1  5651 117 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
2  2187  78 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	
                                                                                                                                                                                                                   
3  1163  56 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  4222  32 METHYLATION AT THE CPG ISLAND SHORE REGION UPREGULATES NR3C1 PROMOTER ACTIVITY AFTER EARLY-LIFE STRESS. EARLY-LIFE STRESS (ELS) INDUCES LONG-LASTING CHANGES IN GENE EXPRESSION CONFERRING AN INCREASED RISK FOR THE DEVELOPMENT OF STRESS-RELATED MENTAL DISORDERS. GLUCOCORTICOID RECEPTORS (GR) MEDIATE THE NEGATIVE FEEDBACK ACTIONS OF GLUCOCORTICOIDS (GC) IN THE PARAVENTRICULAR NUCLEUS (PVN) OF THE HYPOTHALAMUS AND ANTERIOR PITUITARY AND THEREFORE PLAY A KEY ROLE IN THE REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND THE ENDOCRINE RESPONSE TO STRESS. WE HERE SHOW THAT ELS PROGRAMS THE EXPRESSION OF THE GR GENE (NR3C1) BY SITE-SPECIFIC HYPERMETHYLATION AT THE CPG ISLAND (CGI) SHORE IN HYPOTHALAMIC NEURONS THAT PRODUCE CORTICOTROPIN-RELEASING HORMONE (CRH), THUS PREVENTING CRH UPREGULATION UNDER CONDITIONS OF CHRONIC STRESS. CPGS MAPPING TO THE NR3C1 CGI SHORE REGION ARE DYNAMICALLY REGULATED BY ELS AND UNDERPIN METHYLATION-SENSITIVE CONTROL OF THIS REGION'S INSULATION-LIKE FUNCTION VIA YING YANG 1 (YY1) BINDING. OUR RESULTS PROVIDE NEW INSIGHT INTO HOW A GENOMIC ELEMENT INTEGRATES EXPERIENCE-DEPENDENT EPIGENETIC PROGRAMMING OF THE COMPOSITE PROXIMAL NR3C1 PROMOTER, AND ASSIGNS AN INSULATING ROLE TO THE CGI SHORE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  1752  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6  3177  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  1751  37 EARLY LIFE STRESS INCREASES STRESS VULNERABILITY THROUGH BDNF GENE EPIGENETIC CHANGES IN THE RAT HIPPOCAMPUS. EARLY LIFE STRESS (ELS) EXERTS LONG-LASTING EPIGENETIC INFLUENCES ON THE BRAIN AND MAKES AN INDIVIDUAL SUSCEPTIBLE TO LATER DEPRESSION. IT IS POORLY UNDERSTOOD WHETHER ELS AND SUBSEQUENT ADULT CHRONIC STRESS MODULATE EPIGENETIC MECHANISMS. WE EXAMINED THE EPIGENETIC MECHANISMS OF THE BDNF GENE IN THE HIPPOCAMPUS, WHICH MAY UNDERLIE STRESS VULNERABILITY TO POSTNATAL MATERNAL SEPARATION (MS) AND ADULT RESTRAINT STRESS (RS). RAT PUPS WERE SEPARATED FROM THEIR DAMS (3 H/DAY FROM P1-P21). WHEN THE PUPS REACHED ADULTHOOD (8 WEEKS OLD), WE INTRODUCED RS (2 H/DAY FOR 3 WEEKS) FOLLOWED BY ESCITALOPRAM TREATMENT. WE SHOWED THAT BOTH THE MS AND RS GROUPS EXPRESSED REDUCED LEVELS OF TOTAL AND EXON IV BDNF MRNA. FURTHERMORE, RS POTENTIATED MS-INDUCED DECREASES IN THESE EXPRESSION LEVELS. SIMILARLY, BOTH THE MS AND RS GROUPS SHOWED DECREASED LEVELS OF ACETYLATED HISTONE H3 AND H4 AT BDNF PROMOTER IV, AND RS EXACERBATED MS-INDUCED DECREASES OF H3 AND H4 ACETYLATION. BOTH THE MS