1 2371 133 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
2 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3 3973  43 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  990  37 CHRONIC SOCIAL STRESS INDUCES DNA METHYLATION CHANGES AT AN EVOLUTIONARY CONSERVED INTERGENIC REGION IN CHROMOSOME X. CHRONIC STRESS RESULTING FROM PROLONGED EXPOSURE TO NEGATIVE LIFE EVENTS INCREASES THE RISK OF MOOD AND ANXIETY DISORDERS. ALTHOUGH CHRONIC STRESS CAN CHANGE GENE EXPRESSION RELEVANT FOR BEHAVIOR, MOLECULAR REGULATORS OF THIS CHANGE HAVE NOT BEEN FULLY DETERMINED. ONE PROCESS THAT COULD PLAY A ROLE IS DNA METHYLATION, AN EPIGENETIC PROCESS WHEREBY A METHYL GROUP IS ADDED ONTO NUCLEOTIDES, PREDOMINANTLY CYTOSINE IN THE CPG CONTEXT, AND WHICH CAN BE INDUCED BY CHRONIC STRESS. IT IS UNKNOWN TO WHAT EXTENT CHRONIC SOCIAL DEFEAT, A MODEL OF HUMAN SOCIAL STRESS, INFLUENCES DNA METHYLATION PATTERNS ACROSS THE GENOME. OUR STUDY ADDRESSED THIS QUESTION BY USING A TARGETED-CAPTURE APPROACH CALLED METHYL-SEQ TO INVESTIGATE DNA METHYLATION PATTERNS OF THE DENTATE GYRUS AT PUTATIVE REGULATORY REGIONS ACROSS THE MOUSE GENOME FROM MICE EXPOSED TO 14 DAYS OF SOCIAL DEFEAT. FINDINGS WERE REPLICATED IN INDEPENDENT COHORTS BY BISULFITE-PYROSEQUENCING. TWO DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE IDENTIFIED. ONE DMR WAS LOCATED AT INTRON 9 OF DROSHA, AND IT SHOWED REDUCED METHYLATION IN STRESSED MICE. THIS OBSERVATION REPLICATED IN ONE OF TWO INDEPENDENT COHORTS. A SECOND DMR WAS IDENTIFIED AT AN INTERGENIC REGION OF CHROMOSOME X, AND METHYLATION IN THIS REGION WAS INCREASED IN STRESSED MICE. THIS METHYLATION DIFFERENCE REPLICATED IN TWO INDEPENDENT COHORTS AND IN MAJOR DEPRESSIVE DISORDER (MDD) POSTMORTEM BRAINS. THESE RESULTS HIGHLIGHT A REGION NOT PREVIOUSLY KNOWN TO BE DIFFERENTIALLY METHYLATED BY CHRONIC SOCIAL DEFEAT STRESS AND WHICH MAY BE INVOLVED IN MDD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5 1418  39 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
6 5019  41 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	
                                                                                                                                                                                                                                                                  
