1 579 163 BEHAVIORAL AND MOLECULAR NEUROEPIGENETIC ALTERATIONS IN PRENATALLY STRESSED MICE: RELEVANCE FOR THE STUDY OF CHROMATIN REMODELING PROPERTIES OF ANTIPSYCHOTIC DRUGS. WE HAVE RECENTLY REPORTED THAT MICE BORN FROM DAMS STRESSED DURING PREGNANCY (PRS MICE), IN ADULTHOOD, HAVE BEHAVIORAL DEFICITS REMINISCENT OF BEHAVIORS OBSERVED IN SCHIZOPHRENIA (SZ) AND BIPOLAR (BP) DISORDER PATIENTS. FURTHERMORE, WE HAVE SHOWN THAT THE FRONTAL CORTEX (FC) AND HIPPOCAMPUS OF ADULT PRS MICE, LIKE THAT OF POSTMORTEM CHRONIC SZ PATIENTS, ARE CHARACTERIZED BY INCREASES IN DNA-METHYLTRANSFERASE 1 (DNMT1), TEN-ELEVEN METHYLCYTOSINE DIOXYGENASE 1 (TET1) AND EXHIBIT AN ENRICHMENT OF 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) AT NEOCORTICAL GABAERGIC AND GLUTAMATERGIC GENE PROMOTERS. HERE, WE SHOW THAT THE BEHAVIORAL DEFICITS AND THE INCREASED 5MC AND 5HMC AT GLUTAMIC ACID DECARBOXYLASE 67 (GAD1), REELIN (RELN) AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROMOTERS AND THE REDUCED EXPRESSION OF THE MESSENGER RNAS (MRNAS) AND PROTEINS CORRESPONDING TO THESE GENES IN FC OF ADULT PRS MICE IS REVERSED BY TREATMENT WITH CLOZAPINE (5 MG KG(-1) TWICE A DAY FOR 5 DAYS) BUT NOT BY HALOPERIDOL (1 MG KG(-1) TWICE A DAY FOR 5 DAYS). INTERESTINGLY, CLOZAPINE HAD NO EFFECT ON EITHER THE BEHAVIOR, PROMOTER METHYLATION OR THE EXPRESSION OF THESE MRNAS AND PROTEINS WHEN ADMINISTERED TO OFFSPRING OF NONSTRESSED PREGNANT MICE. CLOZAPINE, BUT NOT HALOPERIDOL, REDUCED THE ELEVATED LEVELS OF DNMT1 AND TET1, AS WELL AS THE ELEVATED LEVELS OF DNMT1 BINDING TO GAD1, RELN AND BDNF PROMOTERS IN PRS MICE SUGGESTING THAT CLOZAPINE, UNLIKE HALOPERIDOL, MAY LIMIT DNA METHYLATION BY INTERFERING WITH DNA METHYLATION DYNAMICS. WE CONCLUDE THAT THE PRS MOUSE MODEL MAY BE USEFUL PRECLINICALLY IN SCREENING FOR THE POTENTIAL EFFICACY OF ANTIPSYCHOTIC DRUGS ACTING ON ALTERED EPIGENETIC MECHANISMS. FURTHERMORE, PRS MICE MAY BE INVALUABLE FOR UNDERSTANDING THE ETIOPATHOGENESIS OF SZ AND BP DISORDER AND FOR PREDICTING TREATMENT RESPONSES AT EARLY STAGES OF THE ILLNESS ALLOWING FOR EARLY DETECTION AND REMEDIAL INTERVENTION. 2016 2 4390 62 MODELING THE MOLECULAR EPIGENETIC PROFILE OF PSYCHOSIS IN PRENATALLY STRESSED MICE. BASED ON POSTMORTEM BRAIN STUDIES, OUR OVERARCHING EPIGENETIC HYPOTHESIS IS THAT CHRONIC SCHIZOPHRENIA (SZ) IS A PSYCHOPATHOLOGICAL CONDITION INVOLVING DYSREGULATION OF THE DYNAMIC EQUILIBRIUM AMONG DNA METHYLATION/DEMETHYLATION NETWORK COMPONENTS AND THE EXPRESSION OF SZ TARGET GENES, INCLUDING GABAERGIC AND GLUTAMATERGIC GENES. SZ HAS A NATURAL COURSE, STARTING WITH A PRODROMAL PHASE, A FIRST EPISODE THAT OCCURS IN ADOLESCENTS OR IN YOUNG ADULTS, AND LATER DETERIORATION OVER THE ADULT YEARS. HENCE, THE EPIGENETIC STATUS AT EACH NEURODEVELOPMENTAL STAGE OF THE DISEASE CANNOT BE STUDIED JUST IN POSTMORTEM BRAIN OF CHRONIC SZ PATIENTS, BUT REQUIRES THE USE OF NEURODEVELOPMENTAL ANIMAL MODELS. WE HAVE DIRECTED THE FOCUS OF OUR RESEARCH TOWARD STUDYING THE EPIGENETIC SIGNATURE OF THE SZ BRAIN IN THE OFFSPRING OF DAMS STRESSED DURING PREGNANCY (PRS MICE). ADULT PRS MICE HAVE BEHAVIORAL DEFICITS REMINISCENT OF BEHAVIORS OBSERVED IN PSYCHOTIC PATIENTS. THE ADULT PRS BRAIN, LIKE THAT OF POSTMORTEM CHRONIC SZ PATIENTS, IS CHARACTERIZED BY A SIGNIFICANT INCREASE IN DNA METHYLTRANSFERASE 1, TET METHYLCYTOSINE DIOXYGENASE 1 (TET1), 5-METHYLCYTOSINE, AND 5-HYDROXYMETHYLCYTOSINE AT SZ CANDIDATE GENE PROMOTERS AND A REDUCTION IN THE EXPRESSION OF GLUTAMATERGIC AND GABAERGIC GENES. IN PRS MICE, MEASUREMENTS OF EPIGENETIC BIOMARKERS FOR SZ CAN BE ASSESSED AT DIFFERENT STAGES OF DEVELOPMENT WITH THE GOAL OF FURTHER ELUCIDATING THE PATHOPHYSIOLOGY OF THIS DISEASE AND PREDICTING TREATMENT RESPONSES AT SPECIFIC STAGES OF THE ILLNESS, WITH PARTICULAR ATTENTION TO EARLY DETECTION AND POSSIBLY EARLY INTERVENTION. 