AND RS GROUPS HAD INCREASED MECP2 LEVELS AT BDNF PROMOTER IV, AS WELL AS INCREASED HDAC5 MRNA, AND THE COMBINATION OF MS AND RS EXERTED A GREATER EFFECT ON THESE PARAMETERS THAN DID RS ALONE. IN THE FORCED SWIMMING TEST, THE IMMOBILITY TIME OF THE MS + RS GROUP WAS SIGNIFICANTLY HIGHER THAN THAT OF THE RS GROUP. ADDITIONALLY, CHRONIC ESCITALOPRAM TREATMENT RECOVERED THESE ALTERATIONS. OUR RESULTS SUGGEST THAT POSTNATAL MS AND SUBSEQUENT ADULT RS MODULATE EPIGENETIC CHANGES IN THE BDNF GENE, AND THAT THESE CHANGES MAY BE RELATED TO BEHAVIORAL PHENOTYPE. THESE EPIGENETIC MECHANISMS ARE INVOLVED IN ESCITALOPRAM ACTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  3972  32 LONG-TERM BEHAVIORAL AND CELL-TYPE-SPECIFIC MOLECULAR EFFECTS OF EARLY LIFE STRESS ARE MEDIATED BY H3K79ME2 DYNAMICS IN MEDIUM SPINY NEURONS. ANIMALS SUSCEPTIBLE TO CHRONIC SOCIAL DEFEAT STRESS (CSDS) EXHIBIT DEPRESSION-RELATED BEHAVIORS, WITH ABERRANT TRANSCRIPTION ACROSS SEVERAL LIMBIC BRAIN REGIONS, MOST NOTABLY IN THE NUCLEUS ACCUMBENS (NAC). EARLY LIFE STRESS (ELS) PROMOTES SUSCEPTIBILITY TO CSDS IN ADULTHOOD, BUT ASSOCIATED ENDURING CHANGES IN TRANSCRIPTIONAL CONTROL MECHANISMS IN THE NAC HAVE NOT YET BEEN INVESTIGATED. IN THIS STUDY, WE EXAMINED LONG-LASTING CHANGES TO HISTONE MODIFICATIONS IN THE NAC OF MALE AND FEMALE MICE EXPOSED TO ELS. DIMETHYLATION OF LYSINE 79 OF HISTONE H3 (H3K79ME2) AND THE ENZYMES (DOT1L AND KDM2B) THAT CONTROL THIS MODIFICATION ARE ENRICHED IN D2-TYPE MEDIUM SPINY NEURONS AND ARE SHOWN TO BE CRUCIAL FOR THE EXPRESSION OF ELS-INDUCED STRESS SUSCEPTIBILITY. WE MAPPED THE SITE-SPECIFIC REGULATION OF THIS HISTONE MARK GENOME WIDE TO REVEAL THE TRANSCRIPTIONAL NETWORKS IT MODULATES. FINALLY, SYSTEMIC DELIVERY OF A SMALL MOLECULE INHIBITOR OF DOT1L REVERSED ELS-INDUCED BEHAVIORAL DEFICITS, INDICATING THE CLINICAL RELEVANCE OF THIS EPIGENETIC MECHANISM.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  3600  53 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10  5834  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  1740  32 EARLY ENRICHED ENVIRONMENT PREVENTS EPIGENETIC P11 GENE CHANGES INDUCED BY ADULTHOOD STRESS IN MICE. POSITIVE EXPERIENCES IN EARLY LIFE MAY IMPROVE THE CAPACITY TO COPE WITH ADULTHOOD STRESS THROUGH EPIGENETIC MODIFICATION. WE INVESTIGATED WHETHER AN ENRICHED ENVIRONMENT (EE) IN THE POSTNATAL PERIOD AFFECTED EPIGENETIC CHANGES IN THE P11 GENE INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS) IN ADULT C57BL/6J MICE. EE WAS INTRODUCED FOR 5 WEEKS DURING POSTNATAL DAYS 21-55. AFTER EE, THE MICE WERE SUBJECTED TO CUS FOR 4 WEEKS. EE PREVENTED DEPRESSION-LIKE BEHAVIOR INDUCED BY ADULT CUS. EE PREVENTED A DECREASE IN P11 MRNA AND HISTONE H3 ACETYLATION INDUCED BY CUS, WITH CHANGES IN THE EXPRESSION OF HISTONE DEACETYLASE 5. MOREOVER, EE PREVENTED CHANGES IN TRIMETHYLATION OF HISTONE H3 LYSINE 4 (H3K4) AND H3K27 INDUCED BY CUS. FURTHERMORE, EE HAD POSITIVE EFFECTS ON BEHAVIOR AND EPIGENETIC ALTERATIONS IN ADULT MICE WITHOUT CUS. THESE RESULTS SUGGEST THAT ONE OF THE UNDERLYING MECHANISMS OF EARLY-LIFE EE MAY INVOLVE EPIGENETIC MODIFICATION OF THE HIPPOCAMPAL P11 GENE PROMOTER.