1  1821 151 EFFECTS OF CHRONIC SOCIAL DEFEAT ON BEHAVIORAL AND NEURAL CORRELATES OF SOCIALITY: VASOPRESSIN, OXYTOCIN AND THE VASOPRESSINERGIC V1B RECEPTOR. CHRONIC SOCIAL STRESS IN RODENTS PRODUCES BEHAVIORAL AND NEUROENDOCRINE PATTERNS ANALOGOUS TO SYMPTOMS ASSOCIATED WITH PSYCHOPATHOLOGIES IN HUMANS. CHRONIC SOCIAL DEFEAT IN MICE HAS BEEN USED TO STUDY THE GENETIC AND EPIGENETIC PRECURSORS OF STRESS-RELATED SOCIAL DISORDERS. THE NEUROPEPTIDES ARGININE VASOPRESSIN (AVP) AND OXYTOCIN (OT) ARE RELEASED IN CENTRAL TARGETS TO MODULATE ANTI- AND PRO-SOCIAL BEHAVIORS, RESPECTIVELY. AVP BINDS TO V1A AND V1B RECEPTORS (V1BRS) IN DISCRETE BRAIN REGIONS RELATED TO ANXIETY, DEPRESSION AND AFFILIATIVE BEHAVIORS. RECENT EVIDENCE SUGGESTS THAT V1BRS ARE INVOLVED IN STRESS AND ANXIETY AND MAY BE AN ATTRACTIVE TARGET FOR THE TREATMENT OF ASSOCIATED DISORDERS. IN THE PRESENT SERIES OF EXPERIMENTS, WE AIMED TO EVALUATE THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS ON: 1) ANXIETY-RELATED BEHAVIORS IN A SOCIAL INVESTIGATION PARADIGM AND THEIR POTENTIAL MODULATION BY AN ACUTE DOSE OF SSR149415, A V1BR ANTAGONIST; 2) AVP AND FOS PROTEIN LEVELS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVN) AND; 3) AVP- AND OT-RECEPTOR (OTR) MRNA LEVELS IN BRAIN REGIONS ASSOCIATED WITH SOCIALITY. WHEN COMPARED TO UNDEFEATED ANIMALS, SOCIALLY DEFEATED MICE EXHIBITED AN ANXIOGENIC BEHAVIORAL PROFILE TOWARDS A NOVEL MALE CONSPECIFIC, WITH SSR149415 PARTLY ATTENUATING THESE EFFECTS. HISTOCHEMISTRY USING IMMUNOFLUORESCENCE SHOWED DEFEAT PRODUCED SIGNIFICANT ELEVATIONS OF FOS AND DOUBLE LABELING OF AVP AND FOS PROTEINS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVN). SSR149415 ATTENUATED THE EFFECTS OF DEFEAT ON FOS AND AVP/FOS DOUBLE LABELING, CONSISTENT WITH AN ANXIOLYTIC EFFECT. DEFEATED MICE SHOWED ELEVATED LEVELS OF OTR MRNA LEVELS IN THE LATERAL SEPTUM (LS) IN ADDITION TO INCREASED V1BR AND OTR MRNA IN THE MEDIAL AMYGDALA (MEA). WE SUGGEST THE INVOLVEMENT OF V1BRS AND OTRS IN A CIRCUIT INVOLVING THE PVN, MEA AND LS IN THE EFFECTS OF DEFEAT ON SOCIALITY. SSR149415 ATTENUATED ANXIOGENESIS IN THE SOCIAL INVESTIGATION MODEL AND BOTH FOS AND AVP/FOS LABELING, SUGGESTING V1BRS ARE AN ATTRACTIVE TARGET FOR THE TREATMENT OF ANXIETY IN GENERAL AND DISORDERS OF SOCIALITY IN PARTICULAR.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  6267  33 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3  5498  32 REVIEW: DNA METHYLATION AND ALCOHOL USE DISORDERS: PROGRESS AND CHALLENGES. BACKGROUND AND OBJECTIVES: RISK FOR ALCOHOL USE DISORDERS (AUDS) IS INFLUENCED BY GENE-ENVIRONMENT INTERACTIONS. ENVIRONMENTAL FACTORS CAN AFFECT GENE EXPRESSION THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION. THIS REVIEW OUTLINES THE FINDINGS REGARDING THE ASSOCIATION OF DNA METHYLATION AND AUDS. METHODS: WE SEARCHED PUBMED (BY APRIL 2016) AND IDENTIFIED 29 STUDIES THAT EXAMINED THE ASSOCIATION OF DNA METHYLATION AND AUDS. WE ALSO EVALUATED THE METHODS USED IN THESE STUDIES. RESULTS: TWO STUDIES DEMONSTRATED ELEVATED GLOBAL (REPETITIVE ELEMENT) DNA METHYLATION LEVELS IN AUD SUBJECTS. FIFTEEN CANDIDATE GENE STUDIES SHOWED HYPERMETHYLATION OF PROMOTER REGIONS OF SIX GENES (AVP, DNMT3B, HERP, HTR3A, OPRM1, AND SNCA) OR HYPOMETHYLATION OF THE GDAP1 PROMOTER REGION IN AUD SUBJECTS. FIVE GENOME-WIDE DNA METHYLATION STUDIES DEMONSTRATED WIDESPREAD DNA METHYLATION CHANGES ACROSS THE GENOME IN AUD SUBJECTS. SIX STUDIES SHOWED SIGNIFICANT CORRELATIONS OF DNA METHYLATION WITH GENE EXPRESSION IN AUD SUBJECTS. THREE STUDIES REVEALED INTERACTIVE EFFECTS OF GENETIC VARIATION AND DNA METHYLATION ON SUSCEPTIBILITY TO AUDS. MOST STUDIES ANALYZED AUD-ASSOCIATED DNA METHYLATION CHANGES IN THE PERIPHERAL BLOOD; A FEW STUDIES EXAMINED DNA METHYLATION CHANGES IN POSTMORTEM BRAINS OF AUD SUBJECTS. DISCUSSION AND CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION MAY RESULT IN DNA METHYLATION CHANGES, LEADING TO NEUROADAPTATIONS THAT MAY UNDERLIE SOME OF THE MECHANISMS OF AUD RISK AND PERSISTENCE. FUTURE STUDIES ARE NEEDED TO CONFIRM THE FEW EXISTING RESULTS, AND THEN TO ELUCIDATE WHETHER DNA METHYLATION CHANGES ARE THE CAUSE OR CONSEQUENCE OF AUDS. SCIENTIFIC SIGNIFICANCE: DNA METHYLATION PROFILES MAY BE USED TO ASSESS AUD STATUS OR MONITOR AUD TREATMENT RESPONSE. (AM J ADDICT 2017;26:502-515).