7  886  40 CHRONIC CORTICOSTERONE EXPOSURE INCREASES EXPRESSION AND DECREASES DEOXYRIBONUCLEIC ACID METHYLATION OF FKBP5 IN MICE. THERE IS EVIDENCE FOR HYPERCORTISOLEMIA PLAYING A ROLE IN THE GENERATION OF PSYCHIATRIC SYMPTOMS AND FOR EPIGENETIC VARIATION WITHIN HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS GENES MEDIATING BEHAVIORAL CHANGES. WE TESTED THE HYPOTHESIS THAT EXPRESSION CHANGES WOULD BE INDUCED IN FKBP5 AND OTHER HPA AXIS GENES BY CHRONIC EXPOSURE TO CORTICOSTERONE AND THAT THESE CHANGES WOULD OCCUR THROUGH THE EPIGENETIC MECHANISM OF LOSS OR GAIN OF DNA METHYLATION (DNAM). WE ADMINISTERED CORTICOSTERONE (CORT) TO C57BL/6J MICE VIA THEIR DRINKING WATER FOR 4 WK AND TESTED FOR BEHAVIORAL AND PHYSIOLOGICAL CHANGES AND CHANGES IN GENE EXPRESSION LEVELS USING RNA EXTRACTED FROM HIPPOCAMPUS, HYPOTHALAMUS, AND BLOOD FOR THE FOLLOWING HPA GENES: FKBP5, NR3C1, HSP90, CRH, AND CRHR1. THE CORT MICE EXHIBITED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE TEST. CHRONIC EXPOSURE TO CORT ALSO CAUSED A SIGNIFICANT DECREASE IN THE HIPPOCAMPAL AND BLOOD MRNA LEVELS OF NR3C1 AND A DECREASE IN HSP90 IN BLOOD AND CAUSED AN INCREASE IN FKBP5 FOR ALL TISSUES. DIFFERENCES WERE SEEN IN FKBP5 METHYLATION IN HIPPOCAMPUS AND HYPOTHALAMUS. TO ISOLATE A SINGLE-CELL TYPE, WE FOLLOWED UP WITH AN HT-22 MOUSE HIPPOCAMPAL NEURONAL CELL LINE EXPOSED TO CORT. AFTER 7 D, WE OBSERVED A 2.4-FOLD INCREASE IN FKBP5 EXPRESSION AND A DECREASE IN DNAM. IN THE CORT-TREATED MICE, WE ALSO OBSERVED CHANGES IN BLOOD DNAM IN FKBP5. OUR RESULTS SUGGEST DNAM PLAYS A ROLE IN MEDIATING EFFECTS OF GLUCOCORTICOID EXPOSURE ON FKBP5 FUNCTION, WITH POTENTIAL CONSEQUENCES FOR BEHAVIOR.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 2740  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9 2905  39 GENE DYSREGULATION IN THE ADULT RAT PARAVENTRICULAR NUCLEUS AND AMYGDALA BY PRENATAL EXPOSURE TO DEXAMETHASONE. FETAL PROGRAMMING IS THE CONCEPT THAT MATERNAL STRESSORS DURING CRITICAL PERIODS OF FETAL DEVELOPMENT CAN ALTER OFFSPRING PHENOTYPES POSTNATALLY. EXCESS GLUCOCORTICOIDS CAN INTERACT WITH THE FETUS TO EFFECT GENETIC AND EPIGENETIC CHANGES IMPLICATED IN ADVERSE DEVELOPMENTAL OUTCOMES. THE PRESENT STUDY INVESTIGATES HOW CHRONIC EXPOSURE TO THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE DURING LATE GESTATION ALTERS THE EXPRESSION OF GENES RELATED TO BEHAVIOR IN BRAIN AREAS RELEVANT TO THE REGULATION AND FUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. PREGNANT WISTAR KYOTO RATS RECEIVED SUBCUTANEOUS INJECTIONS OF DEXAMETHASONE (100 MUG/KG) DAILY FROM GESTATIONAL DAY 15-21 OR VEHICLE ONLY AS SHAM CONTROLS. THE AMYGDALA AND PARAVENTRICULAR NUCLEUS (PVN) WERE MICRO-PUNCHED TO EXTRACT MRNA FOR REVERSE TRANSCRIPTION AND QUANTITATIVE POLYMERASE CHAIN REACTION FOR THE ANALYSIS OF THE EXPRESSION OF SPECIFIC GENES. IN THE PVN, THE EXPRESSION