1 1783 128 EFFECT OF AGOMELATINE ON MEMORY DEFICITS AND HIPPOCAMPAL GENE EXPRESSION INDUCED BY CHRONIC SOCIAL DEFEAT STRESS IN MICE. CHRONIC STRESS IS KNOWN TO INDUCE NOT ONLY ANXIETY AND DEPRESSIVE-LIKE PHENOTYPES IN MICE BUT ALSO COGNITIVE IMPAIRMENTS, FOR WHICH THE ACTION OF CLASSICAL ANTIDEPRESSANT COMPOUNDS REMAINS UNSATISFACTORY. IN THIS CONTEXT, WE INVESTIGATED THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS (CSDS) ON ANXIETY-, SOCIAL- AND COGNITIVE-RELATED BEHAVIORS, AS WELL AS HIPPOCAMPAL BDNF, SYNAPTIC PLASTICITY MARKERS (PSD-95, SYNAPTOPHYSIN, SPINOPHILIN, SYNAPSIN I AND MAP-2), AND EPIGENETIC MODIFYING ENZYMES (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) GENE EXPRESSION IN C57BL/6J MICE. CSDS FOR 10 DAYS PROVOKED LONG-LASTING ANXIOUS-LIKE PHENOTYPE IN THE OPEN FIELD AND EPISODIC MEMORY DEFICITS IN THE NOVEL OBJECT RECOGNITION TEST. WHILE TOTAL BDNF MRNA LEVEL WAS UNCHANGED, BDNF EXON IV, MAP-2, HDAC2, HDAC6 AND MLL3 GENE EXPRESSION WAS SIGNIFICANTLY DECREASED IN THE CSDS MOUSE HIPPOCAMPUS. IN CSDS MICE TREATED 3 WEEKS WITH 50 MG/KG/D AGOMELATINE, AN ANTIDEPRESSANT WITH MELATONERGIC RECEPTOR AGONIST AND 5-HT(2C) RECEPTOR ANTAGONIST PROPERTIES, THE ANXIOUS-LIKE PHENOTYPE WAS NOT REVERSED, BUT THE TREATMENT SUCCESSFULLY PREVENTED THE COGNITIVE IMPAIRMENTS AND HIPPOCAMPAL GENE EXPRESSION MODIFICATIONS. ALTOGETHER, THESE DATA EVIDENCED THAT, IN MICE, AGOMELATINE WAS EFFECTIVE IN ALLEVIATING STRESS-INDUCED ALTERED COGNITIVE FUNCTIONS, POSSIBLY THROUGH A MECHANISM INVOLVING BDNF SIGNALING, SYNAPTIC PLASTICITY AND EPIGENETIC REMODELING. 2017 2 581 48 BEHAVIORAL AND NEUROCHEMICAL CHARACTERIZATION OF TRKB-DEPENDENT MECHANISMS OF AGOMELATINE IN GLUCOCORTICOID RECEPTOR-IMPAIRED MICE. GROWING EVIDENCE INDICATES THAT IMPAIRMENT OF THE STRESS RESPONSE, IN PARTICULAR THE NEGATIVE FEEDBACK REGULATION MECHANISM EXERTED BY THE HYPOTHALAMO-PITUITARY-ADRENAL (HPA) AXIS, MIGHT BE RESPONSIBLE FOR THE HIPPOCAMPAL ATROPHY OBSERVED IN DEPRESSED PATIENTS. ANTIDEPRESSANTS, POSSIBLY THROUGH THE ACTIVATION OF BDNF SIGNALING, MAY ENHANCE NEUROPLASTICITY AND RESTORE NORMAL HIPPOCAMPAL FUNCTIONS. IN THIS CONTEXT, GLUCOCORTICOID RECEPTOR-IMPAIRED (GR-I) MICE-A TRANSGENIC MOUSE MODEL OF REDUCED GR-INDUCED NEGATIVE FEEDBACK REGULATION OF THE HPA AXIS-WERE USED TO INVESTIGATE THE ROLE OF BDNF/TRKB SIGNALING IN THE BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF THE NEW GENERATION ANTIDEPRESSANT DRUG, AGOMELATINE. GR-I MICE EXHIBITED MARKED ALTERATIONS IN DEPRESSIVE-LIKE AND ANXIETY-LIKE BEHAVIORS, TOGETHER WITH A DECREASED CELL PROLIFERATION AND ALTERED LEVELS OF NEUROPLASTIC AND EPIGENETIC MARKERS