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  5651  24 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  4606  31 NEIGHBORHOOD CHARACTERISTICS INFLUENCE DNA METHYLATION OF GENES INVOLVED IN STRESS RESPONSE AND INFLAMMATION: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS. LIVING IN A DISADVANTAGED NEIGHBORHOOD IS ASSOCIATED WITH POOR HEALTH OUTCOMES EVEN AFTER ACCOUNTING FOR INDIVIDUAL-LEVEL SOCIOECONOMIC FACTORS. THE CHRONIC STRESS OF UNFAVORABLE NEIGHBORHOOD CONDITIONS MAY LEAD TO DYSREGULATION OF THE STRESS REACTIVITY AND INFLAMMATORY PATHWAYS, POTENTIALLY MEDIATED THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION. WE USED MULTI-LEVEL MODELS TO EXAMINE THE RELATIONSHIP BETWEEN 2 NEIGHBORHOOD CONDITIONS AND METHYLATION LEVELS OF 18 GENES RELATED TO STRESS REACTIVITY AND INFLAMMATION IN PURIFIED MONOCYTES FROM 1,226 PARTICIPANTS OF THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), A POPULATION-BASED SAMPLE OF US ADULTS. NEIGHBORHOOD SOCIOECONOMIC DISADVANTAGE, A SUMMARY OF 16 CENSUS-BASED METRICS, WAS ASSOCIATED WITH DNA METHYLATION [FALSE DISCOVERY RATE (FDR) Q-VALUE </= 0.1] IN 2 OUT OF 7 STRESS-RELATED GENES EVALUATED (CRF, SLC6A4) AND 2 OUT OF 11 INFLAMMATION-RELATED GENES (F8, TLR1). NEIGHBORHOOD SOCIAL ENVIRONMENT, A SUMMARY MEASURE OF AESTHETIC QUALITY, SAFETY, AND SOCIAL COHESION, WAS ASSOCIATED WITH METHYLATION IN 4 OF THE 7 STRESS-RELATED GENES (AVP, BDNF, FKBP5, SLC6A4) AND 7 OF THE 11 INFLAMMATION-RELATED GENES (CCL1, CD1D, F8, KLRG1, NLRP12, SLAMF7, TLR1). HIGH SOCIOECONOMIC DISADVANTAGE AND WORSE SOCIAL ENVIRONMENT WERE PRIMARILY ASSOCIATED WITH INCREASED METHYLATION. IN 5 GENES WITH SIGNIFICANT ASSOCIATIONS BETWEEN NEIGHBORHOOD AND METHYLATION (FKBP5, CD1D, F8, KLRG1, NLRP12), METHYLATION WAS ASSOCIATED WITH GENE EXPRESSION OF AT LEAST ONE TRANSCRIPT. THESE RESULTS DEMONSTRATE THAT MULTIPLE DIMENSIONS OF NEIGHBORHOOD CONTEXT MAY INFLUENCE METHYLATION LEVELS AND SUBSEQUENT GENE EXPRESSION OF STRESS- AND INFLAMMATION-RELATED GENES, EVEN AFTER ACCOUNTING FOR INDIVIDUAL SOCIOECONOMIC FACTORS. FURTHER ELUCIDATING THE MOLECULAR MECHANISMS UNDERLYING THESE RELATIONSHIPS WILL BE IMPORTANT FOR UNDERSTANDING THE ETIOLOGY OF HEALTH DISPARITIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6  3321  34 HISTONE ACETYLATION OF THE HTR3A GENE IN THE PREFRONTAL CORTEX OF WISTAR RATS REGULATES ETHANOL-SEEKING BEHAVIOR. PREVIOUS REPORTS SHOWED THAT DECREASED HISTONE DEACETYLASE ACTIVITY SIGNIFICANTLY POTENTIATED THE REWARDING EFFECTS OF PSYCHOSTIMULANTS, AND THAT ENCODING OF THE 5-HT3 RECEPTOR BY THE HTR3A GENE WAS RELATED TO ETHANOL-SEEKING BEHAVIOR. HOWEVER, THE EFFECTS OF A HISTONE DEACETYLASE INHIBITOR ON ETHANOL-SEEKING BEHAVIOR AND EPIGENETIC REGULATION OF HTR3A MRNA EXPRESSION AFTER CHRONIC ETHANOL EXPOSURE ARE NOT FULLY UNDERSTOOD. USING QUANTITATIVE REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS, WE INVESTIGATED THE EFFECTS OF CHRONIC ETHANOL EXPOSURE AND ITS INTERACTION WITH A HISTONE DEACETYLASE INHIBITOR ON HISTONE-ACETYLATION-MEDIATED CHANGES IN HTR3A MRNA EXPRESSION IN THE HTR3A PROMOTER REGION. THE CONDITIONED PLACE PREFERENCE PROCEDURE WAS USED TO EVALUATE ETHANOL-SEEKING BEHAVIOR. CHRONIC EXPOSURE TO ETHANOL EFFECTIVELY ELICITED PLACE CONDITIONING. IN THE PREFRONTAL CORTEX, THE ACETYLATION OF H3K9 AND HTR3A MRNA EXPRESSION IN THE HTR3A PROMOTER REGION WERE SIGNIFICANTLY HIGHER IN THE ETHANOL GROUP THAN IN THE SALINE GROUP. THE HISTONE DEACETYLASE INHIBITOR SODIUM BUTYRATE POTENTIATED THE EFFECTS OF ETHANOL ON HTR3A MRNA EXPRESSION AND ENHANCED ETHANOL-INDUCED CONDITIONED PLACE PREFERENCES. THESE RESULTS SUGGEST THAT ETHANOL UPREGULATES HTR3A LEVELS THROUGH MECHANISMS INVOLVING H3K9 ACETYLATION, AND THAT HISTONE ACETYLATION MAY BE A THERAPEUTIC TARGET FOR TREATING ETHANOL ABUSE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