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  2201  37 EPIGENETIC MODIFICATION OF GLUCOCORTICOID RECEPTOR PROMOTER I(7) IN MATERNALLY SEPARATED AND RESTRAINT-STRESSED RATS. GLUCOCORTICOID RECEPTOR (GR) PROMOTER I(7) IS SUSCEPTIBLE TO EPIGENETIC CHANGES INDUCED BY ENVIRONMENTAL INFLUENCES. EARLY LIFE STRESS (ELS) HAS A PERSISTENT IMPACT ON GR EXPRESSION, AS WELL AS BEHAVIOR, IN ADULT RODENTS VIA EPIGENETIC CHANGES OF GR PROMOTER I(7). MOREOVER, VARIOUS STRESSORS CAN INDUCE HISTONE MODIFICATIONS IN THIS REGION DURING ADULTHOOD. THUS, THE PRESENT STUDY AIMED TO INVESTIGATE WHETHER MATERNALLY SEPARATED (MS) RATS EXPOSED TO CHRONIC RESTRAINT STRESS (RS) WOULD EXHIBIT HISTONE MODIFICATIONS OF GR PROMOTER I(7) IN THE HIPPOCAMPUS. RATS WERE SUBJECTED TO MS (3H PER DAY) ON POSTNATAL DAYS (PND) 1-21. THEN, DURING ADULTHOOD (PND 56-77), THE RATS WERE EXPOSED TO RS (2H PER DAY) FOLLOWED BY TREATMENT WITH ESCITALOPRAM (10MG/KG). THE MS AND RS GROUPS EXHIBITED SIGNIFICANT DECREASES IN TOTAL AND EXON I(7) GR MRNA LEVELS AND THE COMBINATION OF MS AND RS EXERTED A GREATER EFFECT ON THESE MRNA LEVELS THAN EITHER MS OR RS ALONE. ADDITIONALLY, BOTH THE MS AND RS GROUPS SHOWED SIGNIFICANT REDUCTIONS IN HISTONE H3 ACETYLATION AT GR PROMOTER I(7) AND THE COMBINATION OF MS AND RS HAD A GREATER EFFECT THAN DID EITHER MS OR RS ALONE. CHRONIC ESCITALOPRAM TREATMENT AMELIORATED THESE CHANGES. THE PRESENT RESULTS INDICATE THAT POSTNATAL MS AND ADULT RS INFLUENCE GR EXPRESSION THROUGH HISTONE MODIFICATION AT GR PROMOTER I(7), AND THAT THE COMBINATION OF THE TWO STRESSORS POTENTIATES THESE CHANGES. FURTHERMORE, EPIGENETIC MECHANISMS ARE INVOLVED IN ESCITALOPRAM ACTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13  5831  31 STRESS-INDUCED CHRONIC VISCERAL PAIN OF GASTROINTESTINAL ORIGIN. VISCERAL PAIN IS GENERALLY POORLY LOCALIZED AND CHARACTERIZED BY HYPERSENSITIVITY TO A STIMULUS SUCH AS ORGAN DISTENSION. IN CONCERT WITH CHRONIC VISCERAL PAIN, THERE IS A HIGH COMORBIDITY WITH STRESS-RELATED PSYCHIATRIC DISORDERS INCLUDING ANXIETY AND DEPRESSION. THE MECHANISMS LINKING VISCERAL PAIN WITH THESE OVERLAPPING COMORBIDITIES REMAIN TO BE ELUCIDATED. EVIDENCE SUGGESTS THAT LONG TERM STRESS FACILITATES PAIN PERCEPTION AND SENSITIZES PAIN PATHWAYS, LEADING TO A FEED-FORWARD CYCLE PROMOTING CHRONIC VISCERAL PAIN DISORDERS SUCH AS IRRITABLE BOWEL SYNDROME (IBS). EARLY LIFE STRESS (ELS) IS A RISK-FACTOR FOR THE DEVELOPMENT OF IBS, HOWEVER THE MECHANISMS RESPONSIBLE FOR THE PERSISTENT EFFECTS OF ELS ON VISCERAL PERCEPTION IN ADULTHOOD REMAIN INCOMPLETELY UNDERSTOOD. IN RODENT MODELS, STRESS IN ADULT ANIMALS INDUCED BY RESTRAINT AND WATER AVOIDANCE HAS BEEN EMPLOYED TO INVESTIGATE