2014 3 1809 45 EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR GENE EXPRESSION IN THE HIPPOCAMPI OF CHRONIC RESTRAINT STRESS RATS. RECENT STUDIES HAVE SHOWN THAT ANTIPSYCHOTIC DRUGS HAVE EPIGENETIC EFFECTS. HOWEVER, THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON HISTONE MODIFICATION REMAIN UNCLEAR. THEREFORE, WE INVESTIGATED THE EFFECTS OF ANTIPSYCHOTIC DRUGS ON THE EPIGENETIC MODIFICATION OF THE BDNF GENE IN THE RAT HIPPOCAMPUS. RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS (6 H/D FOR 21 D) AND THEN WERE ADMINISTERED WITH EITHER OLANZAPINE (2 MG/KG) OR HALOPERIDOL (1 MG/KG). THE LEVELS OF HISTONE H3 ACETYLATION AND MECP2 BINDING AT BDNF PROMOTER IV WERE ASSESSED WITH CHROMATIN IMMUNOPRECIPITATION ASSAYS. THE MRNA LEVELS OF TOTAL BDNF WITH EXON IV, HDAC5, DNMT1, AND DNMT3A WERE ASSESSED WITH A QUANTITATIVE RT-PCR PROCEDURE. CHRONIC RESTRAINT STRESS RESULTED IN THE DOWNREGULATION OF TOTAL AND EXON IV BDNF MRNA LEVELS AND A DECREASE IN HISTONE H3 ACETYLATION AND AN INCREASE IN MECP2 BINDING AT BDNF PROMOTER IV. FURTHERMORE, THERE WERE ROBUST INCREASES IN THE EXPRESSION OF HDAC5 AND DNMTS. OLANZAPINE ADMINISTRATION LARGELY PREVENTED THESE CHANGES. THE ADMINISTRATION OF HALOPERIDOL HAD NO EFFECT. THESE FINDINGS SUGGEST THAT THE ANTIPSYCHOTIC DRUG OLANZAPINE INDUCED HISTONE MODIFICATION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS AND THAT THESE EPIGENETIC ALTERATIONS MAY REPRESENT ONE OF THE MECHANISMS UNDERLYING THE ACTIONS OF ANTIPSYCHOTIC DRUGS. 2018 4 2740 28 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 5 5974 36 TET1 IN NUCLEUS ACCUMBENS OPPOSES DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. DEPRESSION IS A LEADING CAUSE OF DISEASE BURDEN, YET CURRENT THERAPIES FULLY TREAT <50% OF AFFECTED INDIVIDUALS. INCREASING EVIDENCE IMPLICATES EPIGENETIC MECHANISMS IN DEPRESSION AND ANTIDEPRESSANT ACTION. HERE WE EXAMINED A POSSIBLE ROLE FOR THE DNA DIOXYGENASE, TEN-ELEVEN TRANSLOCATION PROTEIN 1 (TET1), IN DEPRESSION-RELATED BEHAVIORAL ABNORMALITIES. WE APPLIED CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MOUSE MODEL OF DEPRESSION-LIKE BEHAVIORS, AND EXAMINED TET1 EXPRESSION CHANGES IN NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW DECREASED TET1 EXPRESSION IN NAC IN STRESS-SUSCEPTIBLE MICE ONLY. SURPRISINGLY, SELECTIVE KNOCKOUT OF TET1 IN NAC NEURONS OF ADULT MICE PRODUCED ANTIDEPRESSANT-LIKE EFFECTS IN SEVERAL BEHAVIORAL ASSAYS. TO IDENTIFY TET1 TARGETS THAT MEDIATE THESE ACTIONS, WE PERFORMED RNASEQ ON NAC AFTER CONDITIONAL DELETION OF TET1 AND FOUND THAT IMMUNE-RELATED GENES ARE THE MOST HIGHLY DYSREGULATED. MOREOVER, MANY OF THESE GENES ARE ALSO UPREGULATED IN THE NAC OF RESILIENT MICE AFTER CHRONIC SOCIAL DEFEAT STRESS. THESE FINDINGS REVEAL A NOVEL ROLE FOR TET1, AN ENZYME IMPORTANT FOR DNA HYDROXYMETHYLATION, IN THE BRAIN'S REWARD CIRCUITRY IN MODULATING STRESS RESPONSES IN MICE. WE ALSO IDENTIFY A SUBSET OF GENES THAT ARE REGULATED BY TET1 IN THIS CIRCUITRY. THESE FINDINGS PROVIDE NEW INSIGHT INTO THE PATHOPHYSIOLOGY OF DEPRESSION, WHICH CAN AID IN FUTURE ANTIDEPRESSANT DRUG DISCOVERY EFFORTS. 