1 6388 134 THE ROLE OF SIRT1 IN THE BASOLATERAL AMYGDALA IN DEPRESSION-LIKE BEHAVIORS IN MICE. PREVIOUS INVESTIGATIONS HAVE IMPLICATED THE BASOLATERAL AMYGDALA (BLA) EPIGENETIC MECHANISMS IN THE PATHOPHYSIOLOGY OF DEPRESSION. SIRT1 IS A NAD+-DEPENDENT CLASS III HISTONE DEACETYLASE, WIDELY EXPRESSES IN BLA. HOWEVER, EPIGENETIC MECHANISMS IN THE BLA UNDER THE REGULATION OF SIRT1 IN THE DEPRESSION ARE LARGELY UNCHARACTERIZED. UNDER THE CHRONIC UNPREDICTABLE CHRONIC MILD STRESS (CUMS) MOUSE MODEL, WE USED ADENO-ASSOCIATED VIRAL VECTORS (AAV) THAT ENCODED SIRT1-SHRNA OR SIRT1 TO SPECIFICALLY KNOCKDOWN OR OVEREXPRESS SIRT1 IN BLA NEURONS, RESPECTIVELY. CUMS PROCEDURE INDUCED SIGNIFICANT DEPRESSION SYMPTOMS INCLUDING THE DECREASED SUCROSE PREFERENCE, THE LESS BODYWEIGHT GAINED, THE DECREASED IMMOBILE LATENCY AND THE INCREASED IMMOBILE TIME BOTH IN FORCED SWIM TEST (FST) AND TAIL SUSPENSION TEST (TST). KNOCKDOWN OF SIRT1 IN BLA GLUTAMATERGIC NEURONS REVERSED THESE DEPRESSION-LIKE BEHAVIORS AND RESTORED THE SYNAPTIC ABNORMALITIES. OVEREXPRESSION OF SIRT1 IN BLA GLUTAMATERGIC NEURONS INDUCED DEPRESSION-LIKE BEHAVIORS IN NON-STRESSED CONTROL MICE. THE RESULT OF PROTEIN EXPRESSIONS AND ULTRASTRUCTURAL CHANGES WERE CONSISTENT WITH THE BEHAVIORAL RESULTS. OUR STUDY SUGGESTED THAT DOWNREGULATION OF SIRT1 IN BLA HAS CERTAIN BENEFICIAL EFFECT ON CUMS-INDUCED DEPRESSION-LIKE BEHAVIORS SUCH AS ANOREXIA, ANHEDONIA, HOPELESSNESS AND DESPAIR. IN ADDITION, THE INCREASED EXPRESSION OF SIRT1 MAY BE THE IMMEDIATE CAUSE OF DEPRESSIVE-LIKE SYMPTOMS. THE ABNORMAL EXPRESSION OF SIRT1 MAY AFFECT THE TRANSCRIPTIONAL REGULATION MECHANISM AND SIGNALING PROTEIN ACETYLATION, AFFECTING NEUROPLASTICITY AND ULTIMATELY CONTRIBUTE TO MDD. IN THE STRESS-SUSCEPTIBLE MICE, THESE TWO MECHANISMS MAY CO-EXIST, BUT THE SPECIFIC MECHANISM NEEDS FURTHER RESEARCH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
2 3177  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3 5712  43 SIRT1 MEDIATES DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS. DEPRESSION IS A RECURRING AND LIFE-THREATENING ILLNESS THAT AFFECTS UP TO 120 MILLION PEOPLE WORLDWIDE. IN THE PRESENT STUDY, WE SHOW THAT CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MODEL OF DEPRESSION IN MICE, INCREASES SIRT1 LEVELS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. INCREASES IN SIRT1, A WELL CHARACTERIZED CLASS III HISTONE DEACETYLASE, AFTER CHRONIC SOCIAL DEFEAT SUGGEST A ROLE FOR THIS ENZYME IN MEDIATING DEPRESSION-LIKE BEHAVIORS. WHEN RESVERATROL, A PHARMACOLOGICAL ACTIVATOR OF SIRT1, WAS DIRECTLY INFUSED BILATERALLY INTO THE