OF THE GLUCOCORTICOID RECEPTOR NR3C1 WAS DOWNREGULATED IN FEMALE RATS IN RESPONSE TO PROGRAMMING. THE EXPRESSION OF CACNA1C ENCODING THE CA(V)1.2 PORE SUBUNIT OF L-TYPE VOLTAGE-GATED CALCIUM CHANNELS WAS DOWNREGULATED IN MALE AND FEMALE RATS PRENATALLY EXPOSED TO DEXAMETHASONE. COLLECTIVELY, THE RESULTS SUGGEST THAT PRENATAL EXPOSURE TO ELEVATED LEVELS OF GLUCOCORTICOIDS PLAYS A ROLE IN THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND POTENTIALLY LEARNING AND MEMORY BY ALTERING THE EXPRESSION OF SPECIFIC GENES WITHIN THE AMYGDALA AND PVN.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
10 3412  35 HPA AXIS REGULATION AND EPIGENETIC PROGRAMMING OF IMMUNE-RELATED GENES IN CHRONICALLY STRESSED AND NON-STRESSED MID-LIFE WOMEN. HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION HAS BEEN ASSOCIATED WITH ALTERED IMMUNE FUNCTION, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, RESPOND TO THE GLUCOCORTICOID END-PRODUCTS OF THE HPA AXIS (CORTISOL IN HUMANS) AND COULD BE INVOLVED IN THIS NEUROENDOCRINE-IMMUNE CROSSTALK. HERE WE EXAMINED THE EXTENT TO WHICH VARIATIONS IN HPA AXIS REGULATION ARE ASSOCIATED WITH PERIPHERAL BLOOD DNA (CPG) METHYLATION CHANGES IN 57 CHRONICALLY STRESSED CAREGIVERS AND 67 CONTROL WOMEN. DNA METHYLATION WAS DETERMINED WITH THE ILLUMINA 450K ARRAY FOR A PANEL OF GENES INVOLVED IN HPA AXIS AND IMMUNE FUNCTION. HPA AXIS FEEDBACK WAS ASSESSED WITH THE LOW-DOSE DEXAMETHASONE SUPPRESSION TEST (DST), MEASURING THE EXTENT TO WHICH CORTISOL SECRETION IS SUPPRESSED BY THE SYNTHETIC GLUCOCORTICOID DEXAMETHASONE. AFTER MULTIPLE TESTING CORRECTION IN THE ENTIRE COHORT, HIGHER POST-DST CORTISOL, REFLECTING BLUNTED HPA AXIS NEGATIVE FEEDBACK, BUT NOT BASELINE WAKING CORTISOL, WAS ASSOCIATED WITH LOWER DNA METHYLATION AT EIGHT TNF AND TWO FKBP5 CPG SITES. CAREGIVER GROUP STATUS WAS ASSOCIATED WITH LOWER METHYLATION AT TWO IL6 CPG SITES. SINCE ASSOCIATIONS WERE MOST ROBUST WITH TNF METHYLATION (32% OF THE 450K-COVERED SITES), WE FURTHER EXAMINED FUNCTIONALITY OF THIS EPIGENETIC SIGNATURE IN CULTURED PERIPHERAL BLOOD MONONUCLEAR CELLS IN 33 PARTICIPANTS; INTRIGUINGLY, LOWER TNF METHYLATION RESULTED IN HIGHER EX VIVO TNF MRNA FOLLOWING IMMUNE STIMULATION. TAKEN TOGETHER, OUR FINDINGS LINK CHRONIC STRESS AND HPA AXIS REGULATION WITH EPIGENETIC SIGNATURES AT IMMUNE-RELATED GENES, THEREBY PROVIDING NOVEL INSIGHTS INTO HOW ABERRANT HPA AXIS FUNCTION MAY CONTRIBUTE TO HEIGHTENED INFLAMMATION AND DISEASE RISK.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