2017 6 1810 33 EFFECTS OF ANTIPSYCHOTICS ON THE BDNF IN SCHIZOPHRENIA. BRAIN-DERIVED NEUROTROPIC FACTOR (BDNF) IS INVOLVED IN THE DEVELOPMENT OF THE BRAIN, AND LIKELY INFLUENCES THE NEUROPLASTICITY IN SCHIZOPHRENIA. BDNF IS ALSO BELIEVED TO INTERACT WITH OTHER NEUROTRANSMITTER SYSTEMS IMPLICATED IN SCHIZOPHRENIA, SUCH AS DOPAMINE, GLUTAMATE, SEROTONIN AND GABA. THEREFORE, BDNF IS A CANDIDATE GENE FOR SCHIZOPHRENIA. IN PAST DECADES, THE BLOOD (SERUM OR PLASMA) BDNF PROTEIN LEVELS AND BDNF GENE ALLELES AND GENOTYPES TO THE CLINICAL FEATURES OF SCHIZOPHRENIA, SUCH AS AGE OF ONSET, CLINICAL SUBTYPES, SYMPTOM SEVERITY, AND DRUG RESPONSE, HAVE BEEN EVALUATED AMONG DIFFERENT POPULATIONS. HOWEVER, THE RESULTS ARE STILL INCONSISTENT. FURTHER, DIFFERENT DRUGS HAVE BEEN REPORTED TO HAVE DIFFERENT EFFECTS ON BDNF PROTEIN LEVELS. A CROSS-SECTIONAL SURVEY REVEALED THAT SERUM BDNF LEVELS IN CHRONIC SCHIZOPHRENIC PATIENTS TREATED WITH CLOZAPINE EXCEEDED THOSE OF PATIENTS TREATED WITH RISPERIDONE OR WITH TYPICAL ANTIPSYCHOTICS. IN RECENT TIMES, BDNF EPIGENETIC STUDIES HAVE ALSO BEEN CONDUCTED IN CLINICAL STUDIES OF SCHIZOPHRENIA TO ADDRESS THE QUESTION OF WHY PATIENTS WITH THE SAME GENE GENOTYPE AND ALLELES HAVE DIFFERENT CLINICAL PRESENTATIONS. IN ADDITION, THE EFFECTS OF DIFFERENT ANTIPSYCHOTIC DRUGS ON GENE METHYLATION AND PROTEIN ACETYLATION HAVE ALSO BEEN REPORTED. IN CONCLUSION, MORE DATA ARE NEEDED REGARDING BDNF IN THE BRAIN AND IN PERIPHERAL BLOOD, INCLUDING PROTEIN LEVELS, SINGLE NUCLEOTIDE POLYMORPHISMS, EPIGENETIC REGULATION, AND CLINICAL DATA IN ORDER TO UNDERSTAND THE ROLE OF BDNF IN SCHIZOPHRENIA. 2013 7 434 49 ANTIDEPRESSANT-LIKE EFFECT OF SODIUM BUTYRATE IS ASSOCIATED WITH AN INCREASE IN TET1 AND IN 5-HYDROXYMETHYLATION LEVELS IN THE BDNF GENE. BACKGROUND: EPIGENETIC DRUGS LIKE SODIUM BUTYRATE (NAB) SHOW ANTIDEPRESSANT-LIKE EFFECTS IN PRECLINICAL STUDIES, BUT THE EXACT MOLECULAR MECHANISMS OF THE ANTIDEPRESSANT EFFECTS REMAIN UNKNOWN. WHILE RESEARCH USING NAB HAS MAINLY FOCUSED ON ITS ROLE AS A HISTONE DEACETYLASE INHIBITOR (HDACI), THERE IS ALSO EVIDENCE THAT NAB AFFECTS DNA METHYLATION. METHODS: THE PURPOSE OF THIS STUDY WAS TO EXAMINE NAB'S PUTATIVE ANTIDEPRESSANT-LIKE EFFICACY IN RELATION TO DNA METHYLATION CHANGES IN THE PREFRONTAL CORTEX OF AN ESTABLISHED GENETIC RAT MODEL OF DEPRESSION (THE FLINDERS SENSITIVE LINE [FSL]) AND ITS CONTROLS (THE FLINDERS RESISTANT LINE). RESULTS: THE FSL RATS HAD LOWER LEVELS OF TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1), WHICH CATALYZES THE CONVERSION OF DNA METHYLATION TO HYDROXYMETHYLATION. AS INDICATED BY THE BEHAVIORAL DESPAIR TEST, CHRONIC ADMINISTRATION OF NAB HAD ANTIDEPRESSANT-LIKE EFFECTS IN THE FSL AND WAS ACCOMPANIED BY INCREASED LEVELS OF TET1. THE TET1 UPREGULATION WAS ALSO ASSOCIATED WITH AN INCREASE OF HYDROXYMETHYLATION AND A DECREASE OF METHYLATION IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), A GENE ASSOCIATED WITH NEUROGENESIS AND SYNAPTIC PLASTICITY. THESE EPIGENETIC CHANGES WERE ASSOCIATED WITH A CORRESPONDING BDNF OVEREXPRESSION. CONCLUSIONS: OUR DATA SUPPORT THE ANTIDEPRESSANT EFFICACY OF HDACIS AND SUGGEST THAT THEIR EPIGENETIC EFFECTS MAY ALSO INCLUDE DNA METHYLATION CHANGES THAT ARE MEDIATED BY DEMETHYLATION-FACILITATING ENZYMES LIKE TET1. 