THE MECHANISMS OF STRESS-INDUCE PAIN. ELS MODELS SUCH AS MATERNAL SEPARATION, LIMITED NESTING, OR ODOR-SHOCK CONDITIONING, WHICH ATTEMPT TO MODEL EARLY CHILDHOOD EXPERIENCES SUCH AS NEGLECT, POVERTY, OR AN ABUSIVE CAREGIVER, CAN PRODUCE CHRONIC, SEXUALLY DIMORPHIC INCREASES IN VISCERAL SENSITIVITY IN ADULTHOOD. CHRONIC VISCERAL PAIN IS A CLASSIC EXAMPLE OF GENE X ENVIRONMENT INTERACTION WHICH RESULTS FROM MALADAPTIVE CHANGES IN NEURONAL CIRCUITRY LEADING TO NEUROPLASTICITY AND ABERRANT NEURONAL ACTIVITY-INDUCED SIGNALING. ONE POTENTIAL MECHANISM UNDERLYING THE PERSISTENT EFFECTS OF STRESS ON VISCERAL SENSITIVITY COULD BE EPIGENETIC MODULATION OF GENE EXPRESSION. WHILE THERE ARE RELATIVELY FEW STUDIES EXAMINING EPIGENETICALLY MEDIATED MECHANISMS INVOLVED IN VISCERAL NOCICEPTION, STRESS-INDUCED VISCERAL PAIN HAS BEEN LINKED TO ALTERATIONS IN DNA METHYLATION AND HISTONE ACETYLATION PATTERNS WITHIN THE BRAIN, LEADING TO INCREASED EXPRESSION OF PRO-NOCICEPTIVE NEUROTRANSMITTERS. THIS REVIEW WILL DISCUSS THE POTENTIAL NEURONAL PATHWAYS AND MECHANISMS RESPONSIBLE FOR STRESS-INDUCED EXACERBATION OF CHRONIC VISCERAL PAIN. ADDITIONALLY, WE WILL REVIEW THE IMPORTANCE OF SPECIFIC EXPERIMENTAL MODELS OF ADULT STRESS AND ELS IN ENHANCING OUR UNDERSTANDING OF THE BASIC MOLECULAR MECHANISMS OF PAIN PROCESSING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  1750  18 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  6108  33 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS.	2019	
                                                                                                                                             
16  4944  26 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
17  2243  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
18  1920  48 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	

19  5253  42 PROGRAMMING CHANGES OF HIPPOCAMPAL MIR-134-5P/SOX2 SIGNAL MEDIATE THE SUSCEPTIBILITY TO DEPRESSION IN PRENATAL DEXAMETHASONE-EXPOSED FEMALE OFFSPRING. DEPRESSION IS A NEUROPSYCHIATRIC DISORDER AND HAS INTRAUTERINE DEVELOPMENTAL ORIGINS. THIS STUDY AIMED TO CONFIRM THE DEPRESSION SUSCEPTIBILITY IN OFFSPRING RATS INDUCED BY PRENATAL DEXAMETHASONE EXPOSURE (PDE) AND TO FURTHER EXPLORE THE INTRAUTERINE PROGRAMMING MECHANISM. WISTAR RATS WERE INJECTED WITH DEXAMETHASONE (0.2 MG/KG.D) SUBCUTANEOUSLY DURING THE GESTATIONAL DAYS 9-20 AND PART OF THE OFFSPRING WAS GIVEN CHRONIC STRESS AT POSTNATAL WEEKS 10-12. BEHAVIORAL RESULTS SHOWED THAT THE ADULT PDE FEMALE OFFSPRING WAS SUSCEPTIBLE TO DEPRESSION, ACCOMPANIED BY INCREASED HIPPOCAMPAL MIR-134-5P EXPRESSION AND DECREASED SEX-DETERMINING REGION Y-BOX 2 (SOX2) EXPRESSION, AS WELL AS DISORDERS OF NEURAL PROGENITOR CELLS PROLIFERATION AND HIPPOCAMPAL NEUROGENESIS. THE PDE FEMALE FETAL RATS PRESENTED CONSISTENT CHANGES WITH THE ADULT OFFSPRING, ACCOMPANIED BY THE UPREGULATION OF GLUCOCORTICOID RECEPTOR (GR) EXPRESSION