NAC, WE OBSERVED AN INCREASE IN DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. CONVERSELY, INTRA-NAC INFUSIONS OF EX-527, A SIRT1 ANTAGONIST, REDUCED THESE BEHAVIORS; EX-527 ALSO REDUCED ACUTE STRESS RESPONSES IN STRESS-NAIVE MICE. NEXT, WE INCREASED SIRT1 LEVELS DIRECTLY IN NAC BY USE OF VIRAL-MEDIATED GENE TRANSFER AND OBSERVED AN INCREASE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS WHEN MICE WERE ASSESSED IN THE OPEN-FIELD, ELEVATED-PLUS-MAZE, AND FORCED SWIM TESTS. USING A CRE-INDUCIBLE VIRAL VECTOR SYSTEM TO OVEREXPRESS SIRT1 SELECTIVELY IN DOPAMINE D1 OR D2 SUBPOPULATIONS OF MEDIUM SPINY NEURONS (MSNS) IN THE NAC, WE FOUND THAT SIRT1 PROMOTES DEPRESSIVE-LIKE BEHAVIORS ONLY WHEN OVEREXPRESSED IN D1 MSNS, WITH NO EFFECT SEEN IN D2 MSNS. CONVERSELY, SELECTIVE ABLATION OF SIRT1 IN THE NAC USING VIRAL-CRE IN FLOXED SIRT1 MICE RESULTED IN DECREASED DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. TOGETHER, THESE RESULTS DEMONSTRATE THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN THE NAC IN REGULATING MOOD-RELATED BEHAVIORAL ABNORMALITIES AND IDENTIFIES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT MAJOR DEPRESSIVE DISORDERS. SIGNIFICANCE STATEMENT: IN THIS STUDY, WE DEMONSTRATE A PIVOTAL ROLE FOR SIRT1 IN ANXIETY- AND DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW THAT STRESS STABLY INDUCES SIRT1 EXPRESSION IN THIS BRAIN REGION AND THAT ALTERING SIRT1 ACTIVITY USING A PHARMACOLOGICAL OR GENETIC APPROACH REGULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIORS. THESE RESULTS SUGGEST THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN REGULATING MOOD-RELATED BEHAVIORS AND INTRODUCES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT DEPRESSION AND OTHER STRESS-RELATED DISORDERS. A RECENT GROUNDBREAKING PUBLICATION BY THE CONVERGE CONSORTIUM (2015) IDENTIFIED A REPRODUCIBLE ASSOCIATION OF THE SIRT1 LOCUS WITH MAJOR DEPRESSION IN HUMANS. THEREFORE, OUR RESULTS ARE TIMELY AND HAVE SIGNIFICANT TRANSLATIONAL RELEVANCE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4 6175  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5 5019  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6 3493  48 IDENTIFICATION OF KEY GENES, PATHWAYS, AND MIRNA/MRNA REGULATORY NETWORKS OF CUMS-INDUCED DEPRESSION IN NUCLEUS ACCUMBENS BY INTEGRATED BIOINFORMATICS ANALYSIS. INTRODUCTION: MAJOR DEPRESSIVE DISORDER (MDD) IS A RECURRENT, DEVASTATING MENTAL DISORDER, WHICH AFFECTS >350 MILLION PEOPLE WORLDWIDE, AND EXERTS SUBSTANTIAL PUBLIC HEALTH AND FINANCIAL COSTS TO SOCIETY. THUS, THERE IS A SIGNIFICANT NEED TO DISCOVER INNOVATIVE