7  5051  41 PHARMACOLOGICAL RESCUE OF NOCICEPTIVE HYPERSENSITIVITY AND OXYTOCIN ANALGESIA IMPAIRMENT IN A RAT MODEL OF NEONATAL MATERNAL SEPARATION. OXYTOCIN (OT), KNOWN FOR ITS NEUROHORMONAL EFFECTS AROUND BIRTH, HAS RECENTLY BEEN SUGGESTED FOR BEING A CRITICAL DETERMINANT IN NEURODEVELOPMENTAL DISORDERS. THIS HYPOTHALAMIC NEUROPEPTIDE EXERTS A POTENT ANALGESIC EFFECT THROUGH AN ACTION ON THE NOCICEPTIVE SYSTEM. THIS ENDOGENOUS CONTROL OF PAIN HAS AN IMPORTANT ADAPTIVE VALUE BUT MIGHT BE ALTERED BY EARLY LIFE STRESS, POSSIBLY CONTRIBUTING TO ITS LONG-TERM CONSEQUENCES ON PAIN RESPONSES AND ASSOCIATED COMORBIDITIES. WE TESTED THIS HYPOTHESIS USING A RAT MODEL OF NEONATAL MATERNAL SEPARATION (NMS) KNOWN TO INDUCE LONG-TERM CONSEQUENCES ON SEVERAL BRAIN FUNCTIONS INCLUDING CHRONIC STRESS, ANXIETY, ALTERED SOCIAL BEHAVIOR, AND VISCERAL HYPERSENSITIVITY. WE FOUND THAT ADULT RATS WITH A HISTORY OF NMS WERE HYPERSENSITIVE TO NOXIOUS MECHANICAL/THERMAL HOT STIMULI AND TO INFLAMMATORY PAIN. WE FAILED TO OBSERVE OT RECEPTOR-MEDIATED STRESS-INDUCED ANALGESIA AND OT ANTIHYPERALGESIA AFTER CARRAGEENAN INFLAMMATION. THESE ALTERATIONS WERE PARTIALLY RESCUED IF NMS PUPS WERE TREATED BY INTRAPERITONEAL DAILY INJECTION DURING NMS WITH OT OR ITS DOWNSTREAM SECOND MESSENGER ALLOPREGNANOLONE. THE INVOLVEMENT OF EPIGENETIC CHANGES IN THESE ALTERATIONS WAS CONFIRMED SINCE NEONATAL TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR SAHA, NOT ONLY NORMALIZED NOCICEPTIVE SENSITIVITIES BUT ALSO RESTORED OT RECEPTOR-MEDIATED STRESS-INDUCED ANALGESIA AND THE ENDOGENOUS ANTIHYPERALGESIA IN INFLAMED NMS RATS. THERE IS GROWING EVIDENCE IN THE LITERATURE THAT EARLY LIFE STRESS MIGHT IMPAIR THE NOCICEPTIVE SYSTEM ONTOGENY AND FUNCTION. THIS STUDY SUGGESTS THAT THESE ALTERATIONS MIGHT BE RESTORED WHILE STIMULATING OT RECEPTOR SIGNALING OR HISTONE DEACETYLASE INHIBITORS, USING MOLECULES THAT ARE CURRENTLY AVAILABLE OR PART OF CLINICAL TRIALS FOR OTHER PATHOLOGIES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  6019  30 THE ASSOCIATION OF HTR3A MRNA EXPRESSION AND CRAVING IN HAN CHINESE ALCOHOL-DEPENDENT PATIENTS: A PRELIMINARY STUDY. BACKGROUND: 5-HYDROXYTRYPTAMINE (5-HT) 3 RECEPTOR PLAYS A CRUCIAL ROLE IN CRAVING OF ALCOHOL DEPENDENCE. RECENT EVIDENCE SHOWS THAT CHRONIC ALCOHOL EXPOSURE CAUSES CHANGES IN GENE EXPRESSION AND INDUCES BEHAVIORAL CHANGES. HOWEVER, THE RELATIONSHIP BETWEEN GENE EXPRESSION OF 5-HT3 RECEPTOR AND CRAVING IN ALCOHOL-DEPENDENT PATIENTS IS NOT FULLY UNDERSTOOD. OBJECTIVES: THE AIM OF THIS PRELIMINARY STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN GENE EXPRESSION OF THE 5-HT3 RECEPTOR AND CRAVING IN ALCOHOL-DEPENDENT PATIENTS AND THE EPIGENETIC MECHANISM. METHODS: WE RECRUITED 50 MALE HAN CHINESE ALCOHOL-DEPENDENT PATIENTS AND 46 MALE HAN CHINESE HEALTHY CONTROLS. WE INVESTIGATED THE CHANGES OF HTR3A MRNA, WHICH ENCODES THE 5-HT3 RECEPTOR A SUBUNIT, AND H3K9 ACETYLATION IN HTR3A PROMOTER REGION. OBSESSIVE COMPULSIVE DRINKING SCALE (OCDS) WAS USED TO ASSESS THE CRAVING OF ALCOHOL-DEPENDENT PATIENTS RELATIVE TO CONTROLS. RESULTS: HTR3A MRNA EXPRESSION LEVELS AND ACETYLATION LEVELS OF H3K9 IN THE HTR3A PROMOTER REGION WERE SIGNIFICANTLY HIGHER IN THE ALCOHOL-DEPENDENT PATIENTS. HTR3A MRNA EXPRESSION LEVELS WERE POSITIVELY CORRELATED WITH OCDS SCORES. MOREOVER, HTR3A MRNA EXPRESSION LEVELS WERE POSITIVELY CORRELATED WITH ACETYLATION LEVELS OF H3K9 IN HTR3A PROMOTER REGION. CONCLUSION: THE CURRENT FINDINGS SUGGEST THAT HTR3A MRNA EXPRESSION LEVELS WERE POSITIVELY CORRELATED WITH CRAVING IN HAN CHINESE ALCOHOL-DEPENDENT PATIENTS. THE REGULATION OF H3K9 HISTONE ACETYLATION IN HTR3A PROMOTER REGION MAY OFFER A TARGET FOR THE TREATMENT OF ALCOHOL DEPENDENCE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
