1 6108 163 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 2 3177 56 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021 3 5874 52 SWIMMING EXERCISE REVERSES CUMS-INDUCED CHANGES IN DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL PLASTICITY-RELATED PROTEINS. BACKGROUND: STRESS-INDUCED FAILED RESILIENCE OF BRAIN PLASTICITY CAN CONTRIBUTE TO THE ONSET AND RECURRENCE OF DEPRESSION. CHRONIC STRESS HAS BEEN REPORTED TO OPEN WINDOWS OF EPIGENETIC PLASTICITY IN HIPPOCAMPUS. HOWEVER, HOW HIPPOCAMPAL PLASTICITY UNDERLIES DEPRESSION-LIKE BEHAVIORS AND HOW IT ADAPTS IN RESPONSE TO STRESS HAS NOT BEEN ADDRESSED. THE PRESENT STUDY AIMED TO INVESTIGATE THE SIGNALING MECHANISMS OF CUMS AFFECTING HIPPOCAMPAL PLASTICITY-RELATED PROTEINS EXPRESSION AND THE REGULATION OF SWIMMING EXERCISE IN MICE. METHODS: MALE C57BL/6 MICE WERE SUBJECTED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) FOR 7 WEEKS. FROM THE 4TH WEEK, CUMS MICE WERE TRAINED IN A MODERATE SWIMMING PROGRAM FOR A TOTAL OF 4 WEEKS. A VIDEOCOMPUTERIZED TRACKING SYSTEM WAS USED TO RECORD BEHAVIORS OF ANIMALS FOR A 5-MIN SESSION. REAL-TIME PCR AND WESTERN BLOTTING WERE USED TO EXAMINE GENE EXPRESSION IN MOUSE HIPPOCAMPUS. RESULTS: OUR RESULTS DEMONSTRATED THAT CUMS INDUCED DEPRESSION-LIKE BEHAVIORS, WHICH WERE REVERSED BY SWIMMING EXERCISE. MOREOVER, THE BEHAVIORAL CHANGES INDUCED BY CUMS AND EXERCISE WERE CORRELATED WITH HIPPOCAMPAL PLASTICITY-RELATED PROTEINS EXPRESSION OF GROWTH-ASSOCIATED PROTEIN-43 (GAP-43) AND SYNAPTOPHYSIN (SYN). THE MOLECULAR MECHANISMS REGULATING THIS PLASTICITY MAY INCLUDE SIRT1/MIRCORNA, CREB/BDNF, AND AKT/GSK-3BETA SIGNALING PATHWAYS. LIMITATIONS: WE DID NOT ESTABLISH A CORRELATION BETWEEN DEPRESSION-LIKE BEHAVIORS INDUCED BY CHRONIC STRESS AND EPIGENETIC CHANGES OF HIPPOCAMPAL PLASTICITY, EITHER A CAUSAL MOLECULAR SIGNALING UNDERLING THIS PLASTICITY. CONCLUSIONS: OUR FINDINGS HAVE IDENTIFIED SWIMMING EXERCISE EFFECTS ON CUMS-INDUCED CHANGES IN DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL PLASTICITY-RELATED PROTEINS, WHICH PROVIDE A FRAMEWORK FOR DEVELOPING NEW STRATEGIES TO TREAT STRESS-INDUCED DEPRESSION. 2018 4 3462 40 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 5 1761 44 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS. 2013 6 1999 33 EPIGENETIC AND NEURONAL ACTIVITY MARKERS SUGGEST THE RECRUITMENT OF THE PREFRONTAL CORTEX AND HIPPOCAMPUS IN THE THREE-HIT MODEL OF DEPRESSION IN MALE PACAP HETEROZYGOUS MICE. DEPRESSION AND ITS INCREASING PREVALENCE CHALLENGE