THERAPEUTICS TO TREAT DEPRESSION EFFICIENTLY. STRESS-INDUCED DYSFUNCTION IN THE SUBTYPE OF NEURONAL CELLS AND THE CHANGE OF SYNAPTIC PLASTICITY AND STRUCTURAL PLASTICITY OF NUCLEUS ACCUMBENS (NAC) ARE IMPLICATED IN DEPRESSION SYMPTOMOLOGY. HOWEVER, THE MOLECULAR AND EPIGENETIC MECHANISMS AND STRESSES TO THE NAC PATHOLOGICAL CHANGES IN DEPRESSION REMAIN ELUSIVE. MATERIALS AND METHODS: IN THIS STUDY, TREATMENT GROUP MICE WERE TREATED CONTINUALLY WITH THE CHRONIC UNPREDICTABLE MILD STRESS (CUMS) UNTIL EXPRESSION OF DEPRESSION-LIKE BEHAVIORS WERE FOUND. DEPRESSION WAS CONFIRMED WITH SUCROSE PREFERENCE, NOVELTY-SUPPRESSED FEEDING, FORCED SWIMMING, AND TAIL SUSPENSION TESTS. WE APPLIED HIGH-THROUGHPUT RNA SEQUENCING TO ASSESS MICRORNA EXPRESSION AND TRANSCRIPTIONAL PROFILES IN THE NAC TISSUE FROM DEPRESSION-LIKE BEHAVIORS MICE AND CONTROL MICE. THE REGULATORY NETWORK OF MIRNAS/MRNAS WAS CONSTRUCTED BASED ON THE HIGH-THROUGHPUT RNA SEQUENCE AND BIOINFORMATICS SOFTWARE PREDICTIONS. RESULTS: A TOTAL OF 17 MIRNAS AND 10 MRNAS WERE SIGNIFICANTLY UPREGULATED IN THE NAC OF CUMS-INDUCED MICE WITH DEPRESSION-LIKE BEHAVIORS, AND 12 MIRNAS AND 29 MRNAS WERE DOWNREGULATED. A SERIES OF BIOINFORMATICS ANALYSES SHOWED THAT THESE ALTERED MIRNAS PREDICTED TARGET MRNA AND DIFFERENTIALLY EXPRESSED MRNAS WERE SIGNIFICANTLY ENRICHED IN THE MAPK SIGNALING PATHWAY, GABAERGIC SYNAPSE, DOPAMINERGIC SYNAPSE, CYTOKINE-CYTOKINE RECEPTOR INTERACTION, AXON GUIDANCE, REGULATION OF AUTOPHAGY, AND SO ON. FURTHERMORE, DUAL LUCIFERASE REPORT ASSAY AND QRT-PCR RESULTS VALIDATED THE MIRNA/MRNA REGULATORY NETWORK. CONCLUSION: THE DETERIORATIONS OF GABAERGIC SYNAPSES, DOPAMINERGIC SYNAPSES, NEUROTRANSMITTER SYNTHESIS, AS WELL AS AUTOPHAGY-ASSOCIATED APOPTOTIC PATHWAY ARE ASSOCIATED WITH THE MOLECULAR PATHOLOGICAL MECHANISM OF CUMS-INDUCED DEPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7 1331  34 DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS ARE ASSOCIATED WITH HDAC7 REDUCTION IN THE NUCLEUS ACCUMBENS. PERSISTENT SYMPTOMS OF DEPRESSION INDICATE THE ADAPTIVE INVOLVEMENT OF STABLE MOLECULES IN THE BRAIN THAT MAY BE MANIFESTED AT THE LEVEL OF CHROMATIN REMODELING, SUCH AS HISTONE ACETYLATION. FORMER STUDIES HAVE IDENTIFIED ALTERATIONS IN HISTONE ACETYLATION AND DEACETYLATION IN SEVERAL ANIMAL MODELS ABOUT DEPRESSION. HOWEVER, THE SPECIFIC HISTONE DEACETYLASES RELATED WITH DEPRESSION ARE NEEDED TO BE EXPLORED. HERE, SOCIAL AVOIDANCE BEHAVIORS, ANXIETY-, AND DEPRESSION-LIKE BEHAVIORS WERE ALL FOUND IN MICE SUFFERED FROM CHRONIC SOCIAL DEFEAT STRESS. MOREOVER, WE ALSO DISCOVERED THAT THE AMOUNT