IN THE HIPPOCAMPUS. GR-I MICE AND THEIR WILD-TYPE LITTERMATES WERE TREATED FOR 21 DAYS WITH VEHICLE, AGOMELATINE (50MG/KG/DAY; I.P) OR THE TRKB INHIBITOR ANA-12 (0.5MG/KG/DAY, I.P) ALONE, OR IN COMBINATION WITH AGOMELATINE. CHRONIC TREATMENT WITH AGOMELATINE RESULTED IN ANTIDEPRESSANT-LIKE EFFECTS IN GR-I MICE AND REVERSED THE DEFICIT IN HIPPOCAMPAL CELL PROLIFERATION AND SOME OF THE ALTERATIONS OF MRNA PLASTICITY MARKERS IN GR-I MICE. ANA-12 BLOCKED THE EFFECT OF AGOMELATINE ON MOTOR ACTIVITY AS WELL AS ITS ABILITY TO RESTORE A NORMAL HIPPOCAMPAL CELL PROLIFERATION AND EXPRESSION OF NEUROTROPHIC FACTORS. ALTOGETHER, OUR FINDINGS INDICATE THAT AGOMELATINE REQUIRES TRKB SIGNALING TO REVERSE SOME OF THE MOLECULAR AND BEHAVIORAL ALTERATIONS CAUSED BY HPA AXIS IMPAIRMENT. 2016 3 3312 52 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 4 869 38 CHRONIC AGOMELATINE TREATMENT CORRECTS BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES INDUCED BY PRENATAL STRESS IN RATS. RATIONALE AND OBJECTIVES: THE RAT MODEL OF PRENATAL RESTRAINT STRESS (PRS) REPLICATES FACTORS THAT ARE IMPLICATED IN THE ETIOLOGY OF ANXIOUS/DEPRESSIVE DISORDERS. WE USED THIS MODEL TO TEST THE THERAPEUTIC EFFICACY OF AGOMELATINE, A NOVEL ANTIDEPRESSANT THAT BEHAVES AS A MIXED MT1/MT2 MELATONIN RECEPTOR AGONIST/5-HT(2C) SEROTONIN RECEPTOR ANTAGONIST. RESULTS: ADULT PRS RATS SHOWED BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES THAT WERE CONSISTENT WITH AN ANXIOUS/DEPRESSIVE PHENOTYPE. THESE INCLUDED AN INCREASED IMMOBILITY IN THE FORCED SWIM TEST, AN ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE, REDUCED HIPPOCAMPAL LEVELS OF PHOSPHORYLATED CAMP-RESPONSIVE ELEMENT BINDING PROTEIN (P-CREB), REDUCED HIPPOCAMPAL LEVELS OF MGLU2/3 AND MGLU5 METABOTROPIC GLUTAMATE RECEPTORS, AND REDUCED NEUROGENESIS IN THE VENTRAL HIPPOCAMPUS, THE SPECIFIC PORTION OF THE HIPPOCAMPUS THAT ENCODES MEMORIES RELATED TO STRESS AND EMOTIONS. ALL OF THESE CHANGES WERE REVERSED BY A 3- OR 6-WEEK TREATMENT WITH AGOMELATINE (40-50 MG/KG, I.P., ONCE A DAY). REMARKABLY, AGOMELATINE HAD NO EFFECT IN AGE-MATCHED CONTROL RATS, THEREBY BEHAVING AS A "DISEASE-DEPENDENT" DRUG. CONCLUSIONS: THESE DATA INDICATE THAT AGOMELATINE DID NOT ACT ON INDIVIDUAL SYMPTOMS BUT CORRECTED ALL ASPECTS OF THE PATHOLOGICAL EPIGENETIC PROGRAMMING TRIGGERED BY PRS. OUR FINDINGS STRONGLY SUPPORT THE ANTIDEPRESSANT ACTIVITY OF AGOMELATINE AND SUGGEST THAT THE DRUG IMPACTS MECHANISMS THAT LIE AT THE CORE OF ANXIOUS/DEPRESSIVE DISORDERS. 