9   886  34 CHRONIC CORTICOSTERONE EXPOSURE INCREASES EXPRESSION AND DECREASES DEOXYRIBONUCLEIC ACID METHYLATION OF FKBP5 IN MICE. THERE IS EVIDENCE FOR HYPERCORTISOLEMIA PLAYING A ROLE IN THE GENERATION OF PSYCHIATRIC SYMPTOMS AND FOR EPIGENETIC VARIATION WITHIN HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS GENES MEDIATING BEHAVIORAL CHANGES. WE TESTED THE HYPOTHESIS THAT EXPRESSION CHANGES WOULD BE INDUCED IN FKBP5 AND OTHER HPA AXIS GENES BY CHRONIC EXPOSURE TO CORTICOSTERONE AND THAT THESE CHANGES WOULD OCCUR THROUGH THE EPIGENETIC MECHANISM OF LOSS OR GAIN OF DNA METHYLATION (DNAM). WE ADMINISTERED CORTICOSTERONE (CORT) TO C57BL/6J MICE VIA THEIR DRINKING WATER FOR 4 WK AND TESTED FOR BEHAVIORAL AND PHYSIOLOGICAL CHANGES AND CHANGES IN GENE EXPRESSION LEVELS USING RNA EXTRACTED FROM HIPPOCAMPUS, HYPOTHALAMUS, AND BLOOD FOR THE FOLLOWING HPA GENES: FKBP5, NR3C1, HSP90, CRH, AND CRHR1. THE CORT MICE EXHIBITED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE TEST. CHRONIC EXPOSURE TO CORT ALSO CAUSED A SIGNIFICANT DECREASE IN THE HIPPOCAMPAL AND BLOOD MRNA LEVELS OF NR3C1 AND A DECREASE IN HSP90 IN BLOOD AND CAUSED AN INCREASE IN FKBP5 FOR ALL TISSUES. DIFFERENCES WERE SEEN IN FKBP5 METHYLATION IN HIPPOCAMPUS AND HYPOTHALAMUS. TO ISOLATE A SINGLE-CELL TYPE, WE FOLLOWED UP WITH AN HT-22 MOUSE HIPPOCAMPAL NEURONAL CELL LINE EXPOSED TO CORT. AFTER 7 D, WE OBSERVED A 2.4-FOLD INCREASE IN FKBP5 EXPRESSION AND A DECREASE IN DNAM. IN THE CORT-TREATED MICE, WE ALSO OBSERVED CHANGES IN BLOOD DNAM IN FKBP5. OUR RESULTS SUGGEST DNAM PLAYS A ROLE IN MEDIATING EFFECTS OF GLUCOCORTICOID EXPOSURE ON FKBP5 FUNCTION, WITH POTENTIAL CONSEQUENCES FOR BEHAVIOR.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  6108  32 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS.	2019	

11  2187  42 EPIGENETIC MECHANISMS UNDERLYING STRESS-INDUCED VISCERAL PAIN: RESILIENCE VERSUS VULNERABILITY IN A TWO-HIT MODEL OF EARLY LIFE STRESS AND CHRONIC ADULT STRESS. BACKGROUND: WOMEN WITH A HISTORY OF EARLY LIFE STRESS (ELS) HAVE A HIGHER RISK OF DEVELOPING IRRITABLE BOWEL SYNDROME (IBS). IN ADDITION, CHRONIC STRESS IN ADULTHOOD CAN EXACERBATE IBS SYMPTOMS SUCH AS ABDOMINAL PAIN DUE TO VISCERAL HYPERSENSITIVITY. WE PREVIOUSLY SHOWED THAT SEX AND THE PREDICTABILITY OF ELS DETERMINE WHETHER RATS DEVELOP VISCERAL HYPERSENSITIVITY IN ADULTHOOD. IN FEMALE RATS, UNPREDICTABLE ELS CONFERS VULNERABILITY AND RESULTS IN VISCERAL HYPERSENSITIVITY, WHEREAS PREDICTABLE ELS INDUCES RESILIENCE AND DOES NOT INDUCE VISCERAL HYPERSENSITIVITY IN ADULTHOOD. HOWEVER, THIS RESILIENCE IS LOST AFTER EXPOSURE TO CHRONIC STRESS IN ADULTHOOD LEADING TO AN EXACERBATION OF VISCERAL HYPERSENSITIVITY. EVIDENCE SUGGESTS THAT CHANGES IN HISTONE ACETYLATION AT THE PROMOTER REGIONS OF GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING FACTOR (CRF) IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) UNDERLIE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. HERE, WE AIMED TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION IN THE CEA ON VISCERAL HYPERSENSITIVITY IN A TWO-HIT MODEL OF ELS FOLLOWED BY CHRONIC STRESS IN ADULTHOOD. METHODS: MALE AND FEMALE NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS. RATS WERE EXPOSED TO CHRONIC WATER AVOIDANCE STRESS (WAS, 1 H/DAY FOR 7 DAYS) OR SHAM STRESS AND RECEIVED INFUSIONS OF VEHICLE, THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) OR THE HISTONE ACETYLTRANSFERASE INHIBITOR GARCINOL (GAR) AFTER EACH WAS SESSION. 