2014 8 4401 43 MODULATION OF NEURONAL PLASTICITY FOLLOWING CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE WITH THE MOOD STABILIZER VALPROIC ACID. RATIONALE: COMBINATORY THERAPY IS WIDELY USED IN PSYCHIATRY OWING TO THE POSSIBILITY THAT DRUGS WITH DIFFERENT MECHANISMS OF ACTION MAY SYNERGIZE TO IMPROVE FUNCTIONS DETERIORATED IN SCHIZOPHRENIA, BIPOLAR DISORDERS, AND MAJOR DEPRESSION. WHILE COMBINATORY STRATEGIES RELY ON RECEPTOR AND SYNAPTIC MECHANISMS, IT SHOULD ALSO BE CONSIDERED THAT TWO DRUGS MAY ALSO "INTERACT" ON THE LONG-TERM TO DETERMINE MORE ROBUST CHANGES IN NEURONAL PLASTICITY, WHICH REPRESENTS A DOWNSTREAM TARGET IMPORTANT FOR FUNCTIONAL RECOVERY. OBJECTIVE: THE AIM OF THE STUDY IS TO INVESTIGATE NEUROADAPTIVE CHANGES SET IN MOTION BY CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE AND THE MOOD STABILIZER VALPROATE. METHODS: ANIMALS WERE CHRONICALLY TREATED WITH LURASIDONE, VALPROATE, OR THE COMBINATION OF THE TWO DRUGS AND KILLED 24 H AFTER THE LAST INJECTION TO EVALUATE ALTERATIONS OF DIFFERENT MEASURES OF NEURONAL PLASTICITY SUCH AS THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), THE IMMEDIATE EARLY GENE ACTIVITY-REGULATED CYTOSKELETAL ASSOCIATED PROTEIN, AND THE EPIGENETIC REGULATORS HDAC 1, 2, AND 5 IN DORSAL AND VENTRAL HIPPOCAMPUS. RESULTS: THE RESULTS SUGGEST THAT COADMINISTRATION OF LURASIDONE AND VALPROATE PRODUCES, WHEN COMPARED TO THE SINGLE DRUGS, A LARGER INCREASE IN THE EXPRESSION OF BDNF IN THE VENTRAL HIPPOCAMPUS, THROUGH THE REGULATION OF SPECIFIC NEUROTROPHIN TRANSCRIPTS. WE ALSO FOUND THAT THE HISTONE DEACETYLASES WERE REGULATED BY THE DRUG COMBINATION, SUGGESTING THAT SOME OF THE TRANSCRIPTIONAL CHANGES MAY BE SUSTAINED BY EPIGENETIC MECHANISMS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE BENEFICIAL EFFECTS ASSOCIATED WITH COMBINATORY TREATMENT BETWEEN A SECOND-GENERATION ANTIPSYCHOTIC AND A MOOD STABILIZER COULD RESULT FROM THE ABILITY TO MODULATE NEUROPLASTIC MOLECULES, WHOSE EXPRESSION AND FUNCTION IS DETERIORATED IN DIFFERENT PSYCHIATRIC CONDITIONS. 2013 9 1538 48 DNA METHYLATION IN ANIMAL MODELS OF PSYCHOSIS. SCHIZOPHRENIA (SZ) IS A DEBILITATING DISEASE THAT IMPACTS 1% OF THE POPULATION WORLDWIDE. ASSOCIATION STUDIES HAVE SHOWN THAT INHERITED GENETIC MUTATIONS ACCOUNT FOR A PORTION OF DISEASE RISK. HOWEVER, ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF THE DISEASE BY ALTERING CELLULAR EPIGENETIC MARKS AT THE LEVEL OF CHROMATIN. POSTMORTEM BRAIN STUDIES OF SZ SUBJECTS SUGGEST THAT THE DYNAMIC EQUILIBRIUM BETWEEN DNA METHYLATION AND DEMETHYLATION NETWORK COMPONENTS IS DISRUPTED AT THE LEVEL OF INDIVIDUAL SZ TARGET GENES. HEREIN, WE REVIEW THE ROLE OF DNA METHYLATION AND DEMETHYLATION IN THE CONTEXT OF WHAT IS CURRENTLY KNOWN REGARDING SZ. FURTHERMORE, WE DESCRIBE THE DEFICITS THAT ACCOMPANY TWO MOUSE MODELS OF SZ. THE CHRONIC METHIONINE MOUSE MODEL OF SZ IS PREDICATED ON THE ADMINISTRATION OF METHIONINE TO SZ PATIENTS AND CONTROLS IN THE CONTEXT OF CLINICAL STUDIES THAT WERE CARRIED OUT DURING THE 1960S AND 1970S. THE PRENATAL RESTRAINT STRESS MODEL OF SZ IS BASED ON A PROLONGED STRESS PARADIGM ADMINISTERED TO PREGNANT DAMS DURING GESTATION DAYS 7-21. THE ADULT OFFSPRING OF THESE DAMS SHOW VARIOUS BEHAVIORAL AND BIOCHEMICAL DEFICITS IN ADULTHOOD. BOTH MODELS ARE EPIGENETIC IN ORIGIN AND MIMIC THE POSITIVE AND NEGATIVE SYMPTOMS, AS WELL AS THE COGNITIVE ENDOPHENOTYPES COMMONLY OBSERVED IN SZ PATIENTS. WE ALSO DISCUSS THE UTILITY OF TYPICAL AND ATYPICAL ANTIPSYCHOTIC DRUGS IN ALLEVIATING THESE SYMPTOMS IN EACH MODEL. 