11 2472  35 EPIGENETIC TRANSMISSION OF THE IMPACT OF EARLY STRESS ACROSS GENERATIONS. BACKGROUND: TRAUMATIC EXPERIENCES IN EARLY LIFE ARE RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL AND EMOTIONAL DISORDERS. SUCH DISORDERS CAN PERSIST THROUGH ADULTHOOD AND HAVE OFTEN BEEN REPORTED TO BE TRANSMITTED ACROSS GENERATIONS. METHODS: TO INVESTIGATE THE TRANSGENERATIONAL EFFECT OF EARLY STRESS, MICE WERE EXPOSED TO CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION FROM POSTNATAL DAY 1 TO 14. RESULTS: WE SHOW THAT CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION INDUCES DEPRESSIVE-LIKE BEHAVIORS AND ALTERS THE BEHAVIORAL RESPONSE TO AVERSIVE ENVIRONMENTS IN THE SEPARATED ANIMALS WHEN ADULT. MOST OF THE BEHAVIORAL ALTERATIONS ARE FURTHER EXPRESSED BY THE OFFSPRING OF MALES SUBJECTED TO MATERNAL SEPARATION, DESPITE THE FACT THAT THESE MALES ARE REARED NORMALLY. CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION ALSO ALTERS THE PROFILE OF DNA METHYLATION IN THE PROMOTER OF SEVERAL CANDIDATE GENES IN THE GERMLINE OF THE SEPARATED MALES. COMPARABLE CHANGES IN DNA METHYLATION ARE ALSO PRESENT IN THE BRAIN OF THE OFFSPRING AND ARE ASSOCIATED WITH ALTERED GENE EXPRESSION. CONCLUSIONS: THESE FINDINGS HIGHLIGHT THE NEGATIVE IMPACT OF EARLY STRESS ON BEHAVIORAL RESPONSES ACROSS GENERATIONS AND ON THE REGULATION OF DNA METHYLATION IN THE GERMLINE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 4093  32 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13 5199  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  578  38 BEHAVIOR, BDNF AND EPIGENETIC MECHANISMS IN RESPONSE TO SOCIAL ISOLATION AND SOCIAL SUPPORT IN MIDDLE AGED RATS EXPOSED TO CHRONIC STRESS. SOCIAL DEPRIVATION CAN BE STRESSFUL FOR GROUP-LIVING MAMMALS. ON THE OTHER HAND, AN AMAZING RESPONSE OF THESE ANIMALS TO STRESS IS SEEKING SOCIAL CONTACT TO GIVE AND RECEIVE JOINT PROTECTION IN THREATENING SITUATIONS. WE EXPLORED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL SUPPORT ON EPIGENETIC AND BEHAVIORAL RESPONSES TO CHRONIC STRESS. MORE SPECIFICALLY, WE INVESTIGATED THE BEHAVIORAL RESPONSES, CORTICOSTERONE LEVELS, BDNF GENE EXPRESSION, AND MARKERS OF HIPPOCAMPAL EPIGENETIC ALTERATIONS (LEVELS OF H3K9 ACETYLATION AND METHYLATION, H3K27 METHYLATION, HDAC5, DNMT1, AND DNMT3A GENE EXPRESSIONS) IN MIDDLE-AGED ADULT RATS MAINTAINED IN DIFFERENT HOUSING CONDITIONS (ISOLATION OR ACCOMPANIED HOUSING) AND EXPOSED TO THE CHRONIC UNPREDICTABLE STRESS PROTOCOL (CUS). ISOLATION WAS ASSOCIATED WITH DECREASED BASAL LEVELS OF CORTICOSTERONE, IMPAIRED LONG-TERM MEMORY, AND DECREASED EXPRESSION OF THE BDNF GENE, BESIDES ALTERING THE BALANCE OF H3K9 FROM ACETYLATION TO