2011 5 4299 34 MICRORNA-15B CONTRIBUTES TO DEPRESSION-LIKE BEHAVIOR IN MICE BY AFFECTING SYNAPTIC PROTEIN LEVELS AND FUNCTION IN THE NUCLEUS ACCUMBENS. MAJOR DEPRESSION IS A PREVALENT AFFECTIVE DISORDER CHARACTERIZED BY RECURRENT LOW MOOD. IT PRESUMABLY RESULTS FROM STRESS-INDUCED DETERIORATIONS OF MOLECULAR NETWORKS AND SYNAPTIC FUNCTIONS IN BRAIN REWARD CIRCUITS OF GENETICALLY-SUSCEPTIBLE INDIVIDUALS THROUGH EPIGENETIC PROCESSES. EPIGENETIC REGULATOR MICRORNA-15B INHIBITS NEURONAL PROGENITOR PROLIFERATION AND IS UP-REGULATED IN THE MEDIAL PREFRONTAL CORTEX OF MICE THAT DEMONSTRATE DEPRESSION-LIKE BEHAVIOR, INDICATING THE CONTRIBUTION OF MICRORNA-15 TO MAJOR DEPRESSION. USING A MOUSE MODEL OF MAJOR DEPRESSION INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS), HERE WE EXAMINED THE EFFECTS OF MICRORNA-15B ON SYNAPSES AND SYNAPTIC PROTEINS IN THE NUCLEUS ACCUMBENS OF THESE MICE. THE APPLICATION OF A MICRORNA-15B ANTAGOMIR INTO THE NUCLEUS ACCUMBENS SIGNIFICANTLY REDUCED THE INCIDENCE OF CUMS-INDUCED DEPRESSION AND REVERSED THE ATTENUATIONS OF EXCITATORY SYNAPSE AND SYNTAXIN-BINDING PROTEIN 3 (STXBP3A)/VESICLE-ASSOCIATED PROTEIN 1 (VAMP1) EXPRESSION. IN CONTRAST, THE INJECTION OF A MICRORNA-15B ANALOG INTO THE NUCLEUS ACCUMBENS INDUCED DEPRESSION-LIKE BEHAVIOR AS WELL AS ATTENUATED EXCITATORY SYNAPSES AND STXBP3A/VAMP1 EXPRESSION SIMILAR TO THE DOWN-REGULATION OF THESE PROCESSES INDUCED BY THE CUMS. WE CONCLUDE THAT MICRORNA-15B-5P MAY PLAY A CRITICAL ROLE IN CHRONIC STRESS-INDUCED DEPRESSION BY DECREASING SYNAPTIC PROTEINS, INNERVATIONS, AND ACTIVITIES IN THE NUCLEUS ACCUMBENS. WE PROPOSE THAT THE TREATMENT OF ANTI-MICRORNA-15B-5P MAY CONVERT STRESS-INDUCED DEPRESSION INTO RESILIENCE. 2020 6 5874 38 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 7 1808 48 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 8 989 33 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS. 2019 9 2672 36 ETHANOL-INDUCED EPIGENETIC REGULATIONS AT THE BDNF GENE IN C57BL/6J MICE. HIGH ETHANOL INTAKE IS WELL KNOWN TO INDUCE BOTH ANXIOLYTIC AND ANXIOGENIC EFFECTS, IN CORRELATION WITH CHROMATIN REMODELING IN THE AMYGDALOID BRAIN REGION AND DEFICITS IN CELL PROLIFERATION AND SURVIVAL IN THE HIPPOCAMPUS OF RODENTS. WHETHER ONLY MODERATE BUT CHRONIC ETHANOL INTAKE IN C57BL/6J MICE COULD ALSO HAVE AN IMPACT ON CHROMATIN REMODELING AND NEUROPLASTICITY WAS ADDRESSED HERE. CHRONIC ETHANOL CONSUMPTION IN A FREE CHOICE PARADIGM WAS FOUND TO INDUCE MARKED CHANGES IN THE EXPRESSION OF GENES IMPLICATED IN NEURAL DEVELOPMENT AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN THE MOUSE HIPPOCAMPUS. TRANSCRIPTS ENCODING NEURAL BHLH ACTIVATORS AND THOSE FROM BDNF EXONS II, III AND VI WERE UPREGULATED, WHEREAS THOSE FROM BDNF EXON VIII AND HDACS WERE DOWNREGULATED