2018 10 431 42 ANTIDEPRESSANT ADMINISTRATION MODULATES STRESS-INDUCED DNA METHYLATION AND DNA METHYLTRANSFERASE EXPRESSION IN RAT PREFRONTAL CORTEX AND HIPPOCAMPUS. STRESS AND ANTIDEPRESSANT TREATMENT CAN MODULATE DNA METHYLATION IN PROMOTER REGION OF GENES RELATED TO NEUROPLASTICITY AND MOOD REGULATION, THUS IMPLICATING THIS EPIGENETIC MECHANISM IN DEPRESSION NEUROBIOLOGY AND TREATMENT. ACCORDINGLY, SYSTEMIC ADMINISTRATION OF DNA METHYLTRANSFERASE (DNMT) INHIBITORS INDUCES ANTIDEPRESSANT-LIKE EFFECTS IN RODENTS. DNA METHYLATION IS CONVEYED BY DNMT 1, 3A AND 3B ISOFORMS, WHICH ARE DIFFERENTIALLY EXPRESSED IN THE BRAIN. IN ORDER TO INVESTIGATE IF THE BEHAVIORAL EFFECTS OF ANTIDEPRESSANTS COULD BE ASSOCIATED WITH CHANGES IN DNA METHYLATION AND DNMT EXPRESSION, WE INVESTIGATED THE EFFECTS INDUCED BY ACUTE AND REPEATED ANTIDEPRESSANT TREATMENT ON DNA METHYLATION AND DNMT EXPRESSION (1, 3A AND 3B ISOFORMS) IN DIFFERENT BRAIN REGIONS OF RATS EXPOSED TO A STRESS MODEL OF DEPRESSION, THE LEARNED HELPLESSNESS (LH). THEREFORE, RATS WERE EXPOSED TO PRETEST AND TREATED WITH ONE OR SEVEN INJECTIONS OF VEHICLE OR IMIPRAMINE (15 MG KG(-1)), WITH TEST SESSION PERFORMED ONE HOUR AFTER THE LAST INJECTION. CHRONIC, BUT NOT ACUTE, IMIPRAMINE ADMINISTRATION ATTENUATED ESCAPE FAILURES DURING THE TEST, A WELL DESCRIBED ANTIDEPRESSANT-LIKE EFFECT IN THIS MODEL. DNA METHYLATION AND DNMT (1, 3A AND 3B) LEVELS WERE MEASURED IN THE DORSAL AND VENTRAL HIPPOCAMPUS (DHPC, VHPC) AND IN THE PREFRONTAL CORTEX (PFC) OF RATS EXPOSED TO STRESS AND TREATMENT. STRESS INCREASED DNA METHYLATION, DNMT3A AND DNMT3B EXPRESSION IN THE DHPC AND PFC. CHRONIC, BUT NOT ACUTE, IMIPRAMINE ADMINISTRATION ATTENUATED STRESS EFFECTS ONLY IN THE PFC. THESE RESULTS SUGGEST THE REGULATION OF DNA METHYLATION IN THE PFC MAY BE AN IMPORTANT MECHANISM FOR ANTIDEPRESSANT-LIKE EFFECTS IN THE LH MODEL. 2018 11 5019 43 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 12 1614 34 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES. 2021 13 1813 45 EFFECTS OF CAFFEIC ACID ON EPIGENETICS IN THE BRAIN OF RATS WITH CHRONIC UNPREDICTABLE MILD STRESS. THE PRESENT STUDY HYPOTHESIZED THAT CAFFEIC ACID (3,4?DIHYDROXYCINNAMIC ACID; CAA) MAY EXERT ANTIDEPRESSANT?LIKE EFFECTS IN RATS WITH CHRONIC UNPREDICTABLE MILD STRESS VIA EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION AND HYDROXYMETHYLATION. THE CHRONIC UNPREDICTABLE MILD STRESS (CUMS) MODEL WAS USED TO ANALYZE THE EFFECTS OF CAA ON BEHAVIORAL PHENOTYPES, AND TO EVALUATE THE DISTRIBUTION OF 5?METHYLCYTOSINE (5MC) AND 5?HYDROXYMETHYLCYTOSINE (5HMC) IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX USING IMMUNOHISTOCHEMISTRY AND IMMUNOFLUORESCENCE. MRNA LEVELS OF THE GENES ENCODING BRAIN?DERIVED NEUROTROPIC FACTOR (BDNF) AND CATECHOL?O?METHYLTRANSFERASE (COMT), AND KEY ENZYMES REGULATING DNA METHYLATION [DNA METHYLTRANSFERASE (DNMT)1 AND DNMT3A] AND HYDROXYMETHYLATION [TEN?ELEVEN TRANSLOCATION (TET)1?3] WERE EXAMINED USING QUANTITATIVE (Q)PCR. FURTHERMORE, ENRICHMENT OF 5MC AND 5HMC AT THE PROMOTOR REGIONS OF THE BDNF AND COMT GENES WAS QUANTIFIED USING CHROMATIN IMMUNOPRECIPITATION?QPCR. BEHAVIORAL DATA SHOWED THAT CAA EXERTED A SLIGHT ANTIDEPRESSANT?LIKE EFFECT. BDNF AND COMT GENES SHOWED DIFFERENTIAL EXPRESSION PATTERNS DUE TO CUMS. CAA INTERVENTION INDUCED DIFFERENT DNMT1/DNMT3A AND TET1/TET2 MRNA LEVELS IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX, RESPECTIVELY. CAA REGULATED THE RATIO OF 5MC/5HMC AT THE PROMOTOR REGION OF THE BDNF AND COMT GENES AND THEREFORE INFLUENCED