PATIENTS, THE HEALTHCARE SYSTEM, AND THE ECONOMY. WE RECENTLY CREATED A MOUSE MODEL BASED ON THE THREE-HIT CONCEPT OF DEPRESSION. AS GENETIC PREDISPOSITION (FIRST HIT), WE APPLIED PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE HETEROZYGOUS MICE ON CD1 BACKGROUND. MATERNAL DEPRIVATION MODELED THE EPIGENETIC FACTOR (SECOND HIT), AND THE CHRONIC VARIABLE MILD STRESS WAS THE ENVIRONMENTAL FACTOR (THIRD HIT). FLUOXETINE TREATMENT WAS APPLIED TO TEST THE PREDICTIVE VALIDITY OF OUR MODEL. WE AIMED TO EXAMINE THE DYNAMICS OF THE EPIGENETIC MARKER ACETYL-LYSINE 9 H3 HISTONE (H3K9AC) AND THE NEURONAL ACTIVITY MARKER FOSB IN THE PREFRONTAL CORTEX (PFC) AND HIPPOCAMPUS. FLUOXETINE DECREASED H3K9AC IN PFC IN NON-DEPRIVED ANIMALS, BUT A HISTORY OF MATERNAL DEPRIVATION ABOLISHED THE EFFECT OF STRESS AND SSRI TREATMENT ON H3K9AC IMMUNOREACTIVITY. IN THE HIPPOCAMPUS, STRESS DECREASED, WHILE SSRI INCREASED H3K9AC IMMUNOSIGNAL, UNLIKE IN THE DEPRIVED MICE, WHERE THE OPPOSITE EFFECT WAS DETECTED. FOSB IN STRESS WAS STIMULATED BY FLUOXETINE IN THE PFC, WHILE IT WAS INHIBITED IN THE HIPPOCAMPUS. THE FOSB IMMUNOREACTIVITY WAS ALMOST COMPLETELY ABOLISHED IN THE HIPPOCAMPUS OF THE DEPRIVED MICE. THIS STUDY SHOWED THAT FOSB AND H3K9AC WERE MODULATED IN A TERRITORY-SPECIFIC MANNER BY EARLY LIFE ADVERSITIES AND LATER LIFE STRESS INTERACTING WITH THE EFFECT OF FLUOXETINE THERAPY SUPPORTING THE RELIABILITY OF OUR MODEL. 2022 7 6388 52 THE ROLE OF SIRT1 IN THE BASOLATERAL AMYGDALA IN DEPRESSION-LIKE BEHAVIORS IN MICE. PREVIOUS INVESTIGATIONS HAVE IMPLICATED THE BASOLATERAL AMYGDALA (BLA) EPIGENETIC MECHANISMS IN THE PATHOPHYSIOLOGY OF DEPRESSION. SIRT1 IS A NAD+-DEPENDENT CLASS III HISTONE DEACETYLASE, WIDELY EXPRESSES IN BLA. HOWEVER, EPIGENETIC MECHANISMS IN THE BLA UNDER THE REGULATION OF SIRT1 IN THE DEPRESSION ARE LARGELY UNCHARACTERIZED. UNDER THE CHRONIC UNPREDICTABLE CHRONIC MILD STRESS (CUMS) MOUSE MODEL, WE USED ADENO-ASSOCIATED VIRAL VECTORS (AAV) THAT ENCODED SIRT1-SHRNA OR SIRT1 TO SPECIFICALLY KNOCKDOWN OR OVEREXPRESS SIRT1 IN BLA NEURONS, RESPECTIVELY. CUMS PROCEDURE INDUCED SIGNIFICANT DEPRESSION SYMPTOMS INCLUDING THE DECREASED SUCROSE PREFERENCE, THE LESS BODYWEIGHT GAINED, THE DECREASED IMMOBILE LATENCY AND THE INCREASED IMMOBILE TIME BOTH IN FORCED SWIM TEST (FST) AND TAIL SUSPENSION TEST (TST). KNOCKDOWN OF SIRT1 IN BLA GLUTAMATERGIC NEURONS REVERSED THESE DEPRESSION-LIKE BEHAVIORS AND RESTORED THE SYNAPTIC ABNORMALITIES. OVEREXPRESSION OF SIRT1 IN BLA GLUTAMATERGIC NEURONS INDUCED