1 2187 175 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	
                                                                                                                                                                                                                  
2 5651  78 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 1163  72 CONTRIBUTION OF AMYGDALA HISTONE ACETYLATION IN EARLY LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND EMOTIONAL COMORBIDITY. PATIENTS WITH IRRITABLE BOWEL SYNDROME (IBS) EXPERIENCE NOT ONLY ENHANCED VISCERAL PAIN BUT ALSO EMOTIONAL COMORBIDITIES, SUCH AS ANXIETY AND DEPRESSION. EARLY LIFE STRESS (ELS) IS A HIGH-RISK FOR THE DEVELOPMENT OF IBS. LITERATURES HAVE REPORTED AN IMPORTANT EPIGENETIC MODULATION IN SUSTAINING EXTRINSIC PHENOTYPES. THE AMYGDALA IS CLOSELY RELATED TO THE REGULATION OF VISCERAL FUNCTIONS AND EMOTIONAL EXPERIENCES. IN THIS STUDY, WE HYPOTHESIZED THAT ELS-INDUCED REPROGRAMMING INAPPROPRIATE ADAPTATION OF HISTONE ACETYLATION MODIFICATION IN THE AMYGDALA MAY RESULT IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS. TO TEST THIS HYPOTHESIS, THE MODEL OF ELS RATS WAS ESTABLISHED BY NEONATAL COLORECTAL DILATATION (CRD). VISCERAL HYPERSENSITIVITY WAS ASSESSED BASED ON THE ELECTROMYOGRAPHY RESPONSE OF THE ABDOMINAL EXTERNAL OBLIQUE MUSCLE TO CRD. EMOTIONAL COMORBIDITIES WERE EXAMINED USING THE ELEVATED PLUS MAZE TEST, OPEN FIELD TEST, AND SUCROSE PREFERENCE TEST. TRICHOSTATIN A (TSA) AND C646 WERE MICROINJECTED INTO THE CENTRAL AMYGDALA (CEA) INDIVIDUALLY TO INVESTIGATE THE EFFECTS OF DIFFERENT LEVELS OF HISTONE ACETYLATION MODIFICATION ON VISCERAL HYPERSENSITIVITY AND EMOTION. WE FOUND NEONATAL CRD RESULTED IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS AFTER ADULTHOOD. INHIBITING HISTONE DEACETYLASES (HDACS) IN THE CEA BY TSA ENHANCED VISCERAL SENSITIVITY BUT DID NOT AFFECT ANXIETY-LIKE BEHAVIORS, WHEREAS INHIBITING HAT BY C646 ATTENUATED VISCERAL HYPERSENSITIVITY IN ELS RATS. INTERESTINGLY, CEA TREATMENT WITH TSA INDUCED VISCERAL SENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN THE CONTROL RATS. WESTERN BLOT SHOWED THAT THE EXPRESSIONS OF ACETYLATED 9 RESIDUE OF HISTONE 3 (H3K9) AND PROTEIN KINASE C ZETA TYPE (PKMZETA) WERE HIGHER IN THE ELS RATS COMPARED TO THOSE OF THE CONTROLS. THE ADMINISTRATION OF THE PKMZETA INHIBITOR ZIP INTO THE CEA ATTENUATED VISCERAL HYPERSENSITIVITY OF ELS RATS. FURTHERMORE, THE EXPRESSION OF AMYGDALA PKMZETA WAS ENHANCED BY TSA TREATMENT IN CONTROL RATS. FINALLY, WESTERN BLOT AND IMMUNOFLUORESCENCE RESULTS INDICATED THE DECREASE OF HDAC1 AND HDAC2 EXPRESSIONS, BUT NOT HDAC3 EXPRESSION, CONTRIBUTED TO THE ENHANCEMENT OF HISTONE ACETYLATION IN ELS RATS. OUR RESULTS SUPPORT OUR HYPOTHESIS THAT AMYGDALA-ENHANCED HISTONE ACETYLATION INDUCED BY STRESS IN EARLY LIFE RESULTS IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS, AND REVERSING THE ABNORMAL EPIGENETIC MECHANISMS MAY BE