BY ETHANOL COMPARED WITH WATER CONSUMPTION. THESE ETHANOL-INDUCED CHANGES WERE ASSOCIATED WITH ENRICHMENT IN BOTH ACETYLATED H3 AT BDNF PROMOTER PVI AND TRIMETHYLATED H3 AT PII AND PIII. CONVERSELY, ACETYLATED H3 AT PIII AND PVIII AND TRIMETHYLATED H3 AT PVIII WERE DECREASED IN ETHANOL-EXPOSED MICE. IN PARALLEL, HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND TRKB-MEDIATED NEUROGENESIS IN THE DENTATE GYRUS WERE SIGNIFICANTLY ENHANCED BY ETHANOL CONSUMPTION. THESE RESULTS SUGGEST THAT, IN C57BL/6J MICE, CHRONIC AND MODERATE ETHANOL INTAKE PRODUCES MARKED EPIGENETIC CHANGES UNDERLYING BDNF OVEREXPRESSION AND DOWNSTREAM HIPPOCAMPAL NEUROGENESIS. 2015 10 3969 36 LONG-LASTING DEPRESSION-LIKE BEHAVIOR AND EPIGENETIC CHANGES OF BDNF GENE EXPRESSION INDUCED BY PERINATAL EXPOSURE TO METHYLMERCURY. SUBSTANTIAL EVIDENCE INDICATES THAT PREDISPOSITION TO DISEASES CAN BE ACQUIRED DURING EARLY STAGES OF DEVELOPMENT AND INTERACTIONS BETWEEN ENVIRONMENTAL AND GENETIC FACTORS MAY BE IMPLICATED IN THE ONSET OF MANY PATHOLOGICAL CONDITIONS. DATA COLLECTED OVER SEVERAL DECADES HAVE SHOWN THAT CHEMICALS ARE AMONG THE RELEVANT FACTORS THAT CAN ENDANGER CNS. WE PREVIOUSLY SHOWED THAT PERINATAL EXPOSURE TO METHYLMERCURY (MEHG) CAUSES PERSISTENT CHANGES IN LEARNING AND MOTIVATIONAL BEHAVIOR IN MICE. IN THIS STUDY, WE REPORT THAT THE DEPRESSION-LIKE BEHAVIOR IN MEHG-EXPOSED MALE MICE IS REVERSED BY CHRONIC TREATMENT WITH THE ANTIDEPRESSANT FLUOXETINE. BEHAVIORAL ALTERATIONS ARE ASSOCIATED WITH A DECREASE IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPAL DENTATE GYRUS AND FLUOXETINE TREATMENT RESTORES BDNF MRNA EXPRESSION. WE ALSO SHOW THAT MEHG-EXPOSURE INDUCES LONG-LASTING REPRESSIVE STATE OF THE CHROMATIN STRUCTURE AT THE BDNF PROMOTER REGION, IN PARTICULAR DNA HYPERMETHYLATION, AN INCREASE IN HISTONE H3-K27 TRI-METHYLATION AND A DECREASE IN H3 ACETYLATION AT THE PROMOTER IV. WHILE FLUOXETINE TREATMENT DOES NOT ALTER HYPERMETHYLATION OF H3-K27, IT SIGNIFICANTLY UP-REGULATES H3 ACETYLATION AT THE BDNF PROMOTER IV IN MEHG-EXPOSED MICE. OUR STUDY SHOWS THAT DEVELOPMENTAL EXPOSURE TO LOW LEVELS OF MEHG PREDISPOSES MICE TO DEPRESSION AND INDUCES EPIGENETIC SUPPRESSION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS. 2008 11 5339 32 QUETIAPINE TREATMENT REVERSES DEPRESSIVE-LIKE BEHAVIOR AND REDUCES DNA METHYLTRANSFERASE ACTIVITY INDUCED BY MATERNAL DEPRIVATION. STRESS IN EARLY LIFE HAS BEEN APPOINTED AS AN IMPORTANT PHENOMENON IN THE ONSET OF DEPRESSION AND POOR RESPONSE TO TREATMENT WITH CLASSICAL ANTIDEPRESSANTS. FURTHERMORE, CHILDHOOD TRAUMA TRIGGERS EPIGENETIC CHANGES, WHICH ARE ASSOCIATED WITH THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD). TREATMENT WITH ATYPICAL ANTIPSYCHOTICS SUCH AS QUETIAPINE, EXERTS THERAPEUTIC EFFECT FOR MDD PATIENTS AND INDUCES EPIGENETIC CHANGES. THIS STUDY AIMED TO ANALYZE THE EFFECT OF CHRONIC TREATMENT WITH QUETIAPINE (20MG/KG) ON DEPRESSIVE-LIKE BEHAVIOR OF RATS SUBMITTED TO MATERNAL DEPRIVATION (MD), AS WELL AS THE ACTIVITY OF HISTONE ACETYLATION BY THE ENZYMES HISTONE ACETYL TRANSFERASES (HAT) AND DEACETYLASES (HDAC) AND DNA METHYLATION, THROUGH DNA METHYLTRANSFERASE ENZYME (DNMT) IN THE PREFRONTAL CORTEX (PFC), NUCLEUS ACCUMBENS (NAC) AND HIPPOCAMPUS. MATERNALLY DEPRIVED RATS HAD A DEPRESSIVE-LIKE BEHAVIOR IN THE FORCED SWIMMING TEST AND AN INCREASE IN THE HDAC AND DNMT ACTIVITIES IN THE HIPPOCAMPUS AND NAC. TREATMENT WITH QUETIAPINE REVERSED DEPRESSIVE-LIKE BEHAVIOR AND REDUCED THE DNMT ACTIVITY IN THE HIPPOCAMPUS. THIS IS THE FIRST STUDY TO SHOW THE ANTIDEPRESSANT-LIKE EFFECT OF QUETIAPINE IN ANIMALS SUBJECTED TO MD AND A PROTECTIVE EFFECT BY QUETIAPINE IN REDUCING EPIGENETIC CHANGES INDUCED BY STRESS IN EARLY LIFE. THESE RESULTS REINFORCE AN IMPORTANT ROLE OF QUETIAPINE AS THERAPY FOR MDD. 2017 12 2705 39 EXERCISE AND LOW-LEVEL GABA(A) RECEPTOR INHIBITION MODULATE LOCOMOTOR ACTIVITY AND THE EXPRESSION OF BDNF ACCOMPANIED BY CHANGES IN EPIGENETIC REGULATION IN THE HIPPOCAMPUS. AEROBIC EXERCISE IS KNOWN TO INCREASE EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN THE HIPPOCAMPUS AND TO IMPROVE COGNITIVE FUNCTION. THE INHIBITION OF GABAERGIC SYNAPSES ENHANCES HIPPOCAMPAL PLASTICITY AS WELL AS LEARNING AND MEMORY. THE OBJECTIVE OF THE PRESENT STUDY WAS TO EXAMINE THE INTERACTIVE EFFECT OF LOW-LEVEL GABA(A) RECEPTOR INHIBITION AND EXERCISE ON BEHAVIOR TESTS (COGNITIVE FUNCTION AND LOCOMOTOR ACTIVITY), EXPRESSION OF BDNF AND EPIGENETIC REGULATIONS INCLUDING THE ACTIVITY LEVELS OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS) IN THE HIPPOCAMPUS. ICR MICE WERE DIVIDED INTO TWO GROUPS: THOSE WHO DID NOT PARTICIPATE IN EXERCISE AND THOSE WHO PARTICIPATED IN EXERCISE. EACH GROUP WAS SUBDIVIDED INTO TWO OTHER GROUPS: THE ONE WHO RECEIVED VEHICLE AND THE ONE WHO RECEIVED GABA(A) RECEPTOR ANTAGONIST, BICUCULLIN. WE ADMINISTERED SALINE OR BICUCULLINE INTRAPERITONEALLY TO THE MICE AT A NON-EPILEPTIC DOSE OF 0.25 MG/KG, WHEREAS THE MICE WERE EXERCISED ON A TREADMILL FOR APPROXIMATELY 1 H A DAY, 5 DAYS A WEEK FOR 4 WEEKS. NOVEL-OBJECT RECOGNITION TEST AND LOCOMOTOR ACTIVITY WERE ASSESSED AT A REST DAY APPROXIMATELY 4 DAYS BEFORE THE EUTHANASIA. THE MICE WERE EUTHANIZED 4 H AFTER THE LAST EXERCISE SESSION. AEROBIC EXERCISE FOR 4 WEEKS INCREASED MRNA AND