DEPRESSION-LIKE BEHAVIORS IN NON-STRESSED CONTROL MICE. THE RESULT OF PROTEIN EXPRESSIONS AND ULTRASTRUCTURAL CHANGES WERE CONSISTENT WITH THE BEHAVIORAL RESULTS. OUR STUDY SUGGESTED THAT DOWNREGULATION OF SIRT1 IN BLA HAS CERTAIN BENEFICIAL EFFECT ON CUMS-INDUCED DEPRESSION-LIKE BEHAVIORS SUCH AS ANOREXIA, ANHEDONIA, HOPELESSNESS AND DESPAIR. IN ADDITION, THE INCREASED EXPRESSION OF SIRT1 MAY BE THE IMMEDIATE CAUSE OF DEPRESSIVE-LIKE SYMPTOMS. THE ABNORMAL EXPRESSION OF SIRT1 MAY AFFECT THE TRANSCRIPTIONAL REGULATION MECHANISM AND SIGNALING PROTEIN ACETYLATION, AFFECTING NEUROPLASTICITY AND ULTIMATELY CONTRIBUTE TO MDD. IN THE STRESS-SUSCEPTIBLE MICE, THESE TWO MECHANISMS MAY CO-EXIST, BUT THE SPECIFIC MECHANISM NEEDS FURTHER RESEARCH. 2021 8 1813 41 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 9 3372 45 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 10 219 49 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE. 2016 11 3493 52 IDENTIFICATION OF KEY GENES, PATHWAYS, AND MIRNA/MRNA REGULATORY NETWORKS OF CUMS-INDUCED DEPRESSION IN NUCLEUS ACCUMBENS BY INTEGRATED BIOINFORMATICS ANALYSIS. INTRODUCTION: MAJOR DEPRESSIVE DISORDER (MDD) IS A RECURRENT, DEVASTATING MENTAL DISORDER, WHICH AFFECTS >350 MILLION PEOPLE WORLDWIDE, AND EXERTS SUBSTANTIAL PUBLIC HEALTH AND FINANCIAL COSTS TO SOCIETY. THUS, THERE IS A SIGNIFICANT NEED TO DISCOVER INNOVATIVE THERAPEUTICS TO TREAT DEPRESSION EFFICIENTLY. STRESS-INDUCED DYSFUNCTION IN THE SUBTYPE OF NEURONAL CELLS AND THE CHANGE OF SYNAPTIC PLASTICITY AND STRUCTURAL PLASTICITY OF NUCLEUS ACCUMBENS (NAC) ARE IMPLICATED IN DEPRESSION SYMPTOMOLOGY. HOWEVER, THE MOLECULAR AND EPIGENETIC MECHANISMS AND STRESSES TO THE NAC PATHOLOGICAL CHANGES IN DEPRESSION REMAIN ELUSIVE. MATERIALS AND METHODS: IN THIS STUDY, TREATMENT GROUP MICE WERE TREATED CONTINUALLY WITH THE CHRONIC UNPREDICTABLE MILD STRESS (CUMS) UNTIL EXPRESSION OF DEPRESSION-LIKE BEHAVIORS WERE FOUND. DEPRESSION WAS CONFIRMED WITH SUCROSE PREFERENCE, NOVELTY-SUPPRESSED FEEDING, FORCED SWIMMING, AND TAIL SUSPENSION TESTS. WE APPLIED HIGH-THROUGHPUT RNA SEQUENCING TO ASSESS MICRORNA EXPRESSION AND TRANSCRIPTIONAL PROFILES IN THE NAC TISSUE FROM DEPRESSION-LIKE BEHAVIORS MICE AND CONTROL MICE. THE REGULATORY NETWORK OF MIRNAS/MRNAS WAS CONSTRUCTED BASED ON THE HIGH-THROUGHPUT RNA SEQUENCE AND BIOINFORMATICS SOFTWARE PREDICTIONS. RESULTS: A TOTAL OF 17 MIRNAS AND 10 MRNAS WERE SIGNIFICANTLY UPREGULATED IN THE NAC OF CUMS-INDUCED MICE WITH DEPRESSION-LIKE BEHAVIORS, AND 12 MIRNAS AND 29 