPRESSION OF EXON I AND IV BDNF TRANSCRIPTS, INDICATING DIFFERENTIAL REGULATION OF BDNF GENE EXPRESSION. DAILY ADMINISTRATION OF THE CREB-BINDING PROTEIN INHIBITOR CURCUMIN ABOLISHED THE UPREGULATION OF BDNF TRANSCRIPTION AND MORPHINE ANALGESIC TOLERANCE. THESE RESULTS SUGGEST THAT CURCUMIN MIGHT BE A PROMISING ADJUVANT TO REDUCE MORPHINE ANALGESIC TOLERANCE, AND THAT EPIGENETIC CONTROL COULD BE A NEW STRATEGY USEFUL FOR THE CONTROL OF THIS PROBLEM.	2009