CRUCIAL TO RELIEVE CHRONIC SYMPTOMS IN ELS RATS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4 5834  64 STRESS-INDUCED VISCERAL PAIN IN FEMALE RATS IS ASSOCIATED WITH EPIGENETIC REMODELING IN THE CENTRAL NUCLEUS OF THE AMYGDALA. STRESS AND ANXIETY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF IRRITABLE BOWEL SYNDROME (IBS), A FEMALE-PREDOMINANT DISORDER OF THE GUT-BRAIN AXIS, CHARACTERIZED BY ABDOMINAL PAIN DUE TO HEIGHTENED VISCERAL SENSITIVITY. IN THE CURRENT STUDY, WE AIMED TO EVALUATE IN FEMALE RATS WHETHER EPIGENETIC REMODELING IN THE LIMBIC BRAIN, SPECIFICALLY IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA), IS A CONTRIBUTING FACTOR IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY. OUR RESULTS SHOWED THAT 1 H EXPOSURE TO WATER AVOIDANCE STRESS (WAS) FOR 7 CONSECUTIVE DAYS DECREASED HISTONE ACETYLATION AT THE GR PROMOTER AND INCREASED HISTONE ACETYLATION AT THE CRH PROMOTER IN THE CEA. CHANGES IN HISTONE ACETYLATION WERE MEDIATED BY THE HISTONE DEACETYLASE (HDAC) SIRT-6 AND THE HISTONE ACETYLTRANSFERASE CBP, RESPECTIVELY. ADMINISTRATION OF THE HDAC INHIBITOR TRICHOSTATIN A (TSA) INTO THE CEA PREVENTED STRESS-INDUCED VISCERAL HYPERSENSITIVITY THROUGH BLOCKADE OF SIRT-6 MEDIATED HISTONE ACETYLATION AT THE GR PROMOTER. IN ADDITION, HDAC INHIBITION WITHIN THE CEA PREVENTED STRESS-INDUCED HISTONE ACETYLATION OF THE CRH PROMOTER. OUR RESULTS SUGGEST THAT, IN FEMALES, EPIGENETIC MODIFICATIONS IN THE LIMBIC BRAIN REGULATING GR AND CRH EXPRESSION CONTRIBUTE TO STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND OFFER A POTENTIAL EXPLANATION OF HOW STRESS CAN TRIGGER SYMPTOMS IN IBS PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5 3600  77 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6 1920  76 ENVIRONMENTAL ENRICHMENT PREVENTS STRESS-INDUCED EPIGENETIC CHANGES IN THE EXPRESSION OF GLUCOCORTICOID RECEPTOR AND CORTICOTROPHIN RELEASING HORMONE IN THE CENTRAL NUCLEUS OF THE AMYGDALA TO INHIBIT VISCERAL HYPERSENSITIVITY. INTRODUCTION: STRESS IS A KNOWN TRIGGER FOR THE SYMPTOMS OF IRRITABLE BOWEL SYNDROME (IBS), A GASTROINTESTINAL (GI) DISORDER THAT PRESENTS WITH ABNORMAL BOWEL HABITS AND ABDOMINAL PAIN DUE TO VISCERAL HYPERSENSITIVITY. WHILE BEHAVIORAL THERAPIES HAVE BEEN USED TO ATTENUATE IBS SYMPTOMS, THE UNDERLYING MECHANISMS BY WHICH THESE THERAPIES INTERACT WITH STRESS-INDUCED PATHOLOGY REMAINS TO BE DELINEATED. HERE WE USE A RAT MODEL TO TEST THE HYPOTHESIS THAT EXPOSURE TO ENVIRONMENTAL ENRICHMENT (EE) INHIBITS STRESS-INDUCED CHANGES WITHIN THE BRAIN-GUT AXIS TO PREVENT VISCERAL AND SOMATIC HYPERSENSITIVITY AND COLONIC HYPERPERMEABILITY. METHODS: FEMALE RATS (N = 8/GROUP) WERE HOUSED IN EE ONE WEEK BEFORE AND ONE WEEK DURING EXPOSURE TO WATER AVOIDANCE STRESS (WAS) WHILE CONTROLS WERE HOUSED IN STANDARD CAGES (SH). ONE DAY AFTER THE FINAL WAS EXPOSURE, COLONIC AND SOMATIC SENSITIVITY WERE ASSESSED BY THE VISCEROMOTOR RESPONSE (VMR) TO COLORECTAL DISTENSION (CRD) AND WITHDRAWAL THRESHOLD ELICITED BY AN ELECTRONIC VON FREY ON THE HIND PAW OF THE RATS RESPECTIVELY. ALL RATS WERE RETURNED TO SH FOR 3 WEEKS BEFORE COLONIC AND SOMATIC SENSITIVITY WERE REASSESSED ON DAY 28. THE RATS WERE THEN IMMEDIATELY EUTHANIZED AND THE SPINAL CORD WAS COLLECTED TO ASSESS CHANGES IN NEURONAL ACTIVATION (ASSESSED VIA ERK PHOSPHORYLATION) IN RESPONSE TO NOXIOUS CRD. A SEPARATE COHORT OF ANIMALS (N = 8/GROUP) THAT DID NOT UNDERGO BEHAVIORAL ASSESSMENTS WAS EUTHANIZED THE DAY AFTER THE FINAL WAS EXPOSURE AND THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA) WAS COLLECTED TO INVESTIGATE WAS AND EE INDUCED EPIGENETIC CHANGES AT THE GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN RELEASING HORMONE (CRH) PROMOTER. THE COLON FROM THESE RATS WAS ALSO COLLECTED TO ASSESS COLONIC PERMEABILITY VIA CHANGES IN TRANSEPITHELIAL ELECTRICAL RESISTANCE (TEER) IN VITRO. RESULTS: EXPOSURE TO STRESS PERSISTENTLY INCREASED VMR TO CRD (P < 0.01) AND DECREASED THE HIND PAW WITHDRAWAL THRESHOLD (P < 0.001) IN FEMALE RATS. WAS ALSO DECREASED TEER IN THE COLON TISSUE OF FEMALE RATS (P = 0.05). IN THE CEA, WAS INDUCED A DECREASE IN HISTONE ACETYLATION AT THE GR PROMOTER BUT INCREASED HISTONE ACETYLATION AT THE CRH PROMOTER AND REDUCED GR-CRH INTERACTIONS IN THE CEA. ANALYSIS OF THE SPINAL CORD SHOWED THAT WAS INCREASED CRD-EVOKED ERK PHOSPHORYLATION IN THE DORSAL HORN. EXPOSURE TO EE PREVENTED WAS-INDUCED CHANGES IN THE CEA, DORSAL HORN AND COLON RESPECTIVELY TO PREVENT VISCERAL AND SOMATIC HYPERSENSITIVITY. CONCLUSION: OUR DATA REVEALS THAT BEHAVIORAL THERAPIES CAN PRODUCE LONG LASTING MOLECULAR AND EPIGENETIC CHANGES THAT CAN PREVENT STRESS-INDUCED PATHOLOGIES EVEN AFTER COMPLETION OF THE THERAPY. THESE RESULTS HIGHLIGHT THE POTENTIAL MECHANISMS BY WHICH BEHAVIORAL THERAPIES MAY AMELIORATE VISCERAL PAIN ASSOCIATED STRESS-RELATED PATHOLOGIES SUCH AS THE IRRITABLE BOWEL SYNDROME.	2021	

7 2243  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8 5019  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9 3177  47 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10 1752  48 EARLY LIFE STRESS RESTRICTS TRANSLATIONAL REACTIVITY IN CA3 NEURONS ASSOCIATED WITH ALTERED STRESS RESPONSES IN ADULTHOOD. EARLY LIFE EXPERIENCES PROGRAM BRAIN STRUCTURE AND FUNCTION AND CONTRIBUTE TO BEHAVIORAL ENDOPHENOTYPES IN ADULTHOOD. EPIGENETIC CONTROL OF GENE EXPRESSION BY THOSE EXPERIENCES AFFECT DISCRETE BRAIN REGIONS INVOLVED IN MOOD, COGNITIVE FUNCTION AND REGULATION OF HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. IN RODENTS, ACUTE RESTRAINT STRESS INCREASES THE EXPRESSION OF THE REPRESSIVE HISTONE H3 LYSINE 9 TRI-METHYLATION (H3K9ME3) IN HIPPOCAMPAL FIELDS, INCLUDING THE CA3 PYRAMIDAL NEURONS. THESE CA3 NEURONS ARE CRUCIALLY INVOLVED IN COGNITIVE FUNCTION AND MOOD REGULATION AS WELL AS ACTIVATION OF GLUCOCORTICOID (CORT) SECRETION. CA3 NEURONS ALSO EXHIBIT STRUCTURAL AND FUNCTIONAL