MRNAS WERE DOWNREGULATED. A SERIES OF BIOINFORMATICS ANALYSES SHOWED THAT THESE ALTERED MIRNAS PREDICTED TARGET MRNA AND DIFFERENTIALLY EXPRESSED MRNAS WERE SIGNIFICANTLY ENRICHED IN THE MAPK SIGNALING PATHWAY, GABAERGIC SYNAPSE, DOPAMINERGIC SYNAPSE, CYTOKINE-CYTOKINE RECEPTOR INTERACTION, AXON GUIDANCE, REGULATION OF AUTOPHAGY, AND SO ON. FURTHERMORE, DUAL LUCIFERASE REPORT ASSAY AND QRT-PCR RESULTS VALIDATED THE MIRNA/MRNA REGULATORY NETWORK. CONCLUSION: THE DETERIORATIONS OF GABAERGIC SYNAPSES, DOPAMINERGIC SYNAPSES, NEUROTRANSMITTER SYNTHESIS, AS WELL AS AUTOPHAGY-ASSOCIATED APOPTOTIC PATHWAY ARE ASSOCIATED WITH THE MOLECULAR PATHOLOGICAL MECHANISM OF CUMS-INDUCED DEPRESSION. 2019 12 1740 37 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 13 2827 39 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS. 2011 14 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 15 1005 37 CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD CAUSES DIFFERENTIAL DEPRESSIVE AND ANXIOGENIC EFFECTS IN THE NOVELTY-SEEKING PHENOTYPE: FUNCTIONAL IMPLICATIONS FOR HIPPOCAMPAL AND AMYGDALAR BRAIN-DERIVED NEUROTROPHIC FACTOR AND THE MOSSY FIBRE PLASTICITY. EXPERIMENTALLY NAIVE RATS SHOW VARIANCE IN THEIR LOCOMOTOR REACTIVITY TO NOVELTY, SOME DISPLAYING HIGHER (HR) WHILE OTHERS DISPLAYING LOWER (LR) REACTIVITY, ASSOCIATED WITH VULNERABILITY TO STRESS. WE EMPLOYED A CHRONIC VARIABLE PHYSICAL STRESS REGIMEN INCORPORATING INTERMITTENT AND RANDOM EXPOSURES OF PHYSICAL STRESSORS OR CONTROL HANDLING DURING THE PERIPUBERTAL-JUVENILE PERIOD TO ASSESS INTERACTIONS BETWEEN STRESS AND THE LRHR PHENOTYPE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS ON THE FORCED SWIM AND SOCIAL INTERACTION TESTS, RESPECTIVELY. A DECREASE IN IMMOBILITY IN THE FORCED SWIM TEST ALONG WITH A DECREASE IN SOCIAL CONTACT IN THE SOCIAL INTERACTION TEST WERE OBSERVED IN THE JUVENILE HRS, COUPLED WITH INCREASES IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPUS AND IN THE BASOLATERAL AMYGDALA WITH CHRONIC VARIABLE PHYSICAL STRESS. IN CONTRAST, AN INCREASE IN IMMOBILITY IN THE FORCED SWIM TEST AND A DECREASE IN SOCIAL CONTACT WAS OBSERVED IN THE LR COUNTERPARTS COUPLED WITH AN INCREASE IN THE BDNF MRNA IN THE BASOLATERAL AMYGDALA FOLLOWING CHRONIC VARIABLE PHYSICAL STRESS. FURTHERMORE, CHRONIC PHYSICAL STRESS LED TO INCREASED H3 AND H4 ACETYLATION AT THE P2 AND P4 PROMOTERS OF THE HIPPOCAMPAL BDNF GENE IN THE HR RATS THAT IS ASSOCIATED WITH INCREASED SUPRAPYRAMIDAL MOSSY FIBRE (SP-MF) TERMINAL FIELD VOLUME. IN CONTRAST, CHRONIC