OF THE CLASS II HISTONE DEACETYLASE, HDAC7 RATHER THAN HDAC2, WAS SIGNIFICANTLY DECREASED IN THE NUCLEUS ACCUMBENS OF DEFEATED MICE, WHICH SUGGESTED THAT HDAC7 MIGHT BE A CRUCIAL HISTONE DEACETYLASE IN A CHRONIC SOCIAL DEFEAT STRESS MODEL. OUR DATA SHOWED THAT THE DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS WERE ASSOCIATED WITH HDAC7 REDUCTION IN NUCLEUS ACCUMBENS. HDAC7 MIGHT BE A PROMISING THERAPEUTIC TARGET FOR DEPRESSION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8 1698  32 DYNAMIC EFFECTS OF EARLY ADOLESCENT STRESS ON DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES AND JMJD3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS. AIMS: EXPRESSION OF INFLAMMATORY CYTOKINES IN THE BRAIN HAS BEEN REPORTED TO BE INVOLVED IN THE PATHOGENESIS OF AND SUSCEPTIBILITY TO DEPRESSION. JUMONJI DOMAIN-CONTAINING 3 (JMJD3), WHICH IS A HISTONE H3 LYSINE 27 (H3K27) DEMETHYLASE AND CAN REGULATE MICROGLIAL ACTIVATION, HAS BEEN REGARDED AS A CRUCIAL ELEMENT IN THE EXPRESSION OF INFLAMMATORY CYTOKINES. FURTHERMORE, RECENT STUDIES HIGHLIGHTED THE FACT THAT LIPOPOLYSACCHARIDES INDUCE DEPRESSIVE-LIKE BEHAVIORS AND HIGHER JMJD3 EXPRESSION AND LOWER H3K27ME3 EXPRESSION IN THE BRAIN. HOWEVER, WHETHER THE PROCESS OF JMJD3 MEDIATING INFLAMMATORY CYTOKINES WAS INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSION DUE TO EARLY-LIFE STRESS REMAINED ELUSIVE. METHODS: RATS EXPOSED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IN ADOLESCENCE WERE USED IN ORDER TO DETECT DYNAMIC ALTERATIONS IN DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES, JMJD3, AND H3K27ME3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS. MOREOVER, MINOCYCLINE, AN INHIBITOR OF MICROGLIAL ACTIVATION, WAS EMPLOYED TO OBSERVE THE PROTECTIVE EFFECTS. RESULTS: OUR RESULTS SHOWED THAT CUMS DURING THE ADOLESCENT PERIOD INDUCED DEPRESSIVE-LIKE BEHAVIORS, OVER-EXPRESSION OF CYTOKINES, AND INCREASED JMJD3 AND DECREASED H3K27ME3 EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF BOTH ADOLESCENT AND ADULT RATS. HOWEVER, MINOCYCLINE RELIEVED ALL THE ALTERATIONS. CONCLUSION: THE STUDY REVEALED THAT JMJD3 MIGHT BE INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSIVE-LIKE BEHAVIORS BY MODULATING H3K27ME3 AND PRO-INFLAMMATORY CYTOKINE EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS THAT HAD BEEN STRESSED DURING EARLY ADOLESCENCE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