24 H AFTER THE FINAL INFUSION, VISCERAL SENSITIVITY WAS ASSESSED AND THE CEA WAS REMOVED FOR MOLECULAR EXPERIMENTS. RESULTS: IN THE TWO-HIT MODEL (ELS + WAS), FEMALE RATS PREVIOUSLY EXPOSED TO PREDICTABLE ELS, SHOWED A SIGNIFICANT REDUCTION IN HISTONE 3 LYSINE 9 (H3K9) ACETYLATION AT THE GR PROMOTER AND A SIGNIFICANT INCREASE IN H3K9 ACETYLATION AT THE CRF PROMOTER. THESE EPIGENETIC CHANGES WERE ASSOCIATED WITH CHANGES IN GR AND CRF MRNA EXPRESSION IN THE CEA AND AN EXACERBATION OF STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN FEMALE ANIMALS. TSA INFUSIONS IN THE CEA ATTENUATED THE EXACERBATED STRESS-INDUCED VISCERAL HYPERSENSITIVITY, WHEREAS GAR INFUSIONS ONLY PARTIALLY AMELIORATED ELS+WAS INDUCED VISCERAL HYPERSENSITIVITY. CONCLUSION: THE TWO-HIT MODEL OF ELS FOLLOWED BY WAS IN ADULTHOOD REVEALED THAT EPIGENETIC DYSREGULATION OCCURS AFTER EXPOSURE TO STRESS IN TWO IMPORTANT PERIODS OF LIFE AND CONTRIBUTES TO THE DEVELOPMENT OF VISCERAL HYPERSENSITIVITY. THESE ABERRANT UNDERLYING EPIGENETIC CHANGES MAY EXPLAIN THE EXACERBATION OF STRESS-INDUCED ABDOMINAL PAIN IN IBS PATIENTS.	2023	
                                                                     
12  2371  34 EPIGENETIC REGULATION OF THE GLUCOCORTICOID RECEPTOR PROMOTER 1(7) IN ADULT RATS. REGULATION OF GLUCOCORTICOID RECEPTOR (GR) LEVELS IS AN IMPORTANT STRESS ADAPTATION MECHANISM. TRANSCRIPTION FACTOR NFGI-A AND ENVIRONMENTALLY INDUCED GR PROMOTER 1 7 METHYLATION HAVE BEEN IMPLICATED IN FINE-TUNING THE EXPRESSION OF GR 1 7 TRANSCRIPTS. HERE, WE INVESTIGATED GR PROMOTER 1 7 METHYLATION AND GR 1 7 EXPRESSION IN ADULT RATS EXPOSED TO EITHER ACUTE OR CHRONIC STRESS PARADIGMS. A STRONG NEGATIVE CORRELATION WAS OBSERVED BETWEEN THE SUM OF PROMOTER-WIDE METHYLATION LEVELS AND GR 1 7 TRANSCRIPT LEVELS, INDEPENDENT OF THE STRESSOR. METHYLATION OF INDIVIDUAL SITES DID NOT, HOWEVER, CORRELATE WITH TRANSCRIPT LEVELS. THIS SUGGESTED THAT PROMOTER 1 7 WAS DIRECTLY REGULATED BY PROMOTER-WIDE DNA METHYLATION. ALTHOUGH ACUTE STRESS INCREASED NGFI-A EXPRESSION IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN), GR 1 7 TRANSCRIPT LEVELS REMAINED UNAFFECTED DESPITE LOW METHYLATION LEVELS. ACUTE STRESS HAD LITTLE EFFECT ON THESE LOW METHYLATION LEVELS, EXCEPT AT FOUR HIPPOCAMPAL CPGS. CHRONIC STRESS ALTERED THE CORTICOSTERONE RESPONSE TO AN ACUTE STRESSOR. IN THE ADRENAL AND PITUITARY GLANDS, BUT NOT IN THE BRAIN, THIS WAS ACCOMPANIED BY AN INCREASE IN METHYLATION LEVELS IN ORCHESTRATED CLUSTERS RATHER THAN INDIVIDUAL CPGS. PVN METHYLATION LEVELS, UNAFFECTED BY ACUTE OR CHRONIC STRESS, WERE SIGNIFICANTLY MORE VARIABLE WITHIN- THAN BETWEEN-GROUPS, SUGGESTING THAT THEY WERE INSTATED PROBABLY DURING THE PERINATAL PERIOD AND REPRESENT A PRE-ESTABLISHED TRAIT. THUS, IN ADDITION TO THE KNOWN PERINATAL PROGRAMMING, THE GR 1 7 PROMOTER IS EPIGENETICALLY REGULATED BY CHRONIC STRESS IN ADULTHOOD, AND RETAINS PROMOTER-WIDE TISSUE-SPECIFIC PLASTICITY. DIFFERENCES IN METHYLATION SUSCEPTIBILITY BETWEEN THE PVN IN THE PERINATAL PERIOD AND THE PERIPHERAL HPA AXIS TISSUES IN ADULTHOOD MAY REPRESENT AN IMPORTANT "TRAIT" VS. "STATE" REGULATION OF THE GR GENE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  3177  35 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  5815  31 STRESS AND GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL PROGRAMMING IN TIME AND SPACE: IMPLICATIONS FOR THE BRAIN-GUT AXIS. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ENHANCED ABDOMINAL PAIN AND ALTERED INTESTINAL BARRIER FUNCTION THAT MAY RESULT FROM A PERTURBATION IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE GLUCOCORTICOID RECEPTOR (GR) EXPLOITS DIVERSE MECHANISMS TO ACTIVATE OR SUPPRESS CONGENERIC GENE EXPRESSION, WITH REGULATORY VARIATION ASSOCIATED WITH STRESS-RELATED DISORDERS IN PSYCHIATRY AND GASTROENTEROLOGY. PURPOSE: DURING ACUTE AND CHRONIC STRESS, CORTICOTROPIN-RELEASING HORMONE DRIVES SECRETION OF ADRENOCORTICOTROPIC HORMONE FROM THE PITUITARY, ULTIMATELY LEADING TO THE RELEASE OF CORTISOL (HUMAN) AND CORTICOSTERONE (RODENT) FROM THE ADRENAL GLANDS. CORTISOL BINDS WITH THE GR IN THE CYTOSOL, TRANSLOCATES TO THE NUCLEUS, AND ACTIVATES THE NR3C1 (NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 [GR]) GENE. THIS REVIEW FOCUSES ON THE RAPIDLY DEVELOPING OBSERVATIONS THAT CORTISOL IS RESPONSIBLE FOR DRIVING CIRCADIAN AND ULTRADIAN BURSTS OF TRANSCRIPTIONAL ACTIVITY IN THE CLOCK (CLOCK CIRCADIAN REGULATOR) AND PER (PERIOD CIRCADIAN CLOCK 1) GENE FAMILIES, AND THIS RHYTHM IS DISRUPTED IN MAJOR DEPRESSIVE DISORDER, BIPOLAR DISORDER, AND STRESS-RELATED GASTROINTESTINAL AND IMMUNE DISORDERS. GLUCOCORTICOID RECEPTOR REGULATES DIFFERENT SETS OF TRANSCRIPTS IN A TISSUE-SPECIFIC MANNER, THROUGH PULSATILE WAVES OF GENE EXPRESSION THAT INCLUDES OCCUPANCY OF GLUCOCORTICOID RESPONSE ELEMENTS LOCATED WITHIN CONSTITUTIVELY OPEN SPATIAL DOMAINS IN CHROMATIN. EMERGING EVIDENCE SUPPORTS A POTENTIALLY PIVOTAL ROLE FOR EPIGENETIC REGULATION OF HOW GR INTERACTS WITH OTHER CHROMATIN REGULATORS TO CONTROL THE EXPRESSION OF ITS TARGET GENES. DYSREGULATION OF THE CENTRAL AND PERIPHERAL GR REGULOME HAS POTENTIALLY SIGNIFICANT CONSEQUENCES FOR STRESS-RELATED DISORDERS AFFECTING THE BRAIN-GUT AXIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15   869  38 CHRONIC AGOMELATINE TREATMENT CORRECTS BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES INDUCED BY PRENATAL STRESS IN RATS. RATIONALE AND OBJECTIVES: THE RAT MODEL OF PRENATAL RESTRAINT STRESS (PRS) REPLICATES FACTORS THAT ARE IMPLICATED IN THE ETIOLOGY OF ANXIOUS/DEPRESSIVE DISORDERS. WE USED THIS MODEL TO TEST THE THERAPEUTIC EFFICACY OF AGOMELATINE, A NOVEL ANTIDEPRESSANT THAT BEHAVES AS A MIXED MT1/MT2 MELATONIN RECEPTOR AGONIST/5-HT(2C) SEROTONIN RECEPTOR ANTAGONIST. RESULTS: ADULT PRS RATS SHOWED BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES THAT WERE CONSISTENT WITH AN ANXIOUS/DEPRESSIVE PHENOTYPE. THESE INCLUDED AN INCREASED IMMOBILITY IN THE FORCED SWIM TEST, AN ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE, REDUCED HIPPOCAMPAL LEVELS OF PHOSPHORYLATED CAMP-RESPONSIVE ELEMENT BINDING PROTEIN (P-CREB), REDUCED HIPPOCAMPAL LEVELS OF MGLU2/3 AND MGLU5 METABOTROPIC GLUTAMATE RECEPTORS, AND REDUCED NEUROGENESIS IN THE VENTRAL HIPPOCAMPUS, THE SPECIFIC PORTION OF THE HIPPOCAMPUS THAT ENCODES MEMORIES RELATED TO STRESS AND EMOTIONS. ALL OF THESE CHANGES WERE REVERSED BY A 3- OR 6-WEEK TREATMENT WITH AGOMELATINE (40-50 MG/KG, I.P., ONCE A DAY). REMARKABLY, AGOMELATINE HAD NO EFFECT IN AGE-MATCHED CONTROL RATS, THEREBY BEHAVING AS A "DISEASE-DEPENDENT" DRUG. CONCLUSIONS: THESE DATA INDICATE THAT AGOMELATINE DID NOT ACT ON INDIVIDUAL SYMPTOMS BUT CORRECTED ALL ASPECTS OF THE PATHOLOGICAL EPIGENETIC PROGRAMMING TRIGGERED BY PRS. OUR FINDINGS STRONGLY SUPPORT THE ANTIDEPRESSANT ACTIVITY OF AGOMELATINE AND SUGGEST THAT THE DRUG IMPACTS MECHANISMS THAT LIE AT THE CORE OF ANXIOUS/DEPRESSIVE DISORDERS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  3600  35 IMPORTANCE OF EPIGENETIC MECHANISMS IN VISCERAL PAIN INDUCED BY CHRONIC WATER AVOIDANCE STRESS. EPIGENETIC MOLECULAR MECHANISMS, WHICH INCLUDE DNA METHYLATION AND HISTONE DEACETYLATION, ARE IMPLICATED IN THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. PREVIOUSLY, WE DEMONSTRATED THAT REPEATED WATER AVOIDANCE STRESS (WAS), A VALIDATED MODEL OF CHRONIC PSYCHOLOGICAL STRESS, INDUCES HEIGHTENED VISCERAL PAIN BEHAVIORS IN RODENTS THAT RESEMBLE IRRITABLE BOWEL SYNDROME (IBS) SEQUELAE. HOWEVER, THE INVOLVEMENT OF EPIGENETIC MOLECULAR