VARIABLE PHYSICAL STRESS LED TO DECREASED H4 ACETYLATION AT THE P4 PROMOTER, ASSOCIATED WITH DECREASED SP-MF VOLUME IN THE LR RATS. THESE FINDINGS SHOW DISSOCIATION IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS FOLLOWING CHRONIC VARIABLE PHYSICAL STRESS IN THE JUVENILE HR ANIMALS THAT MAY BE MEDIATED BY INCREASED LEVELS OF BDNF IN THE HIPPOCAMPUS AND IN THE AMYGDALA, RESPECTIVELY. MOREOVER, CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD RESULTS IN OPPOSITE EFFECTS IN DEPRESSIVE-LIKE BEHAVIOR IN THE LRHR RATS BY WAY OF INDUCING DIFFERENTIAL EPIGENETIC REGULATION OF THE HIPPOCAMPAL BDNF GENE THAT, IN TURN, MAY MEDIATE MOSSY FIBRE SPROUTING. 2011 16 1698 43 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 17 5752 44 SOCIAL ISOLATION AND SOCIAL SUPPORT AT ADULTHOOD AFFECT EPIGENETIC MECHANISMS, BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS AND BEHAVIOR OF CHRONICALLY STRESSED RATS. EPIGENETIC MODULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROVIDES ONE POSSIBLE EXPLANATION FOR THE DYSFUNCTIONS INDUCED BY STRESS, SUCH AS PSYCHIATRIC DISORDERS AND COGNITIVE DECLINE. INTERESTINGLY, SOCIAL SUPPORT CAN BE PROTECTIVE AGAINST SOME OF THESE EFFECTS, BUT THE MECHANISMS OF SOCIAL BUFFERING ARE POORLY UNDERSTOOD. CONVERSELY, EARLY ISOLATION EXACERBATES THE RESPONSES TO STRESSORS, ALTHOUGH ITS EFFECTS IN ADULTHOOD REMAIN UNCLEAR. THIS STUDY INVESTIGATED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL BUFFERING ON HIPPOCAMPAL EPIGENETIC MECHANISMS, BDNF LEVELS AND BEHAVIORAL RESPONSES OF CHRONICALLY STRESSED YOUNG ADULT RATS. MALE WISTAR RATS (3 MONTHS) WERE ASSIGNED TO ACCOMPANIED (PAIRED) OR ISOLATED HOUSING. AFTER ONE-MONTH HALF OF EACH GROUP WAS SUBMITTED TO A CHRONIC UNPREDICTABLE STRESS (CUS) PROTOCOL FOR 18 DAYS. AMONG ACCOMPANIED ANIMALS, ONLY ONE WAS EXPOSED TO STRESS. BEHAVIORAL ANALYSIS ENCOMPASSED THE OPEN FIELD, PLUS MAZE AND INHIBITORY AVOIDANCE TASKS. HIPPOCAMPAL H3K9 AND H4K12 ACETYLATION, HDAC5 EXPRESSION AND BDNF LEVELS WERE EVALUATED. ISOLATED HOUSING INCREASED HDAC5 EXPRESSION, DECREASED H3K9 AND H4K12 ACETYLATION, REDUCED BDNF LEVELS, AND IMPAIRED LONG-TERM MEMORY. STRESS AFFECTED WEIGHT GAIN, INDUCED ANXIETY-LIKE BEHAVIOR AND DECREASED ACK9H3 LEVELS. INTERACTIONS BETWEEN HOUSING CONDITIONS AND SOCIAL STRESS WERE SEEN ONLY FOR HDAC5 EXPRESSION, WHICH SHOWED A FURTHER INCREASE IN THE ISOLATED + CUS GROUP BUT REMAINED CONSTANT IN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION AT ADULTHOOD INDUCED EPIGENETIC ALTERATIONS AND EXACERBATED THE EFFECTS OF CHRONIC STRESS ON HDAC5. NOTWITHSTANDING, SOCIAL SUPPORT COUNTERACTED THE ADVERSE EFFECTS OF STRESS ON HDAC5 EXPRESSION. 