GENE EXPRESSION, WHICH MAY BE A VALUABLE THERAPEUTIC OPTION FOR MAJOR DEPRESSIVE DISORDER (MDD). IN CONCLUSION, THERE WERE EPIGENETIC CHANGES IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX IN CUMS RATS, AND CAA MAY FUNCTION AS A MODULATOR OF DNA METHYLATION TO REGULATE GENE TRANSCRIPTION, THUS PROVIDING A MECHANISTIC BASIS FOR THE USE OF THIS PHYTOCHEMICAL AGENT IN THE TREATMENT OF MDD. 2020 14 4628 35 NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX OF TYPE 2 DIABETIC MICE THROUGH DNA HYPERMETHYLATION. BACKGROUND: DNA METHYLATION CHANGES HAVE KNOWN TO DOWNREGULATE SEVERAL REGULATORY PROTEINS EPIGENETICALLY DURING VARIOUS NEURODEGENERATIVE DISORDERS. OUR STUDY AIMS TO UNDERSTAND THE EFFECT OF THIS GLOBAL DNA METHYLATION ON THE CEREBRAL COMPLICATIONS OF TYPE 2 DIABETES MICE, AND ITS NOTABLE EFFECT ON MAINTAINING THE SYNAPTIC FIDELITY. METHODS AND RESULTS: CHRONIC HIGH FAT DIET AND STREPTOZOTOCIN-INDUCED DIABETIC MICE WERE STUDIED FOR THE NEUROBEHAVIORAL AND NEUROANATOMIC PARAMETERS PERTAINING TO PREFRONTAL CORTEX, SUBSEQUENTLY ELUCIDATING THE ASSOCIATED CHANGES IN DNA METHYLATION WITHIN THESE DIABETIC BRAINS. FURTHER, THE IMPACT OF THIS EPIGENETIC DYSREGULATION ON HSF1, BDNF AND PSD95 WERE STUDIED BY ASSESSING THE BINDING AFFINITY AND LEVEL OF % METHYLATION WITHIN THE PROMOTER SITE OF THEIR RESPECTIVE GENES. OUR STUDY SUGGEST INCREASED DNMT ABERRATIONS WITHIN THE PREFRONTAL CORTEX, WITH INCREASED MECP2 LEVELS, CONFIRMING DNA HYPERMETHYLATION. THIS WAS IN ACCORDANCE WITH THE ALTERED NEUROBEHAVIORAL CHANGES. FURTHER, THE HYPERMETHYLATION WAS FOUND TO PARTICIPATE IN GENE SILENCING OF HSF1, BDNF AND PSD95 PROTEINS, RESPONSIBLE FOR MAINTAINING THE SYNAPTIC FIDELITY. CONCLUSION: OVERALL, OUR STUDY CONCLUDES THE PLAUSIBLE INVOLVEMENT OF NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX (PFC) OF THE TYPE 2 DIABETES MICE, SPECIFICALLY DNA HYPERMETHYLATION. PFC PLAYS A CENTRAL ROLE IN MODULATING COGNITIVE AND OTHER EXECUTIVE FUNCTIONS THROUGH ITS CONNECTION WITH SEVERAL BRAIN REGIONS, AND THUS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC MODULATIONS IN IT, CAN PAVE A WAY IN CONTROLLING SEVERAL NEUROLOGICAL ALTERATIONS IN THE BRAIN. 2022 15 4828 38 OLANZAPINE INDUCED DNA METHYLATION CHANGES SUPPORT THE DOPAMINE HYPOTHESIS OF PSYCHOSIS. BACKGROUND: THE DOPAMINE (DA) HYPOTHESIS OF SCHIZOPHRENIA PROPOSES THE MENTAL ILLNESS IS CAUSED BY EXCESSIVE TRANSMISSION OF DOPAMINE IN SELECTED BRAIN REGIONS. MULTIPLE LINES OF EVIDENCE, INCLUDING BLOCKAGE OF DOPAMINE RECEPTORS BY ANTIPSYCHOTIC DRUGS THAT ARE USED TO TREAT SCHIZOPHRENIA, SUPPORT THE HYPOTHESIS. HOWEVER, THE DOPAMINE D2 RECEPTOR (DRD2) BLOCKADE CANNOT EXPLAIN SOME IMPORTANT ASPECTS OF THE THERAPEUTIC EFFECT OF ANTIPSYCHOTIC DRUGS. IN THIS STUDY, WE HYPOTHESIZED THAT ANTIPSYCHOTIC DRUGS COULD AFFECT THE TRANSCRIPTION OF GENES IN THE DA PATHWAY BY ALTERING THEIR EPIGENETIC PROFILE. METHODS: TO TEST THIS HYPOTHESIS, WE EXAMINED THE EFFECT OF OLANZAPINE, A COMMONLY USED ATYPICAL ANTIPSYCHOTIC DRUG, ON THE DNA METHYLATION STATUS OF GENES FROM DA NEUROTRANSMISSION IN THE BRAIN AND LIVER OF RATS. GENOMIC DNA ISOLATED FROM HIPPOCAMPUS, CEREBELLUM, AND LIVER OF OLANZAPINE TREATED (N = 2) AND CONTROL (N = 2) RATS WERE ANALYZED USING RAT SPECIFIC METHYLATION ARRAYS. RESULTS: OUR RESULTS SHOW THAT OLANZAPINE CAUSES METHYLATION CHANGES IN GENES ENCODING FOR DA RECEPTORS (DOPAMINE D1 RECEPTOR, DOPAMINE D2 RECEPTOR AND DOPAMINE D5 RECEPTOR), A DA