CHANGES AFTER EARLY-LIFE STRESS (ELS) AS WELL AS AFTER CHRONIC STRESS IN ADULTHOOD. USING A PROTOCOL OF CHRONIC ELS INDUCED BY LIMITED BEDDING AND NESTING MATERIAL FOLLOWED BY ACUTE-SWIM STRESS (AS) IN ADULTHOOD, WE SHOW THAT MICE WITH A HISTORY OF ELS DISPLAY A BLUNTED CORT RESPONSE TO AS, DESPITE EXHIBITING ACTIVATION OF IMMEDIATE EARLY GENES AFTER STRESS SIMILAR TO THAT FOUND IN CONTROL MICE. WE FIND THAT ELS INDUCED PERSISTENTLY INCREASED EXPRESSION OF THE REPRESSIVE H3K9ME3 HISTONE MARK IN THE CA3 SUBFIELD AT BASELINE THAT WAS SUBSEQUENTLY DECREASED FOLLOWING AS. IN CONTRAST, AS INDUCED A TRANSIENT INCREASE OF THIS MARK IN CONTROL MICE. USING TRANSLATING RIBOSOME AFFINITY PURIFICATION (TRAP) METHOD TO ISOLATE CA3 TRANSLATING MRNAS, WE FOUND THAT EXPRESSION OF GENES OF THE EPIGENETIC GENE FAMILY, GABA/GLUTAMATE FAMILY, AND GLUCOCORTICOID RECEPTORS BINDING GENES WERE DECREASED TRANSIENTLY IN CONTROL MICE BY AS AND SHOWED A PERSISTENT REDUCTION IN ELS MICE. IN MOST CASES, AS IN ELS MICE DID NOT INDUCE GENE EXPRESSION CHANGES. A STRINGENT FILTERING OF GENES AFFECTED BY AS IN CONTROL AND ELS MICE REVEALED A NOTEWORTHY DECREASE IN GENE EXPRESSION CHANGE IN ELS MICE COMPARED TO CONTROL. ONLY 18 GENES WERE SELECTIVELY REGULATED BY AS IN ELS MICE AND ENCOMPASSED PATHWAYS SUCH AS CIRCADIAN RHYTHM, INFLAMMATORY RESPONSE, OPIOID RECEPTORS, AND MORE GENES INCLUDED IN THE GLUCOCORTICOID RECEPTOR BINDING FAMILY. THUS, ELS PROGRAMS A RESTRICTED TRANSLATIONAL RESPONSE TO STRESS IN STRESS-SENSITIVE CA3 NEURONS LEADING TO PERSISTENT CHANGES IN GENE EXPRESSION, SOME OF WHICH MIMIC THE TRANSIENT EFFECTS OF AS IN CONTROL MICE, WHILE LEAVING IN OPERATION THE IMMEDIATE EARLY GENE RESPONSE TO AS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11 1773  45 EARLY-LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND ANXIETY BEHAVIOR IS REVERSED BY HISTONE DEACETYLASE INHIBITION. STRESSFUL LIFE EVENTS, ESPECIALLY IN CHILDHOOD, CAN HAVE DETRIMENTAL EFFECTS ON HEALTH AND ARE ASSOCIATED WITH A HOST OF PSYCHIATRIC AND GASTROINTESTINAL DISORDERS INCLUDING IRRITABLE BOWEL SYNDROME (IBS). EARLY-LIFE STRESS CAN BE RECAPITULATED IN ANIMALS USING THE MATERNAL SEPARATION (MS) MODEL, EXHIBITING MANY KEY PHENOTYPIC OUTCOMES INCLUDING VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS. THE MOLECULAR MECHANISMS OF MS ARE UNCLEAR, BUT RECENT STUDIES POINT TO A ROLE FOR EPIGENETICS. HISTONE ACETYLATION IS A KEY EPIGENETIC MARK THAT IS ALTERED IN NUMEROUS STRESS-RELATED DISEASE STATES. HERE, WE INVESTIGATED THE ROLE OF HISTONE ACETYLATION IN EARLY-LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY. INTERESTINGLY, INCREASED NUMBER OF PAIN BEHAVIORS AND REDUCED THRESHOLD OF VISCERAL SENSATION WERE ASSOCIATED WITH ALTERATIONS IN HISTONE ACETYLATION IN THE LUMBOSACRAL SPINAL CORD, A KEY REGION IN VISCERAL PAIN PROCESSING. MOREOVER, WE ALSO INVESTIGATED WHETHER THE HISTONE DEACETYLASE (HDAC) INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), COULD