2019 18 1751 43 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 19 1848 50 EFFECTS OF VENLAFAXINE ON THE EXPRESSION LEVEL AND METHYLATION STATUS OF GENES INVOLVED IN OXIDATIVE STRESS IN RATS EXPOSED TO A CHRONIC MILD STRESS. RECENT HUMAN AND ANIMAL STUDIES INDICATE THAT OXIDATIVE AND NITROSATIVE STRESS MAY PLAY A ROLE IN THE AETIOLOGY AND PATHOGENESIS OF DEPRESSION. THIS STUDY INVESTIGATES THE EFFECT OF CHRONIC ADMINISTRATION OF THE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITOR, VENLAFAXINE, ON THE EXPRESSION AND METHYLATION STATUS OF SOD1, SOD2, GPX1, GPX4, CAT, NOS1 AND NOS2 IN THE BRAIN AND BLOOD OF RATS EXPOSED TO A CHRONIC MILD STRESS (CMS) MODEL OF DEPRESSION. SEPARATE GROUPS OF ANIMALS WERE EXPOSED TO CMS FOR 2 OR 7 WEEKS; THE SECOND GROUP RECEIVED SALINE OR VENLAFAXINE (10 MG/KG/D, IP) FOR 5 WEEKS. AFTER COMPLETION OF BOTH STRESS CONDITIONS AND DRUG ADMINISTRATION, THE MRNA AND PROTEIN EXPRESSION OF SELECTED GENES AND THE METHYLATION STATUS OF THEIR PROMOTERS WERE MEASURED IN PERIPHERAL MONONUCLEAR BLOOD CELLS (PBMCS) AND IN BRAIN STRUCTURES (HIPPOCAMPUS, AMYGDALA, HYPOTHALAMUS, MIDBRAIN, CORTEX, BASAL GANGLIA) WITH THE USE OF TAQMAN GENE EXPRESSION ASSAY, WESTERN BLOT AND METHYLATION-SENSITIVE HIGH-RESOLUTION MELTING TECHNIQUES. CMS CAUSED A DECREASE IN SUCROSE CONSUMPTION, AND THIS EFFECT WAS NORMALIZED BY FLUOXETINE. IN PBMCS, SOD1, SOD2 AND NOS2 MRNA EXPRESSION CHANGED ONLY AFTER VENLAFAXINE ADMINISTRATION. IN BRAIN, CAT, GPX1, GPX4 AND NOS1 GENE EXPRESSION CHANGED FOLLOWING CMS OR VENLAFAXINE EXPOSURE, MOST PROMINENTLY IN THE HIPPOCAMPUS, MIDBRAIN AND BASAL GANGLIA. CMS INCREASED THE METHYLATION OF THE GPX1 PROMOTER IN PBMCS, THE SECOND GPX4 PROMOTER IN MIDBRAIN AND BASAL GANGLIA, AND SOD1 AND SOD2 IN HIPPOCAMPUS. THE CMS ANIMALS TREATED WITH VENLAFAXINE DISPLAYED A SIGNIFICANTLY HIGHER CAT LEVEL IN MIDBRAIN AND CEREBRAL CORTEX. CMS CAUSED AN ELEVATION OF GPX4 IN THE HIPPOCAMPUS, WHICH WAS LOWERED IN CEREBRAL CORTEX BY VENLAFAXINE. THE RESULTS INDICATE THAT CMS AND VENLAFAXINE ADMINISTRATION AFFECT THE METHYLATION OF PROMOTERS OF GENES INVOLVED IN OXIDATIVE AND NITROSATIVE STRESS. THEY ALSO INDICATE THAT PERIPHERAL AND CENTRAL TISSUE DIFFER IN THEIR RESPONSE TO STRESS OR ANTIDEPRESSANT TREATMENTS. IT IS POSSIBLE THAT THAT APART FROM DNA METHYLATION, A CRUCIAL ROLE OF EXPRESSION LEVEL OF GENES MAY BE PLAYED