METHYLATION AND INCREASING THE DNMT1 GENE EXPRESSION. THE CUS PROTOCOL DECREASED H3K9 ACETYLATION, BESIDES INCREASING H3K27 METHYLATION AND DNMT1 GENE EXPRESSION, BUT HAD NO SIGNIFICANT EFFECTS ON MEMORY AND BDNF GENE EXPRESSION. INTERESTINGLY, THE EFFECTS OF CUS ON CORTICOSTERONE AND HDAC5 GENE EXPRESSION WERE SEEN ONLY IN ISOLATED ANIMALS, WHEREAS THE EFFECTS OF CUS ON DNMT1 GENE EXPRESSION WERE MORE PRONOUNCED IN ISOLATED THAN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION IN MIDDLE AGE SHOWED BROADER EFFECTS THAN CHRONIC UNPREDICTABLE STRESS ON BEHAVIORAL AND EPIGENETIC ALTERATIONS POTENTIALLY ASSOCIATED WITH DECREASED BDNF EXPRESSION. MOREOVER, SOCIAL SUPPORT PREVENTED THE ADVERSE EFFECTS OF CUS ON HPA AXIS FUNCTIONING, HDAC5, AND DNMT1 GENE EXPRESSIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15 3080  40 GENOME-WIDE METHYLATION IN ALCOHOL USE DISORDER SUBJECTS: IMPLICATIONS FOR AN EPIGENETIC REGULATION OF THE CORTICO-LIMBIC GLUCOCORTICOID RECEPTORS (NR3C1). ENVIRONMENTAL FACTORS, INCLUDING SUBSTANCE ABUSE AND STRESS, CAUSE LONG-LASTING CHANGES IN THE REGULATION OF GENE EXPRESSION IN THE BRAIN VIA EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION. WE EXAMINED GENOME-WIDE DNA METHYLATION PATTERNS IN THE PREFRONTAL CORTEX (PFC, BA10) OF 25 PAIRS OF CONTROL AND INDIVIDUALS WITH ALCOHOL USE DISORDER (AUD), USING THE INFINIUM((R)) METHYLATIONEPIC BEADCHIP. WE IDENTIFIED 5254 DIFFERENTIALLY METHYLATED CPGS (P(NOMINAL) < 0.005). BIOINFORMATIC ANALYSES HIGHLIGHTED BIOLOGICAL PROCESSES CONTAINING GENES RELATED TO STRESS ADAPTATION, INCLUDING THE GLUCOCORTICOID RECEPTOR (ENCODED BY NR3C1). CONSIDERING THAT ALCOHOL IS A STRESSOR, WE FOCUSED OUR ATTENTION ON DIFFERENTIALLY METHYLATED REGIONS OF THE NR3C1 GENE AND VALIDATED THE DIFFERENTIAL METHYLATION OF SEVERAL GENES IN THE NR3C1 NETWORK. CHRONIC ALCOHOL DRINKING RESULTS IN A SIGNIFICANT INCREASED METHYLATION OF THE NR3C1 EXON VARIANT 1(H), WITH A PARTICULAR INCREASE IN THE LEVELS OF 5-HYDROXYMETHYLCYTOSINE OVER 5-METHYLCYTOSINE. THESE CHANGES IN DNA METHYLATION WERE ASSOCIATED WITH REDUCED NR3C1 MRNA AND PROTEIN EXPRESSION LEVELS IN PFC, AS WELL AS OTHER CORTICO-LIMBIC REGIONS OF AUD SUBJECTS WHEN COMPARED WITH CONTROLS. FURTHERMORE, WE SHOW THAT THE EXPRESSION OF SEVERAL STRESS-RESPONSIVE GENES (E.G., CRF, POMC, AND FKBP5) IS ALTERED IN THE PFC OF AUD SUBJECTS. THESE STRESS-RESPONSE GENES WERE ALSO CHANGED IN THE HIPPOCAMPUS, A REGION THAT IS HIGHLY SUSCEPTIBLE TO STRESS. THESE DATA SUGGEST THAT ALCOHOL-DEPENDENT ABERRANT DNA METHYLATION OF NR3C1 AND CONSEQUENT CHANGES IN OTHER STRESS-RELATED