REVERSE EARLY-LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND STRESS-INDUCED FECAL PELLET OUTPUT IN THE MS MODEL. SIGNIFICANTLY, SAHA REVERSED BOTH OF THESE PARAMETERS. TAKEN TOGETHER, THESE DATA DESCRIBE, FOR THE FIRST TIME, A KEY ROLE OF HISTONE ACETYLATION IN THE PATHOPHYSIOLOGY OF EARLY-LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN A WELL-ESTABLISHED MODEL OF IBS. THESE FINDINGS WILL INFORM NEW RESEARCH AIMED AT THE DEVELOPMENT OF NOVEL PHARMACEUTICAL APPROACHES TARGETING THE EPIGENETIC MACHINERY FOR NOVEL ANTI-IBS DRUGS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12 5206  49 PRENATAL STRESS INDUCES LONG-TERM BEHAVIORAL SEX-DEPENDENT CHANGES IN RATS OFFSPRING: THE ROLE OF THE HPA AXIS AND EPIGENETICS. PRECLINICAL GENETIC STUDIES HAVE RELATED STRESS EARLY EXPOSURES WITH CHANGES IN GENE REGULATORY MECHANISMS, INCLUDING EPIGENETIC ALTERATIONS, SUCH AS MODIFICATIONS OF DNA METHYLATION, HISTONE DEACETYLATION, AND HISTONES ACETYLATION. THIS STUDY EVALUATES THE EFFECTS OF PRENATAL STRESS ON THE BEHAVIOR, HYPOTHALAMUS-PITUITARY-ADRENAL (HPA)-AXIS, AND EPIGENETIC PARAMETERS IN STRESSED DAMS AND THEIR OFFSPRING. THE RATS WERE SUBJECTED TO A PROTOCOL OF CHRONIC UNPREDICTABLE MILD STRESS ON THE FOURTEENTH DAY OF PREGNANCY UNTIL THE BIRTH OF OFFSPRING. AFTER BIRTH, MATERNAL CARE WAS EVALUATED FOR SIX DAYS. FOLLOWING WEANING, THE LOCOMOTOR AND DEPRESSIVE-LIKE BEHAVIORS OF THE DAMS AND THEIR OFFSPRING (60 DAYS OLD) WERE ASSESSED. THE HPA AXIS PARAMETERS WERE EVALUATED IN SERUM FROM DAMS AND OFFSPRING, AND EPIGENETIC PARAMETERS (HISTONE ACETYLTRANSFERASE (HAT), HISTONE DEACETYLASE (HDAC), DNA METHYLTRANSFERASE (DNMT) ACTIVITIES, AND THE LEVELS OF HISTONE H3 ACETYLATED AT LYSINE RESIDUE 9 (H3K9AC) AND HISTONE 3 ACETYLATED AT LYSINE RESIDUE 14 (H3K14AC)) WERE ASSESSED IN DAMS' AND OFFSPRING' BRAINS. PRENATAL STRESS DID NOT SIGNIFICANTLY INFLUENCE MATERNAL CARE; HOWEVER, IT INDUCED MANIC BEHAVIOR IN FEMALE OFFSPRING. THESE BEHAVIORAL ALTERATIONS IN THE OFFSPRING WERE ACCOMPANIED BY HYPERACTIVITY OF THE HPA-AXIS, EPIGENETIC ADAPTATIONS IN THE ACTIVITY OF HDAC AND DNMT, AND ACETYLATION IN THE HISTONES H3K9 AND H3K14. IN ADDITION, THE PRENATAL STRESSED FEMALE OFFSPRING SHOWED INCREASED LEVELS OF ACTH COMPARED TO THEIR MALE COUNTERPART. OUR FINDINGS REINFORCE THE IMPACT OF PRENATAL STRESS ON BEHAVIOR, STRESS RESPONSE, AND EPIGENETIC PROFILE OF OFFSPRING.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
13 2371  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 6582  43 TRICHOSTATIN A, A HISTONE DEACETYLASE INHIBITOR, ALLEVIATES THE EMOTIONAL ABNORMALITY INDUCED BY MALADAPTATION TO STRESS IN MICE. RECENT REPORTS HAVE IMPLIED THAT ABERRANT BIOCHEMICAL PROCESSES IN THE BRAIN ARE FREQUENTLY ACCOMPANIED BY SUBTLE SHIFTS IN THE CELLULAR EPIGENETIC PROFILE THAT MIGHT UNDERLIE THE PATHOGENIC PROGRESSION OF PSYCHIATRIC DISORDERS. THE AIM OF THE PRESENT STUDY WAS TO EXAMINE