9 5709  49 SIRT1 DECREASES EMOTIONAL PAIN VULNERABILITY WITH ASSOCIATED CAMKIIALPHA DEACETYLATION IN CENTRAL AMYGDALA. EMOTIONAL DISORDERS ARE COMMON COMORBID CONDITIONS THAT FURTHER EXACERBATE THE SEVERITY AND CHRONICITY OF CHRONIC PAIN. HOWEVER, INDIVIDUALS SHOW CONSIDERABLE VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN UNDER SIMILAR PAIN CONDITIONS. IN THIS STUDY ON MALE RAT AND MOUSE MODELS OF CHRONIC NEUROPATHIC PAIN, WE IDENTIFY THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) IN CENTRAL AMYGDALA AS A KEY EPIGENETIC REGULATOR THAT CONTROLS THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDERLYING THE INDIVIDUAL VULNERABILITY TO CHRONIC PAIN. WE FOUND THAT ANIMALS THAT WERE VULNERABLE TO DEVELOPING BEHAVIORS OF ANXIETY AND DEPRESSION UNDER THE PAIN CONDITION DISPLAYED REDUCED SIRT1 PROTEIN LEVELS IN CENTRAL AMYGDALA, BUT NOT THOSE ANIMALS RESISTANT TO THE EMOTIONAL DISORDERS. VIRAL OVEREXPRESSION OF LOCAL SIRT1 REVERSED THIS VULNERABILITY, BUT VIRAL KNOCKDOWN OF LOCAL SIRT1 MIMICKED THE PAIN EFFECT, ELICITING THE PAIN VULNERABILITY IN PAIN-FREE ANIMALS. THE SIRT1 ACTION WAS ASSOCIATED WITH CAMKIIALPHA DOWNREGULATION AND DEACETYLATION OF HISTONE H3 LYSINE 9 AT THE CAMKIIALPHA PROMOTER. THESE RESULTS SUGGEST THAT, BY TRANSCRIPTIONAL REPRESSION OF CAMKIIALPHA IN CENTRAL AMYGDALA, SIRT1 FUNCTIONS TO GUARD AGAINST THE EMOTIONAL PAIN VULNERABILITY UNDER CHRONIC PAIN CONDITIONS. THIS STUDY INDICATES THAT SIRT1 MAY SERVE AS A POTENTIAL THERAPEUTIC MOLECULE FOR INDIVIDUALIZED TREATMENT OF CHRONIC PAIN WITH VULNERABLE EMOTIONAL DISORDERS.SIGNIFICANCE STATEMENT CHRONIC PAIN IS A PREVALENT NEUROLOGICAL DISEASE WITH NO EFFECTIVE TREATMENT AT PRESENT. PAIN PATIENTS DISPLAY CONSIDERABLY VARIABLE VULNERABILITY TO DEVELOPING CHRONIC PAIN, INDICATING INDIVIDUAL-BASED MOLECULAR MECHANISMS UNDERLYING THE PAIN VULNERABILITY, WHICH IS HARDLY ADDRESSED IN CURRENT PRECLINICAL RESEARCH. IN THIS STUDY, WE HAVE IDENTIFIED THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) AS A KEY REGULATOR THAT CONTROLS THIS PAIN VULNERABILITY. THIS STUDY REVEALS THAT THE SIRT1-CAMKIIAALPHA PATHWAY IN CENTRAL AMYGDALA ACTS AS AN EPIGENETIC MECHANISM THAT GUARDS AGAINST THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDER CHRONIC PAIN, AND THAT ITS DYSFUNCTION CAUSES INCREASED VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN. THESE FINDINGS SUGGEST THAT SIRT1 ACTIVATORS MAY BE USED IN A NOVEL THERAPEUTIC APPROACH FOR INDIVIDUAL-BASED TREATMENT OF CHRONIC PAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10 2243  32 EPIGENETIC MODULATION OF CHRONIC ANXIETY AND PAIN BY HISTONE DEACETYLATION. PROLONGED EXPOSURE OF THE CENTRAL AMYGDALA (CEA) TO ELEVATED CORTICOSTEROIDS (CORT) FACILITATES LONG-TERM ANXIETY AND PAIN THROUGH ACTIVATION OF GLUCOCORTICOID