GENES MIGHT BE FUNDAMENTAL IN THE PATHOPHYSIOLOGY OF AUD AND LAY THE GROUNDWORK FOR TREATMENTS TARGETING THE EPIGENETIC MECHANISMS REGULATING NR3C1 IN AUD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 3372  40 HISTONE MODIFICATIONS OF THE CRHR1 GENE IN A RAT MODEL OF DEPRESSION FOLLOWING CHRONIC STRESS. MULTIPLE LINES OF EVIDENCE SUGGEST A LINK BETWEEN DEPRESSION AND CHANGES IN HYPOTHALAMIC-PITUITARY-ADRENAL (HPA)-AXIS HORMONE DYNAMICS, INCLUDING ALTERED REGULATION OF THE CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ITS MAIN RECEPTOR, CORTICOTROPHIN-RELEASING HORMONE RECEPTOR 1 (CRHR1). HOWEVER, THE PRECISE MOLECULAR MECHANISMS UNDERLYING DEPRESSION REMAIN POORLY UNDERSTOOD. IN THIS STUDY, WE EMPLOYED A MODEL OF DEPRESSION IN RATS BY SUBJECTING ANIMALS TO 21 DAYS OF CHRONIC UNPREDICTABLE MILD STRESS (CUMS). REAL-TIME PCR AND WESTERN BLOTTING WERE USED TO STUDY THE MRNA AND PROTEIN EXPRESSION LEVELS OF CRHR1 IN THE HYPOTHALAMUS. IN ADDITION, CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE USED TO DETECT HISTONE METHYLATION AT THE CRHR1 GENE PROMOTER; THE LEVELS OF HISTONE H3 TRIMETHYLATION AT LYSINES 4 (H3K4) AND 9 (H3K9) REFLECT ACTIVE TRANSCRIPTION AND TRANSCRIPTIONAL REPRESSION, RESPECTIVELY. RATS EXPOSED TO CUMS EXHIBITED SIGNIFICANT REDUCTION IN LOCOMOTION AND SUCROSE PREFERENCE. THESE BEHAVIORAL ALTERATIONS WERE ASSOCIATED WITH ELEVATED EXPRESSION LEVELS OF CRHR1 MRNA AND PROTEIN IN THE HYPOTHALAMUS OF RATS IN THE CUMS GROUP. WE ALSO FOUND THAT THE LEVELS OF H3K9 TRIMETHYLATION AT THE CRHR1 GENE PROMOTER IN THE CUMS GROUP WERE SIGNIFICANTLY LOWER THAN THOSE IN THE CONTROL GROUP, WHEREAS H3K4 TRIMETHYLATION LEVELS WERE THE SAME FOR BOTH GROUPS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT THE INCREASE IN CRHR1 EXPRESSION IN THE HYPOTHALAMUS OF STRESSED RATS CORRELATES WITH A DECREASE IN THE REPRESSIVE CHROMATIN STATE CAUSED BY REDUCED H3K9 TRIMETHYLATION LEVELS. THESE DATA ARE THE FIRST IN VIVO EVIDENCE OF A ROLE FOR CHROMATIN MODIFICATIONS IN THE REGULATION OF CRHR1 GENE EXPRESSION IN THE HYPOTHALAMUS, AND MAY PROVIDE NOVEL INSIGHT INTO THERAPEUTIC APPROACHES TO TREAT DEPRESSION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 5207  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  887  33 CHRONIC CORTISOL EXPOSURE IN EARLY DEVELOPMENT LEADS TO NEUROENDOCRINE DYSREGULATION IN ADULTHOOD. OBJECTIVE: CHRONIC EARLY LIFE STRESS CAN AFFECT DEVELOPMENT OF THE NEUROENDOCRINE STRESS SYSTEM, LEADING TO ITS PERSISTENT DYSREGULATION AND CONSEQUENTLY INCREASED DISEASE RISK IN ADULTHOOD. ONE CONTRIBUTING FACTOR IS THOUGHT TO BE