TRANSPORTER (SOLUTE CARRIER FAMILY 18 MEMBER 2), A DA SYNTHESIS (DIFFERENTIAL DISPLAY CLONE 8), AND A DA METABOLISM (CATECHOL-O-METHYLTRANSFERASE). WE ASSESSED A TOTAL OF 40 GENES IN THE DA PATHWAY AND FOUND 19 TO BE DIFFERENTIALLY METHYLATED BETWEEN OLANZAPINE TREATED AND CONTROL RATS. MOST (17/19) GENES SHOWED AN INCREASE IN METHYLATION, IN THEIR PROMOTER REGIONS WITH IN SILICO ANALYSIS STRONGLY INDICATING A FUNCTIONAL POTENTIAL TO SUPPRESS TRANSCRIPTION IN THE BRAIN. CONCLUSION: OUR RESULTS SUGGEST THAT CHRONIC OLANZAPINE MAY REDUCE DA ACTIVITY BY ALTERING GENE METHYLATION. IT MAY ALSO EXPLAIN THE DELAYED THERAPEUTIC EFFECT OF ANTIPSYCHOTICS, WHICH OCCURS DESPITE RAPID DOPAMINE BLOCKADE. FURTHERMORE, GIVEN THE COMMON NATURE OF EPIGENETIC VARIATION, THIS LENDS INSIGHT INTO THE DIFFERENTIAL THERAPEUTIC RESPONSE OF PSYCHOTIC PATIENTS WHO DISPLAY ADEQUATE BLOCKAGE OF DOPAMINE RECEPTORS. 2013 16 1418 37 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 17 578 35 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 18 1831 42 EFFECTS OF MATERNAL SEPARATION AND ANTIDEPRESSANT DRUG ON EPIGENETIC REGULATION OF THE BRAIN-DERIVED NEUROTROPHIC FACTOR EXON I PROMOTER IN THE ADULT RAT HIPPOCAMPUS. AIM: EARLY LIFE STRESS CAN INDUCE EPIGENETIC CHANGES THROUGH GENETIC AND ENVIRONMENTAL INTERACTIONS AND IS A RISK FACTOR FOR DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN IMPLICATED IN THE PATHOPHYSIOLOGY OF DEPRESSION AND ANTIDEPRESSANT DRUG ACTION. WE INVESTIGATED EPIGENETIC CHANGES AT THE BDNF EXON I PROMOTER IN THE HIPPOCAMPUS OF ADULT RATS SUBJECTED TO MATERNAL SEPARATION (MS) DURING EARLY LIFE AND TREATED WITH AN ANTIDEPRESSANT DRUG AS ADULTS. METHODS: RAT PUPS WERE SUBJECTED TO MS FROM POSTNATAL DAY 1 TO 21 AND RECEIVED CHRONIC ESCITALOPRAM (ESC) AS ADULTS. WE ASSESSED THE EFFECTS OF MS AND ESC ON BDNF EXON I AND DNA METHYLTRANSFERASES (DNMT) MRNA LEVELS (QUANTITATIVE REVERSE-TRANSCRIPTION POLYMERASE CHAIN REACTION), ACETYLATED HISTONE H3, AND MECP2 BINDING TO THE BDNF PROMOTER I (CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY REAL-TIME POLYMERASE CHAIN REACTION), AND BDNF PROTEIN LEVELS (ENZYME-LINKED IMMUNOSORBENT ASSAY). RESULTS: THE LEVELS OF BDNF PROTEIN, EXON I MRNA, HISTONE H3 ACETYLATION, AND DNMT1 AND DNMT3A MRNA WERE ALTERED IN THE MS GROUP COMPARED WITH THE CONTROL GROUP. SIGNIFICANT DECREASES WERE OBSERVED IN THE BDNF PROTEIN, EXON I MRNA, AND HISTONE H3 ACETYLATION LEVELS AND THERE WERE SIGNIFICANT INCREASES IN DNMT1 AND DNMT3A MRNA LEVELS. THE COMPARISON BETWEEN THE MS + ESC AND MS GROUPS REVEALED SIGNIFICANT INCREASES IN BDNF PROTEIN, EXON I MRNA, AND HISTONE H3 ACETYLATION LEVELS AND SIGNIFICANT DECREASES IN MECP2 AND DNMT1 AND DNMT3A MRNA LEVELS. CONCLUSION: THESE FINDINGS INDICATE THAT MS INDUCED EPIGENETIC CHANGES AT THE BDNF EXON I PROMOTER AND THESE CHANGES WERE PREVENTED BY ANTIDEPRESSANT DRUG TREATMENT DURING ADULTHOOD. 2018 19 1808 49 EFFECTS OF ADOLESCENT SOCIAL STRESS AND ANTIDEPRESSANT TREATMENT ON COGNITIVE INFLEXIBILITY AND BDNF EPIGENETIC MODIFICATIONS IN THE MPFC OF ADULT MICE. ADOLESCENT SOCIAL STRESS (ASS) CAN INCREASE SUSCEPTIBILITY TO DEPRESSION IN ADULTHOOD. HOWEVER, THE UNDERLYING PSYCHOLOGICAL AND NEURAL MECHANISMS REMAIN UNCLEAR. CORTICALLY MEDIATED COGNITIVE DYSFUNCTIONS ARE INCREASINGLY RECOGNIZED AS AN INDEPENDENT AND IMPORTANT RISK FACTOR OF DEPRESSION. USING SOCIAL DEFEAT STRESS, A CLASSICAL ANIMAL MODEL OF DEPRESSION, OUR PREVIOUS STUDIES FOUND THAT MICE