RECEPTORS (GRS) AND CORTICOTROPIN-RELEASING FACTOR (CRF). HOWEVER, THE MECHANISMS MAINTAINING THESE RESPONSES ARE UNKNOWN. SINCE CHRONIC PHENOTYPES CAN BE SUSTAINED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS SUCH AS DEACETYLATION, WE TESTED THE HYPOTHESIS THAT HISTONE DEACETYLATION CONTRIBUTES TO THE MAINTENANCE OF CHRONIC ANXIETY AND PAIN INDUCED BY PROLONGED EXPOSURE OF THE CEA TO CORT. WE FOUND THAT BILATERAL INFUSIONS OF A HISTONE DEACETYLASE INHIBITOR INTO THE CEA ATTENUATED ANXIETY-LIKE BEHAVIOR AS WELL AS SOMATIC AND VISCERAL HYPERSENSITIVITY RESULTING FROM ELEVATED CORT EXPOSURE. MOREOVER, WE DELINEATED A NOVEL PATHWAY THROUGH WHICH HISTONE DEACETYLATION COULD CONTRIBUTE TO CORT REGULATION OF GR AND SUBSEQUENT CRF EXPRESSION IN THE CEA. SPECIFICALLY, DEACETYLATION OF HISTONE 3 AT LYSINE 9 (H3K9), THROUGH THE COORDINATED ACTION OF THE NAD+-DEPENDENT PROTEIN DEACETYLASE SIRTUIN-6 (SIRT6) AND NUCLEAR FACTOR KAPPA B (NFKAPPAB), SEQUESTERS GR EXPRESSION LEADING TO DISINHIBITION OF CRF. OUR RESULTS INDICATE THAT EPIGENETIC PROGRAMMING IN THE AMYGDALA, SPECIFICALLY HISTONE MODIFICATIONS, IS IMPORTANT IN THE MAINTENANCE OF CHRONIC ANXIETY AND PAIN.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 5874  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12 1614  41 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13 5974  34 TET1 IN NUCLEUS ACCUMBENS OPPOSES DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. DEPRESSION IS A LEADING CAUSE OF DISEASE BURDEN, YET CURRENT THERAPIES FULLY TREAT <50% OF AFFECTED INDIVIDUALS. INCREASING EVIDENCE IMPLICATES EPIGENETIC MECHANISMS IN DEPRESSION AND ANTIDEPRESSANT ACTION. HERE WE EXAMINED A POSSIBLE ROLE FOR THE DNA DIOXYGENASE, TEN-ELEVEN TRANSLOCATION PROTEIN 1 (TET1), IN DEPRESSION-RELATED BEHAVIORAL ABNORMALITIES. WE APPLIED CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MOUSE MODEL OF DEPRESSION-LIKE BEHAVIORS, AND EXAMINED TET1 EXPRESSION CHANGES IN NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW DECREASED TET1 EXPRESSION IN NAC IN STRESS-SUSCEPTIBLE MICE ONLY. SURPRISINGLY, SELECTIVE KNOCKOUT OF TET1 IN NAC NEURONS OF ADULT MICE PRODUCED ANTIDEPRESSANT-LIKE EFFECTS IN SEVERAL BEHAVIORAL ASSAYS. TO IDENTIFY TET1 TARGETS THAT MEDIATE THESE ACTIONS, WE PERFORMED RNASEQ ON NAC AFTER CONDITIONAL DELETION OF TET1 AND FOUND THAT IMMUNE-RELATED GENES ARE THE MOST HIGHLY DYSREGULATED. MOREOVER, MANY OF THESE GENES ARE ALSO UPREGULATED IN THE NAC OF RESILIENT MICE AFTER CHRONIC SOCIAL DEFEAT STRESS. THESE FINDINGS REVEAL A NOVEL ROLE FOR TET1, AN ENZYME IMPORTANT FOR DNA HYDROXYMETHYLATION, IN