AND DECREASED SIRTUIN 1 (SIRT1) EXPRESSION. WE FURTHER FOUND THAT THE H3K9AC LEVEL OF THE MIR-134-5P PROMOTER WAS SIGNIFICANTLY INCREASED IN THE PDE FETAL HIPPOCAMPUS, AS WELL AS IN ADULT OFFSPRING BEFORE AND AFTER CHRONIC STRESS. IN VITRO, THE CHANGES OF GR/SIRT1/MIR-134-5P/SOX2 SIGNAL BY DEXAMETHASONE WERE CONSISTENT WITH IN VIVO EXPERIMENTS, WHICH COULD BE REVERSED BY GR RECEPTOR ANTAGONIST, SIRT1 AGONIST, AND MIR-134-5P INHIBITOR. THIS STUDY CONFIRMED THAT PDE LED TO AN INCREASED EXPRESSION LEVEL AS WELL AS H3K9AC LEVEL OF MIR-134-5P BY ACTIVATING THE GR/SIRT1 PATHWAY IN THE FETAL HIPPOCAMPUS AND THEN INHIBITED THE SOX2 EXPRESSION. THE PROGRAMMING EFFECT MEDIATED BY THE ABNORMAL EPIGENETIC MODIFICATION COULD LAST FROM INTRAUTERINE TO ADULTHOOD, WHICH CONSTITUTES THE INTRAUTERINE PROGRAMMING MECHANISM LEADING TO HIPPOCAMPAL NEUROGENESIS DISORDERS AND DEPRESSION SUSCEPTIBILITY IN FEMALE OFFSPRING. INTRAUTERINE PROGRAMMING MECHANISM FOR THE INCREASED DEPRESSIVE SUSCEPTIBILITY IN ADULT FEMALE OFFSPRING BY PRENATAL DEXAMETHASONE EXPOSURE (PDE). GR, GLUCOCORTICOID RECEPTOR; SIRT1, SIRTUIN 1; SOX2, SEX-DETERMINING REGION Y-BOX 2; NPCS, NEUROPROGENITOR CELLS; H3K9AC, HISTONE 3 LYSINE 9 ACETYLATION; GRE, GLUCOCORTICOID RESPONSE ELEMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
20  3462  33 HYPOTHALAMIC NR3C1 DNA METHYLATION IN RATS EXPOSED TO PRENATAL STRESS. BACKGROUND: HUMAN AND ANIMAL STUDIES HAVE INDICATED THAT MATERNAL PRENATAL STRESS (PS) HAS MOLECULAR AND BEHAVIORAL EFFECTS DURING PREGNANCY AND EARLY LIFE. THE PRESENT STUDY AIMED TO EVALUATE THE EPIGENETIC CHANGES OF THE NR3C1 GENE INVOLVED IN THE HPA AXIS IN THE HYPOTHALAMIC TISSUES OF RATS EXPOSED TO PS INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS). BEHAVIORAL AND MOLECULAR EFFECTS OF THESE CHANGES ON THE NEXT GENERATION WERE ALSO ASSESSED. METHODS AND RESULTS: CUMS PROTOCOL WAS USED TO GENERATE STRESS IN PREGNANT WISTAR RATS. TO DETERMINE THE EFFECTS OF STRESS ON ANHEDONIA AND MOVEMENT, SUCROSE PREFERENCE TEST, FORCED SWIMMING TEST, AND OPEN FIELD TEST WERE PERFORMED. FOLLOWING THESE BEHAVIORAL EXPERIMENTS, BISULFITE SEQUENCING PCR FOR DNA METHYLATION LEVELS OF THE NR3C1 GENE, RT-QPCR FOR MRNA LEVELS, AND WESTERN BLOT TECHNIQUES FOR PROTEIN ANALYSIS WERE USED IN THE HYPOTHALAMIC TISSUE OF SACRIFICED RATS. DEPRESSION-LIKE BEHAVIORS WERE EVIDENT IN THE BEHAVIORAL TESTS OF STRESS-EXPOSED MOTHERS AND PUPS. IN PS-EXPOSED PUPS, HYPOTHALAMIC NR3C1 PROMOTER METHYLATION WAS HIGHER, AND NR3C1 MRNA LEVELS AND NR3C1 PROTEIN LEVELS WERE LOWER COMPARED WITH CONTROLS, REGARDLESS OF SEX. CONCLUSION: OUR RESULTS CONFIRM THE RELATIONSHIP BETWEEN PS AND EPIGENETIC CHANGES OF HPA AXIS-RELATED GENES AND SHOW THAT NR3C1 GENE METHYLATION STATUS IN PUPS IS SENSITIVE TO PS DURING PREGNANCY. ENVIRONMENTAL MATERNAL STRESS MAY HAVE TRANSGENERATIONAL EFFECTS THAT ARE POTENTIALLY ASSOCIATED WITH ADVERSE OUTCOMES IN THE PUPS.	2022