THE EFFECT OF TRICHOSTATIN A (TSA), A HISTONE DEACETYLASE (HDAC) INHIBITOR, ON THE EMOTIONAL ABNORMALITY INDUCED BY MALADAPTATION TO STRESS IN MICE. MICE WERE EXPOSED TO REPEATED RESTRAINT STRESS FOR 240 MIN/DAY FOR 14 DAYS. WE APPLIED DOSING SCHEDULES. IN ONE SCHEDULE, FROM THE 3RD DAY OF STRESS EXPOSURE, MICE WERE TREATED WITH TSA (1650 MUM/4 MUL, I.C.V.) IMMEDIATELY AFTER THE DAILY EXPOSURE TO RESTRAINT STRESS. IN THE OTHER SCHEDULE, FROM THE 1ST DAY OF STRESS EXPOSURE, MICE WERE TREATED WITH TSA 2 H BEFORE EXPOSURE TO RESTRAINT STRESS. AFTER THE FINAL EXPOSURE TO RESTRAINT STRESS, THE EMOTIONALITY OF MICE WAS EVALUATED USING THE HOLE-BOARD TEST. MICE THAT WERE EXPOSED TO RESTRAINT STRESS FOR 240 MIN/DAY FOR 14 DAYS SHOWED A DECREASE IN HEAD-DIPPING BEHAVIOR. THIS DECREASED EMOTIONALITY OBSERVED IN STRESS-MALADAPTIVE MICE WAS SIGNIFICANTLY RECOVERED BY CHRONIC TREATMENT WITH TSA 2 H BEFORE DAILY EXPOSURE TO RESTRAINT STRESS, WHICH CONFIRMED THE DEVELOPMENT OF STRESS ADAPTATION. ON THE OTHER HAND, NO SUCH STRESS ADAPTATION WAS OBSERVED UNDER CHRONIC TREATMENT WITH TSA IMMEDIATELY AFTER DAILY STRESS EXPOSURE. A BIOCHEMICAL STUDY SHOWED THAT TRYPTOPHAN HYDROXYLASE, THE RATE-LIMITING ENZYME IN SEROTONIN (5-HT) SYNTHESIS, WAS INCREASED IN MIDBRAIN CONTAINING RAPHE NUCLEI OBTAINED FROM STRESS-ADAPTED MICE THAT WERE CHRONICALLY TREATED WITH TSA 2 H BEFORE DAILY STRESS EXPOSURE. THESE FINDINGS SUGGEST THAT AN HDAC INHIBITOR MAY HAVE A BENEFICIAL EFFECT ON STRESS ADAPTATION BY AFFECTING 5-HT NEURAL FUNCTION IN THE BRAIN AND ALLEVIATE THE EMOTIONAL ABNORMALITY UNDER CONDITIONS OF EXCESSIVE STRESS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15 5207  35 PRENATAL STRESS INDUCES SPATIAL MEMORY DEFICITS AND EPIGENETIC CHANGES IN THE HIPPOCAMPUS INDICATIVE OF HETEROCHROMATIN FORMATION AND REDUCED GENE EXPRESSION. STRESS DURING PREGNANCY HAS A WIDE VARIETY OF NEGATIVE EFFECTS IN BOTH HUMAN [1] AND ANIMAL OFFSPRING [2]. THESE EFFECTS ARE ESPECIALLY APPARENT IN VARIOUS FORMS OF LEARNING AND MEMORY SUCH AS OBJECT RECOGNITION [3] AND SPATIAL MEMORY [4]. THE COGNITIVE EFFECTS OF PRENATAL STRESS (PNS) MAY BE MEDIATED THROUGH EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION AND DNA METHYLATION [5]. AS SUCH, THE PRESENT STUDY INVESTIGATED THE EFFECTS OF CHRONIC UNPREDICTABLE PNS ON MEMORY AND EPIGENETIC MEASURES IN ADULT OFFSPRING. MICE THAT UNDERWENT PNS EXHIBITED IMPAIRED SPATIAL MEMORY IN THE MORRIS WATER MAZE, AS WELL AS SEX-SPECIFIC CHANGES IN LEVELS OF DNA METHYLTRANSFERASE (DNMT) 1 PROTEIN, AND ACETYLATED HISTONE H3 (ACH3) IN THE HIPPOCAMPUS, AND SERUM CORTICOSTERONE. MALE MICE EXPOSED TO PNS EXHIBITED DECREASED HIPPOCAMPAL ACH3, WHEREAS FEMALE PNS MICE DISPLAYED A FURTHER REDUCTION IN ACH3, AS WELL AS HEIGHTENED HIPPOCAMPAL DNMT1 PROTEIN LEVELS AND CORTICOSTERONE LEVELS. THESE DATA SUGGEST THAT PNS MAY EPIGENETICALLY REDUCE TRANSCRIPTION IN THE HIPPOCAMPUS, PARTICULARLY IN FEMALES IN WHOM THIS EFFECT