SUBJECTED TO THIS FORM OF STRESS DURING EARLY ADOLESCENCE DISPLAYED COGNITIVE INFLEXIBILITY (CI) IN ADULTHOOD. THIS CHANGE WAS ACCOMPANIED BY A DOWN-REGULATION OF BDNF GENE EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX (MPFC); THIS GENE ENCODES A KEY MOLECULE INVOLVED IN DEPRESSION AND ANTIDEPRESSANT ACTION. IN THE PRESENT PAPER, WE IDENTIFIED EPIGENETIC MODIFICATION OF BDNF AS A POSSIBLE MECHANISM UNDERLYING THE BEHAVIORAL AND MOLECULAR CHANGES. ASS INDUCED A SET OF DEPRESSIVE PHENOTYPES, INCLUDING INCREASED SOCIAL AVOIDANCE AND CI, AS WELL AS REDUCED LEVELS OF TOTAL BDNF AND ISOFORM IV BUT NOT ISOFORM I OR VI TRANSCRIPTS IN THE MPFC. IN PARALLEL WITH CHANGES IN BDNF GENE EXPRESSION, PREVIOUSLY STRESSED ADULT MICE SHOWED INCREASED LEVELS OF DIMETHYLATION OF HISTONE H3 AT LYSINE K9 (H3K9ME2) IMMEDIATELY DOWNSTREAM OF THE BDNF IV PROMOTER. ON THE OTHER HAND, NO DIFFERENCES WERE FOUND IN TRIMETHYLATION OF HISTONE H3 AT LYSINE K4 (H3K4ME3) OR IN ACETYLATION OF HISTONE H3 AT LYSINE K9 (H3K9AC) OR AT K4 (H3K4AC) IN THE BDNF IV PROMOTER. LIKEWISE, NO ALTERATIONS WERE FOUND IN DNA METHYLATION OF THE BDNF IV PROMOTER. ADDITIONALLY, TREATMENT WITH THE CHRONIC ANTIDEPRESSANT TRANYLCYPROMINE REVERSED BDNF EPIGENETIC CHANGES AND RELATED GENE TRANSCRIPTION WHILE ALSO REVERSING CI, BUT NOT SOCIAL AVOIDANCE, IN PREVIOUSLY STRESSED ADULT MICE. THESE RESULTS SUGGEST THAT EPIGENETIC CHANGES TO THE BDNF GENE IN THE MPFC AFTER ADOLESCENT SOCIAL ADVERSITY MAY BE INVOLVED IN THE REGULATION OF COGNITIVE DYSFUNCTION IN DEPRESSION AND ANTIDEPRESSANT ACTION IN ADULTHOOD. 2018 20 1698 28 DYNAMIC EFFECTS OF EARLY ADOLESCENT STRESS ON DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES AND JMJD3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS. AIMS: EXPRESSION OF INFLAMMATORY CYTOKINES IN THE BRAIN HAS BEEN REPORTED TO BE INVOLVED IN THE PATHOGENESIS OF AND SUSCEPTIBILITY TO DEPRESSION. JUMONJI DOMAIN-CONTAINING 3 (JMJD3), WHICH IS A HISTONE H3 LYSINE 27 (H3K27) DEMETHYLASE AND CAN REGULATE MICROGLIAL ACTIVATION, HAS BEEN REGARDED AS A CRUCIAL ELEMENT IN THE EXPRESSION OF INFLAMMATORY CYTOKINES. FURTHERMORE, RECENT STUDIES HIGHLIGHTED THE FACT THAT LIPOPOLYSACCHARIDES INDUCE DEPRESSIVE-LIKE BEHAVIORS AND HIGHER JMJD3 EXPRESSION AND LOWER H3K27ME3 EXPRESSION IN THE BRAIN. HOWEVER, WHETHER THE PROCESS OF JMJD3 MEDIATING INFLAMMATORY CYTOKINES WAS INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSION DUE TO EARLY-LIFE STRESS REMAINED ELUSIVE. METHODS: RATS EXPOSED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IN ADOLESCENCE WERE USED IN ORDER TO DETECT DYNAMIC ALTERATIONS IN DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES, JMJD3, AND H3K27ME3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS. MOREOVER, MINOCYCLINE, AN INHIBITOR OF MICROGLIAL ACTIVATION, WAS EMPLOYED TO OBSERVE THE PROTECTIVE EFFECTS. RESULTS: OUR RESULTS SHOWED THAT CUMS DURING THE ADOLESCENT PERIOD INDUCED DEPRESSIVE-LIKE BEHAVIORS, OVER-EXPRESSION OF CYTOKINES, AND INCREASED JMJD3 AND DECREASED H3K27ME3 EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF BOTH ADOLESCENT AND ADULT RATS. HOWEVER, MINOCYCLINE RELIEVED ALL THE ALTERATIONS. CONCLUSION: THE STUDY REVEALED THAT JMJD3 MIGHT BE INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSIVE-LIKE BEHAVIORS BY MODULATING H3K27ME3 AND PRO-INFLAMMATORY CYTOKINE EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS THAT HAD BEEN STRESSED DURING EARLY ADOLESCENCE. 2018