MECHANISMS IN THE PATHOPHYSIOLOGY OF STRESS-INDUCED VISCERAL PAIN HAS NOT BEEN EXPLORED. OUR HYPOTHESIS IS THAT EPIGENETIC MECHANISMS WITHIN THE CENTRAL NERVOUS SYSTEM (CNS) ARE IMPORTANT TO CHRONIC STRESS-INDUCED VISCERAL HYPERSENSITIVITY. ADULT MALE F-344 RATS WITH INTRACEREBROVENTRICULAR (I.C.V.) CANNULAE WERE EXPOSED TO 7 DAYS OF REPEATED WAS. CONTROLS RECEIVED A SHAM STRESS. FOLLOWING THE DAILY 1H STRESSOR, TRICHOSTATIN A (TSA; 100 NG/ML), A POTENT HISTONE DEACETYLASE INHIBITOR, OR VEHICLE (VEH; 0.1% DMSO/SALINE,) AS CONTROL WAS ADMINISTERED VIA THE I.C.V. CANNULA. VISCERAL SENSITIVITY WAS ASSESSED 24H AFTER THE FINAL WAS AND QUANTIFIED THE VISCEROMOTOR RESPONSE (VMR) BY RECORDING THE NUMBER OF ABDOMINAL CONTRACTIONS IN RESPONSE TO GRADED PRESSURES (20-60 MMHG) OF COLORECTAL DISTENSIONS (CRD). FROM A SEPARATE GROUP OF RATS THAT WERE EXPOSED TO REPEATED WAS OR SHAM STRESS, THE AMYGDALA WAS ISOLATED TO ASSESS THE METHYLATION STATUS OF GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPIN RELEASING-FACTOR (CRF) GENES VIA BISULFITE SEQUENCING AND VERIFIED BY PYROSEQUENCING. GR AND CRF GENE EXPRESSION WAS QUANTIFIED VIA QRT-PCR. STRESSED RATS EXHIBITED VISCERAL HYPERSENSITIVITY THAT WAS SIGNIFICANTLY ATTENUATED BY TSA. COMPARED TO SHAM CONTROLS, METHYLATION OF THE GR GENE WAS INCREASED FOLLOWING WAS WHILE EXPRESSION OF THE GR GENE WAS DECREASED. METHYLATION OF THE CRF PROMOTER WAS DECREASED WITH WAS WITH A CONCOMITANT INCREASE IN CRF EXPRESSION. THIS STUDY DEMONSTRATES THE INVOLVEMENT OF CENTRAL EPIGENETIC MECHANISMS IN REGULATING STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND PROVIDES A FOUNDATION FOR EXPLORING THE EPIGENETIC MECHANISMS THAT MAY CONTRIBUTE TO IBS-LIKE SYMPTOMATOLOGY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
17  1761  29 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18   578  26 BEHAVIOR, BDNF AND EPIGENETIC MECHANISMS IN RESPONSE TO SOCIAL ISOLATION AND SOCIAL SUPPORT IN MIDDLE AGED RATS EXPOSED TO CHRONIC STRESS. SOCIAL DEPRIVATION CAN BE STRESSFUL FOR GROUP-LIVING MAMMALS. ON THE OTHER HAND, AN AMAZING RESPONSE OF THESE ANIMALS TO STRESS IS SEEKING SOCIAL CONTACT TO GIVE AND RECEIVE JOINT PROTECTION IN THREATENING SITUATIONS. WE EXPLORED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL SUPPORT ON EPIGENETIC AND BEHAVIORAL RESPONSES TO CHRONIC STRESS. MORE SPECIFICALLY, WE INVESTIGATED THE BEHAVIORAL RESPONSES, CORTICOSTERONE LEVELS, BDNF GENE EXPRESSION, AND MARKERS OF HIPPOCAMPAL EPIGENETIC ALTERATIONS (LEVELS OF H3K9 ACETYLATION AND METHYLATION, H3K27 METHYLATION, HDAC5, DNMT1, AND DNMT3A GENE EXPRESSIONS) IN MIDDLE-AGED ADULT RATS MAINTAINED IN DIFFERENT HOUSING CONDITIONS (ISOLATION OR ACCOMPANIED HOUSING) AND EXPOSED TO THE CHRONIC UNPREDICTABLE STRESS PROTOCOL (CUS). ISOLATION WAS ASSOCIATED WITH DECREASED BASAL LEVELS OF CORTICOSTERONE, IMPAIRED LONG-TERM MEMORY, AND DECREASED EXPRESSION OF THE BDNF GENE, BESIDES ALTERING THE BALANCE OF H3K9 FROM ACETYLATION TO METHYLATION AND INCREASING THE DNMT1 GENE EXPRESSION. THE CUS PROTOCOL DECREASED H3K9 ACETYLATION, BESIDES INCREASING H3K27 METHYLATION AND DNMT1 GENE EXPRESSION, BUT HAD NO SIGNIFICANT EFFECTS ON MEMORY AND BDNF GENE EXPRESSION. INTERESTINGLY, THE EFFECTS OF CUS ON CORTICOSTERONE AND HDAC5 GENE EXPRESSION WERE SEEN ONLY IN ISOLATED ANIMALS, WHEREAS THE EFFECTS OF CUS ON DNMT1 GENE EXPRESSION WERE MORE PRONOUNCED IN ISOLATED THAN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION IN MIDDLE AGE SHOWED BROADER EFFECTS THAN CHRONIC UNPREDICTABLE STRESS ON BEHAVIORAL AND EPIGENETIC ALTERATIONS POTENTIALLY ASSOCIATED WITH DECREASED BDNF EXPRESSION. MOREOVER, SOCIAL SUPPORT PREVENTED THE ADVERSE EFFECTS OF CUS ON HPA AXIS FUNCTIONING, HDAC5, AND DNMT1 GENE EXPRESSIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  5749  40 SOCIAL DEFEAT INDUCES CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VENTRAL HIPPOCAMPUS, PREFRONTAL CORTEX, AND DORSAL RAPHE NUCLEUS. CHRONIC EXPOSURE TO STRESS IS ASSOCIATED WITH A NUMBER OF PSYCHIATRIC DISORDERS, BUT LITTLE IS KNOWN ABOUT THE EPIGENETIC MECHANISMS THAT UNDERLIE THE STRESS RESPONSE OR RESILIENCE TO CHRONIC STRESS. WE INVESTIGATED HISTONE ACETYLATION IN SEVEN DIFFERENT BRAIN REGIONS OF RATS EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS: THE DORSAL HIPPOCAMPUS (DHPC), VENTRAL HIPPOCAMPUS (VHPC), MEDIAL PREFRONTAL CORTEX (MPFC), BASOLATERAL AMYGDALA (BLA), LOCUS COERULEUS (LC), PARAVENTRICULAR THALAMUS (PVT), AND DORSAL RAPHE (DR) NUCLEUS. THIS STRESS PARADIGM WAS UNIQUE IN THAT IT ALLOWED RATS TO DISPLAY RESILIENCE IN THE FORM OF AN ACTIVE COPING MECHANISM. WE FOUND THAT THERE WAS AN INCREASE IN ACETYLATION OF H3K9/14 (H3K9/14AC) AND BULK ACETYLATION OF H4K5,8,12,16 (H4K5,8,12,16AC) IN THE DR NUCLEUS OF RATS THAT WERE LESS RESILIENT. LESS RESILIENT RATS ALSO DISPLAYED INCREASED LEVELS OF H3K18 ACETYLATION (H3K18AC) IN THE MPFC WHEN COMPARED TO NON-STRESSED CONTROLS. IN THE VHPC, THERE WAS AN INCREASE IN H3K18AC AND H4K12 (H4K12AC) IN RATS THAT WERE LESS RESILIENT WHEN COMPARED TO NON-STRESSED CONTROL RATS. IN ADDITION, THERE WAS A DECREASE IN LEVELS OF H4K8 ACETYLATION (H4K8AC) IN BOTH RESILIENT AND NON-RESILIENT RATS AS COMPARED TO CONTROLS. WE ASSESSED EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VHPC AND THE MPFC USING QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (PCR) AND FOUND CHANGES IN EXPRESSION OF A NUMBER OF TARGETS. THESE INCLUDED CHANGES IN SIRT1 AND SIRT2 IN THE VHPC AND CHANGES IN KAT5 IN THE MPFC. OVERALL, THESE RESULTS SUGGEST THAT CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THESE REGIONS CORRELATE WITH THE BEHAVIORAL RESPONSE TO STRESS IN SOCIALLY DEFEATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  5752  30 SOCIAL ISOLATION AND SOCIAL SUPPORT AT ADULTHOOD AFFECT EPIGENETIC MECHANISMS, BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS AND BEHAVIOR OF CHRONICALLY STRESSED RATS. EPIGENETIC MODULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROVIDES ONE POSSIBLE EXPLANATION FOR THE DYSFUNCTIONS INDUCED BY STRESS, SUCH AS PSYCHIATRIC DISORDERS AND COGNITIVE DECLINE. INTERESTINGLY, SOCIAL SUPPORT CAN BE PROTECTIVE AGAINST SOME OF THESE EFFECTS, BUT THE MECHANISMS OF SOCIAL BUFFERING ARE POORLY UNDERSTOOD. CONVERSELY, EARLY ISOLATION EXACERBATES THE RESPONSES TO STRESSORS, ALTHOUGH ITS EFFECTS IN ADULTHOOD REMAIN UNCLEAR. THIS STUDY INVESTIGATED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL BUFFERING ON HIPPOCAMPAL EPIGENETIC MECHANISMS, BDNF LEVELS AND BEHAVIORAL RESPONSES OF CHRONICALLY STRESSED YOUNG ADULT RATS. MALE WISTAR RATS (3 MONTHS) WERE ASSIGNED TO ACCOMPANIED (PAIRED) OR ISOLATED HOUSING. AFTER ONE-MONTH HALF OF EACH GROUP WAS SUBMITTED TO A CHRONIC UNPREDICTABLE STRESS (CUS) PROTOCOL FOR 18 DAYS. AMONG ACCOMPANIED ANIMALS, ONLY ONE WAS EXPOSED TO STRESS. BEHAVIORAL ANALYSIS ENCOMPASSED THE OPEN FIELD, PLUS MAZE AND INHIBITORY AVOIDANCE TASKS. HIPPOCAMPAL H3K9 AND H4K12 ACETYLATION, HDAC5 EXPRESSION AND BDNF LEVELS WERE EVALUATED. ISOLATED HOUSING INCREASED HDAC5 EXPRESSION, DECREASED H3K9 AND H4K12 ACETYLATION, REDUCED BDNF LEVELS, AND IMPAIRED LONG-TERM MEMORY. STRESS AFFECTED WEIGHT GAIN, INDUCED ANXIETY-LIKE BEHAVIOR AND DECREASED ACK9H3 LEVELS. INTERACTIONS BETWEEN HOUSING CONDITIONS AND SOCIAL STRESS WERE SEEN ONLY FOR HDAC5 EXPRESSION, WHICH SHOWED A FURTHER INCREASE IN THE ISOLATED + CUS GROUP BUT REMAINED CONSTANT IN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION AT ADULTHOOD INDUCED EPIGENETIC ALTERATIONS AND EXACERBATED THE EFFECTS OF CHRONIC STRESS ON HDAC5. NOTWITHSTANDING, SOCIAL SUPPORT COUNTERACTED THE ADVERSE EFFECTS OF STRESS ON HDAC5 EXPRESSION.	2019