MAY BE RELATED TO INCREASED BASELINE STRESS HORMONE LEVELS, AND WHICH MAY UNDERLIE THE SEXUAL DIMORPHISM IN RATES OF MENTAL ILLNESS IN HUMANS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 6175  47 THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ALLEVIATES DEPRESSION-LIKE BEHAVIOR AND NORMALIZES EPIGENETIC CHANGES IN THE HIPPOCAMPUS DURING ETHANOL WITHDRAWAL. WITHDRAWAL FROM CHRONIC ALCOHOL DRINKING CAN CAUSE DEPRESSION, LEADING TO AN INABILITY TO FUNCTION IN DAILY LIFE AND AN INCREASED RISK FOR RELAPSE TO HARMFUL DRINKING. UNDERSTANDING THE CAUSES OF ALCOHOL WITHDRAWAL-RELATED DEPRESSION MAY LEAD TO NEW THERAPEUTIC TARGETS FOR TREATMENT. EPIGENETIC FACTORS HAVE RECENTLY EMERGED AS IMPORTANT CONTRIBUTORS TO BOTH DEPRESSION AND ALCOHOL USE DISORDER (AUD). SPECIFICALLY, ACETYLATION OF THE N-TERMINAL TAILS OF HISTONE PROTEINS THAT PACKAGE DNA INTO NUCLEOSOMES IS ALTERED IN STRESS-INDUCED MODELS OF DEPRESSION AND DURING ALCOHOL WITHDRAWAL. THE GOAL OF THIS STUDY WAS TO EXAMINE DEPRESSION-LIKE BEHAVIOR DURING ALCOHOL WITHDRAWAL AND ASSOCIATED CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE DEACETYLASE 2 (HDAC2) IN THE HIPPOCAMPUS, A BRAIN REGION CRITICAL FOR MOOD REGULATION AND DEPRESSION. MALE SPRAGUE-DAWLEY RATS WERE TREATED WITH THE LIEBER-DECARLI ETHANOL LIQUID DIET FOR 15 DAYS AND THEN UNDERWENT WITHDRAWAL. RATS WERE TREATED WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), DURING WITHDRAWAL AND WERE TESTED FOR DEPRESSION-LIKE BEHAVIOR. IN A SEPARATE GROUP OF RATS, THE HIPPOCAMPUS WAS ANALYZED FOR MRNA AND PROTEIN EXPRESSION OF HDAC2 AND LEVELS OF HISTONE H3 LYSINE 9 ACETYLATION (H3K9AC) DURING CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL. RATS UNDERGOING ETHANOL WITHDRAWAL EXHIBITED DEPRESSION-LIKE BEHAVIOR AND HAD INCREASED HDAC2 AND DECREASED H3K9AC LEVELS IN SPECIFIC STRUCTURES OF THE HIPPOCAMPUS. TREATMENT WITH SAHA DURING WITHDRAWAL AMELIORATED DEPRESSION-LIKE BEHAVIOR AND NORMALIZED CHANGES IN HIPPOCAMPAL HDAC2 AND H3K9AC LEVELS. THESE RESULTS DEMONSTRATE THAT ETHANOL WITHDRAWAL CAUSES AN ALTERED EPIGENETIC STATE IN THE HIPPOCAMPUS. TREATMENT WITH AN HDAC INHIBITOR CAN CORRECT THIS STATE AND ALLEVIATE DEPRESSION-LIKE SYMPTOMS DEVELOPED DURING WITHDRAWAL. TARGETING HISTONE ACETYLATION MAY BE A NOVEL STRATEGY TO REDUCE ETHANOL WITHDRAWAL-INDUCED DEPRESSION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17 1753  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18 5752  48 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19 2740  32 EXPOSURE TO EARLY LIFE STRESS RESULTS IN EPIGENETIC CHANGES IN NEUROTROPHIC FACTOR GENE EXPRESSION IN A PARKINSONIAN RAT MODEL. EARLY LIFE ADVERSITY INCREASES THE RISK OF MENTAL DISORDERS LATER IN LIFE. CHRONIC EARLY LIFE STRESS MAY ALTER NEUROTROPHIC FACTOR GENE EXPRESSION INCLUDING THOSE FOR BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND GLIAL CELL DERIVED NEUROTROPHIC FACTOR (GDNF) THAT ARE IMPORTANT IN