THE BRAIN'S REWARD CIRCUITRY IN MODULATING STRESS RESPONSES IN MICE. WE ALSO IDENTIFY A SUBSET OF GENES THAT ARE REGULATED BY TET1 IN THIS CIRCUITRY. THESE FINDINGS PROVIDE NEW INSIGHT INTO THE PATHOPHYSIOLOGY OF DEPRESSION, WHICH CAN AID IN FUTURE ANTIDEPRESSANT DRUG DISCOVERY EFFORTS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14 5820  33 STRESS DYNAMICALLY REGULATES BEHAVIOR AND GLUTAMATERGIC GENE EXPRESSION IN HIPPOCAMPUS BY OPENING A WINDOW OF EPIGENETIC PLASTICITY. EXCITATORY AMINO ACIDS PLAY A KEY ROLE IN BOTH ADAPTIVE AND DELETERIOUS EFFECTS OF STRESSORS ON THE BRAIN, AND DYSREGULATED GLUTAMATE HOMEOSTASIS HAS BEEN ASSOCIATED WITH PSYCHIATRIC AND NEUROLOGICAL DISORDERS. HERE, WE ELUCIDATE MECHANISMS OF EPIGENETIC PLASTICITY IN THE HIPPOCAMPUS IN THE INTERACTIONS BETWEEN A HISTORY OF CHRONIC STRESS AND FAMILIAR AND NOVEL ACUTE STRESSORS THAT ALTER EXPRESSION OF ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. WE DEMONSTRATE THAT ACUTE RESTRAINT AND ACUTE FORCED SWIM STRESSORS INDUCE DIFFERENTIAL EFFECTS ON THESE BEHAVIORS IN NAIVE MICE AND IN MICE WITH A HISTORY OF CHRONIC-RESTRAINT STRESS (CRS). THEY REVEAL A KEY ROLE FOR EPIGENETIC UP- AND DOWN-REGULATION OF THE PUTATIVE PRESYNAPTIC TYPE 2 METABOTROPIC GLUTAMATE (MGLU2) RECEPTORS AND THE POSTSYNAPTIC NR1/NMDA RECEPTORS IN THE HIPPOCAMPUS AND PARTICULARLY IN THE DENTATE GYRUS (DG), A REGION OF ACTIVE NEUROGENESIS AND A TARGET OF ANTIDEPRESSANT TREATMENT. WE SHOW CHANGES IN DG LONG-TERM POTENTIATION (LTP) THAT PARALLEL BEHAVIORAL RESPONSES, WITH HABITUATION TO THE SAME ACUTE RESTRAINT STRESSOR AND SENSITIZATION TO A NOVEL FORCED-SWIM STRESSOR. IN WT MICE AFTER CRS AND IN UNSTRESSED MICE WITH A BDNF LOSS-OF-FUNCTION ALLELE (BDNF VAL66MET), WE SHOW THAT THE EPIGENETIC ACTIVATOR OF HISTONE ACETYLATION, P300, PLAYS A PIVOTAL ROLE IN THE DYNAMIC UP- AND DOWN-REGULATION OF MGLU2 IN HIPPOCAMPUS VIA HISTONE-3-LYSINE-27-ACETYLATION (H3K27AC) WHEN ACUTE STRESSORS ARE APPLIED. THESE HIPPOCAMPAL RESPONSES REVEAL A WINDOW OF EPIGENETIC PLASTICITY THAT MAY BE USEFUL FOR TREATMENT OF DISORDERS IN WHICH GLUTAMATERGIC TRANSMISSION IS DYSREGULATED.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15 5818  38 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
16 5624  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17 6801  50 [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	