BY OTHER FORMS OF EPIGENETIC REGULATION, SUCH AS HISTONE MODIFICATION OR MICRORNA INTERFERENCE. THESE FINDINGS PROVIDE STRONG EVIDENCE FOR THESIS THAT ANALYSIS OF THE LEVEL OF MRNA AND PROTEIN EXPRESSION AS WELL AS THE STATUS OF PROMOTER METHYLATION CAN HELP IN UNDERSTANDING THE PATHOMECHANISMS OF MENTAL DISEASES, INCLUDING DEPRESSION, AND THE MECHANISMS OF ACTION OF DRUGS EFFECTIVE IN THEIR THERAPY. 2020 20 3312 53 HIPPOCAMPAL AND BEHAVIORAL DYSFUNCTIONS IN A MOUSE MODEL OF ENVIRONMENTAL STRESS: NORMALIZATION BY AGOMELATINE. STRESS-INDUCED ALTERATIONS IN NEURONAL PLASTICITY AND IN HIPPOCAMPAL FUNCTIONS HAVE BEEN SUGGESTED TO BE INVOLVED IN THE DEVELOPMENT OF MOOD DISORDERS. IN THIS CONTEXT, WE INVESTIGATED IN THE HIPPOCAMPUS THE ACTIVATION OF INTRACELLULAR SIGNALING CASCADES, THE EXPRESSION OF EPIGENETIC MARKERS AND PLASTICITY-RELATED GENES IN A MOUSE MODEL OF STRESS-INDUCED HYPERACTIVITY AND OF MIXED AFFECTIVE DISORDERS. WE ALSO DETERMINED WHETHER THE ANTIDEPRESSANT DRUG AGOMELATINE, A MT1/MT2 MELATONERGIC RECEPTOR AGONIST/5-HT2C RECEPTOR ANTAGONIST, COULD PREVENT SOME NEUROBIOLOGICAL AND BEHAVIORAL ALTERATIONS PRODUCED BY STRESS. C57BL/6J MICE, EXPOSED FOR 3 WEEKS TO DAILY UNPREDICTABLE SOCIO-ENVIRONMENTAL STRESSORS OF MILD INTENSITY, WERE TREATED DURING THE WHOLE PROCEDURE WITH AGOMELATINE (50 MG KG(-1) PER DAY, INTRAPERITONEAL). STRESSED MICE DISPLAYED ROBUST INCREASES IN EMOTIONAL AROUSAL, VIGILANCE AND MOTOR ACTIVITY, TOGETHER WITH A REWARD DEFICIT AND A REDUCTION IN ANXIETY-LIKE BEHAVIOR. NEUROBIOLOGICAL INVESTIGATIONS SHOWED AN INCREASED PHOSPHORYLATION OF INTRACELLULAR SIGNALING PROTEINS, INCLUDING ATF1, CREB AND P38, IN THE HIPPOCAMPUS OF STRESSED MICE. DECREASED HIPPOCAMPAL LEVEL OF THE REPRESSIVE EPIGENETIC MARKS HDAC2 AND H3K9ME2, AS WELL AS INCREASED LEVEL OF THE PERMISSIVE MARK H3K9/14AC SUGGESTED THAT CHRONIC MILD STRESS WAS ASSOCIATED WITH INCREASED GENE TRANSCRIPTION, AND CLEAR-CUT EVIDENCE WAS FURTHER INDICATED BY CHANGES IN NEUROPLASTICITY-RELATED GENES, INCLUDING ARC, BCL2, BDNF, GDNF, IGF1 AND NEUROD1. TOGETHER WITH OTHER FINDINGS, THE PRESENT DATA SUGGEST THAT CHRONIC ULTRA-MILD STRESS CAN MODEL THE HYPERACTIVITY OR PSYCHOMOTOR AGITATION, AS WELL AS THE MIXED AFFECTIVE BEHAVIORS OFTEN OBSERVED DURING THE MANIC STATE OF BIPOLAR DISORDER PATIENTS. INTERESTINGLY, AGOMELATINE COULD NORMALIZE BOTH THE BEHAVIORAL AND THE MOLECULAR ALTERATIONS INDUCED BY STRESS, PROVIDING FURTHER INSIGHTS INTO THE MECHANISM OF ACTION OF THIS NEW GENERATION ANTIDEPRESSANT DRUG. 2014