NEURONAL GROWTH, SURVIVAL, AND MAINTENANCE. MATERNAL SEPARATION WAS USED IN THIS STUDY TO MODEL EARLY LIFE STRESS. FOLLOWING UNILATERAL INJECTION OF A MILD DOSE OF 6-HYDROXYDOPAMINE (6-OHDA), WE MEASURED CORTICOSTERONE (CORT) IN THE BLOOD AND STRIATUM OF STRESSED AND NONSTRESSED RATS; WE ALSO MEASURED DNA METHYLATION AND BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM USING REAL TIME PCR. IN THE PRESENCE OF STRESS, WE FOUND THAT THERE WAS INCREASED CORTICOSTERONE CONCENTRATION IN BOTH BLOOD AND STRIATAL TISSUE. FURTHER TO THIS, WE FOUND HIGHER DNA METHYLATION AND DECREASED NEUROTROPHIC FACTOR GENE EXPRESSION. 6-OHDA LESION INCREASED NEUROTROPHIC FACTOR GENE EXPRESSION IN BOTH STRESSED AND NONSTRESSED RATS BUT THIS INCREASE WAS HIGHER IN THE NONSTRESSED RATS. OUR RESULTS SUGGEST THAT EXPOSURE TO EARLY POSTNATAL STRESS INCREASES CORTICOSTERONE CONCENTRATION WHICH LEADS TO INCREASED DNA METHYLATION. THIS EFFECT RESULTS IN DECREASED BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM LEADING TO DECREASED PROTECTION AGAINST SUBSEQUENT INSULTS LATER IN LIFE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20 5199  49 PRENATAL MATERNAL STRESS IS ASSOCIATED WITH INCREASED SENSITIVITY TO NEUROPATHIC PAIN AND SEX-SPECIFIC CHANGES IN SUPRASPINAL MRNA EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES IN ADULTHOOD. EXPOSURE TO PRENATAL MATERNAL STRESS IMPACTS ADULT BEHAVIORAL OUTCOMES AND HAS BEEN SUGGESTED AS A RISK FACTOR FOR CHRONIC PAIN. HOWEVER, THE NEUROBIOLOGICAL MECHANISMS IMPLICATED ARE NOT WELL-CHARACTERIZED. IN THIS STUDY, WE ANALYZED THE EFFECT OF A PRENATAL MATERNAL STRESS ON THE DEVELOPMENT OF NEUROPATHIC PAIN-RELATED BEHAVIOURS AND GENE EXPRESSION IN THE FRONTAL CORTEX AND HIPPOCAMPUS IN ADULT OFFSPRING FOLLOWING CHRONIC CONSTRICTION INJURY OF THE SCIATIC NERVE IN MALE AND FEMALE CD1 MICE. NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY WAS AMPLIFIED IN BOTH MALE AND FEMALE PRENATALLY-STRESSED OFFSPRING, SUGGESTING THAT PRENATAL STRESS EXACERBATES PAIN AFTER INJURY. ANALYSIS OF MRNA EXPRESSION OF GENES RELATED TO EPIGENETIC REGULATION AND STRESS RESPONSES IN THE FRONTAL CORTEX AND HIPPOCAMPUS, BRAIN STRUCTURES IMPLICATED IN CHRONIC PAIN, SHOWED DISTINCT SEX AND REGION-SPECIFIC PATTERNS OF DYSREGULATION. IN GENERAL, MRNA EXPRESSION WAS MOST FREQUENTLY ALTERED IN THE MALE HIPPOCAMPUS AND EFFECTS OF PRENATAL STRESS WERE MORE PREVALENT THAN EFFECTS OF NERVE INJURY IN BOTH SUPRASPINAL AREAS. THESE FINDINGS DEMONSTRATE THE IMPACT OF PRENATAL STRESS ON BEHAVIORAL SENSITIVITY TO A PAINFUL INJURY. CHANGES IN THE EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES SUGGEST A POSSIBLE MECHANISM BY WHICH THE EARLY LIFE STRESS BECOMES EMBEDDED IN THE CENTRAL NERVOUS SYSTEM. INCREASED UNDERSTANDING OF THE INTERACTIONS AMONG EARLY-LIFE STRESS, SEX, AND PAIN MAY LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND EPIGENETIC DRUGS FOR THE TREATMENT OF CHRONIC PAIN DISORDERS.	2020