18 1753  36 EARLY LIFE STRESS TRIGGERS SUSTAINED CHANGES IN HISTONE DEACETYLASE EXPRESSION AND HISTONE H4 MODIFICATIONS THAT ALTER RESPONSIVENESS TO ADOLESCENT ANTIDEPRESSANT TREATMENT. EARLY LIFE STRESS CAN ELICIT LONG-LASTING CHANGES IN GENE EXPRESSION AND BEHAVIOR. RECENT STUDIES ON RODENTS SUGGEST THAT THESE LASTING EFFECTS DEPEND ON THE GENETIC BACKGROUND. WHETHER EPIGENETIC FACTORS ALSO PLAY A ROLE REMAINS TO BE INVESTIGATED. HERE WE EXPOSED THE STRESS-SUSCEPTIBLE MOUSE STRAIN BALB/C AND THE MORE RESILIENT STRAIN C57BL/6 TO A POWERFUL EARLY LIFE STRESS PARADIGM, INFANT MATERNAL SEPARATION. IN BALB/C MICE, INFANT MATERNAL SEPARATION LED TO DECREASED EXPRESSION OF MRNA ENCODING THE HISTONE DEACETYLASES (HDACS) 1, 3, 7, 8, AND 10 IN THE FOREBRAIN NEOCORTEX IN ADULTHOOD, AN EFFECT ACCOMPANIED BY INCREASED EXPRESSION OF ACETYLATED HISTONE H4 PROTEINS, ESPECIALLY ACETYLATED H4K12 PROTEIN. THESE CHANGES IN HDAC EXPRESSION AND HISTONE MODIFICATIONS WERE NOT DETECTED IN C57BL/6 MICE EXPOSED TO EARLY LIFE STRESS. MOREOVER, A REVERSAL OF THE H4K12 HYPERACETYLATION DETECTED IN INFANT MATERNALLY SEPARATED BALB/C MICE (ACHIEVED WITH CHRONIC ADOLESCENT TREATMENT WITH A LOW DOSE OF THEOPHYLLINE THAT ONLY ACTIVATES HDACS) WORSENED THE ABNORMAL EMOTIONAL PHENOTYPE RESULTING FROM THIS EARLY LIFE STRESS EXPOSURE. IN CONTRAST, FLUOXETINE, A DRUG WITH POTENT ANTIDEPRESSANT EFFICACY IN INFANT MATERNALLY SEPARATED BALB/C MICE, POTENTIATED ALL HISTONE MODIFICATIONS TRIGGERED BY EARLY LIFE STRESS. MOREOVER, IN NON-STRESSED BALB/C MICE, CO-ADMINISTRATION OF AN HDAC INHIBITOR AND FLUOXETINE, BUT NOT FLUOXETINE ALONE, ELICITED ANTIDEPRESSANT EFFECTS AND ALSO TRIGGERED CHANGES IN HISTONE H4 EXPRESSION THAT WERE SIMILAR TO THOSE PROVOKED BY FLUOXETINE TREATMENT OF MICE EXPOSED TO EARLY LIFE STRESS. THESE RESULTS SUGGEST THAT BALB/C MICE DEVELOP EPIGENETIC MODIFICATIONS AFTER EARLY LIFE STRESS EXPOSURE THAT, IN TERMS OF THE EMOTIVE PHENOTYPE, ARE OF ADAPTIVE NATURE, AND THAT ENHANCE THE EFFICACY OF ANTIDEPRESSANT DRUGS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19 1803  17 EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS ON THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NUCLEI OF HIPPOCAMPAL NEURONS IN RATS WITH DIFFERENT EXCITABILITY OF THE NERVOUS SYSTEM. IN RATS WITH LOW EXCITABILITY THRESHOLD OF THE NERVOUS SYSTEM DEMONSTRATING SIGNIFICANT AND PERSISTENT BEHAVIORAL DISORDERS UNDER STRESS CONDITIONS, THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NEURONAL NUCLEI OF HIPPOCAMPAL FIELD CA3 DECREASED OVER 2 WEEKS AFTER LONG-TERM EMOTIONAL AND PAIN STRESS. IT WAS HYPOTHESIZED THAT PROTEIN MECP2 TRIGGERS EPIGENETIC CHANGES IN DNA THAT UNDERLIE "STRESS MEMORY".	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  578  28 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