EPIGENETIC PROGRAMMING IN RESPONSE TO CHRONIC CORTISOL EXPOSURE DURING EARLY DEVELOPMENT. WE HAVE PREVIOUSLY SHOWN THAT ZEBRAFISH EMBRYOS TREATED CHRONICALLY WITH CORTISOL DEVELOP INTO ADULTS WITH CONSTITUTIVELY ELEVATED WHOLE-BODY CORTISOL AND ABERRANT IMMUNE GENE EXPRESSION. HERE WE FURTHER CHARACTERIZE THAT PHENOTYPE BY ASSESSING PERSISTENT EFFECTS OF THE TREATMENT ON CORTISOL TISSUE DISTRIBUTION AND DYNAMICS, CHROMATIN ACCESSIBILITY, AND ACTIVITIES OF GLUCOCORTICOID-RESPONSIVE REGULATORY GENES KLF9 AND FKBP5. TO THAT END CORTISOL LEVELS IN DIFFERENT TISSUES OF FED AND FASTED ADULTS WERE MEASURED USING ELISA, OPEN CHROMATIN IN ADULT BLOOD CELLS WAS MAPPED USING ATAC-SEQ, AND GENE ACTIVITY IN ADULT BLOOD AND BRAIN CELLS WAS MEASURED USING QRT-PCR. RESULTS: ADULTS DERIVED FROM CORTISOL-TREATED EMBRYOS HAVE ELEVATED WHOLE-BODY CORTISOL WITH ABERRANTLY REGULATED TISSUE DISTRIBUTION AND DYNAMICS THAT CORRELATE WITH DIFFERENTIAL ACTIVITY OF KLF9 AND FKBP5 IN BLOOD AND BRAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
19 1752  40 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	

20  586  38 BEHAVIOURAL AND EPIGENETIC EFFECTS OF PATERNAL EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ON OFFSPRING VULNERABILITY TO STRESS. CHRONIC CANNABINOID EXPOSURE DURING ADOLESCENCE IN MALE RATS INDUCES CHRONIC COGNITIVE AND EMOTIONAL IMPAIRMENTS. HOWEVER, THE IMPACT OF THIS FORM OF EXPOSURE ON OFFSPRING VULNERABILITY TO STRESS IS UNKNOWN. THE AIM OF THIS STUDY WAS TO EVALUATE THE BEHAVIOURAL AND EPIGENETIC EFFECTS OF STRESS IN THE OFFSPRING OF MALE RATS WHOSE FATHERS WERE EXPOSED TO CANNABINOIDS DURING ADOLESCENCE. MALE ADOLESCENT OFFSPRING OF WIN55,212-2 (1.2 MG/KG) TREATED RATS WERE EXPOSED DURING ONE WEEK TO VARIABLE STRESSORS AND SUBJECTED TO BEHAVIOURAL TESTS OF ANXIETY AND EPISODIC-LIKE MEMORY, FOLLOWED BY AN ASSESSMENT OF GLOBAL DNA METHYLATION AND EXPRESSION OF DNA METHYLTRANSFERASES ENZYMES DNMT1 AND DNMT3A MRNA IN THE PREFRONTAL CORTEX. STRESS EXPOSURE INDUCED A SIGNIFICANT ANXIOGENIC-LIKE EFFECT BUT DID NOT AFFECT THE EPISODIC-LIKE MEMORY IN THE OFFSPRING OF WIN55,212-2 EXPOSED FATHERS IN COMPARISON TO THE OFFSPRING OF NON-EXPOSED FATHERS. THESE BEHAVIOURAL CHANGES WERE SUBSEQUENT TO A SIGNIFICANT INCREASE IN GLOBAL DNA METHYLATION AND DNMT1 AND DNMTA3 TRANSCRIPTION IN THE PREFRONTAL CORTEX. THESE DATA SUGGEST THAT THE DELETERIOUS EFFECT OF CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ARE NOT LIMITED TO THE EXPOSED INDIVIDUALS BUT MAY INCREASE THE VULNERABILITY TO STRESS-INDUCED ANXIETY IN THE OFFSPRING AND ALTER THEIR EPIGENETIC PROGRAMMING.	2019