PROTEIN EXPRESSION OF BDNF IN THE HIPPOCAMPUS, ACCOMPANIED BY ENHANCED HAT ACTIVITY. ALTERNATIVELY, BICUCULLINE ADMINISTRATION INCREASED HDAC ACTIVITY IN THE HIPPOCAMPUS. FURTHERMORE, EXERCISE IN THE PRESENCE OF BICUCULLINE ADMINISTRATION INCREASED LOCOMOTOR ACTIVITY, INDICATING THAT EXERCISE COMBINED WITH LOW-LEVEL GABA(A) RECEPTOR INHIBITION POTENTIATED THE ACTIVITY OF THE MICE. ALTOGETHER, THE PRESENT STUDY SUGGESTED THAT EXERCISE BENEFICIALLY CONTRIBUTES TO NEUROPROTECTION IN THE HIPPOCAMPUS ACCOMPANIED BY THE UP-REGULATION OF BDNF EXPRESSION AND EPIGENETIC REGULATION, WHEREAS THE CHRONIC INHIBITION OF GABA(A) RECEPTOR POTENTIATES EXERCISE-INDUCED BEHAVIORAL ACTIVITY. 2018 13 2152 40 EPIGENETIC MECHANISM OF 5-HT/NE/DA TRIPLE REUPTAKE INHIBITOR ON ADULT DEPRESSION SUSCEPTIBILITY IN EARLY STRESS MICE. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC, REMITTING AND DEBILITATING DISEASE AND THE ETIOLOGY OF MDD IS HIGHLY COMPLICATED THAT INVOLVES GENETIC AND ENVIRONMENTAL INTERACTIONS. DESPITE MANY PHARMACOTHERAPEUTIC OPTIONS, MANY PATIENTS REMAIN POORLY TREATED AND THE DEVELOPMENT OF EFFECTIVE TREATMENTS REMAINS A HIGH PRIORITY IN THE FIELD. LPM570065 IS A POTENT 5-HYDROXYTRYPTAMINE (5-HT), NOREPINEPHRINE (NE) AND DOPAMINE (DA) TRIPLE REUPTAKE INHIBITOR AND BOTH PRECLINICAL AND CLINICAL RESULTS DEMONSTRATE SIGNIFICANT EFFICACY AGAINST MDD. THIS STUDY EXTENDS PREVIOUS FINDINGS TO EXAMINE THE EFFECTS AND UNDERLYING MECHANISMS OF LPM570065 ON STRESS VULNERABILITY USING A "TWO-HIT" STRESS MOUSE MODEL. THE "TWO-HIT" STRESS MODEL USED ADULT MICE THAT HAD EXPERIENCED EARLY LIFE MATERNAL SEPARATION (MS) STRESS FOR SOCIAL DEFEAT STRESS (SDS) AND THEN THEY WERE EVALUATED IN THREE BEHAVIORAL ASSAYS: SUCROSE PREFERENCE TEST, TAIL SUSPENSION TEST AND FORCED SWIMMING TEST. FOR THE MECHANISTIC STUDIES, METHYLATION-SPECIFIC DIFFERENTIALLY EXPRESSED GENES IN MOUSE HIPPOCAMPAL TISSUE AND VENTRAL TEGMENTAL AREA (VTA) WERE ANALYZED BY WHOLE-GENOME TRANSCRIPTOME ANALYSIS ALONG WITH NEXT-GENERATION BISULFITE SEQUENCING ANALYSIS, FOLLOWED BY RT-PCR AND PYROPHOSPHATE SEQUENCING TO CONFIRM GENE EXPRESSION AND METHYLATION. LPM570065 SIGNIFICANTLY REVERSED DEPRESSIVE-LIKE BEHAVIORS IN THE MICE IN THE SUCROSE PREFERENCE TEST, THE TAIL SUSPENSION TEST, AND THE FORCED SWIMMING TEST. MORPHOLOGICALLY, LPM570065 INCREASED THE DENSITY OF DENDRITIC SPINES IN HIPPOCAMPAL CA1 NEURONS. HYPERMETHYLATION AND DOWNREGULATION OF OXYTOCIN RECEPTOR (OXTR) IN THE HIPPOCAMPAL TISSUES ALONG WITH INCREASED PROTEIN EXPRESSION OF DNMT1 AND DNMT3A IN MICE THAT EXPERIENCED THE "TWO-HIT" STRESS COMPARED TO THOSE THAT ONLY EXPERIENCED ADULTHOOD SOCIAL DEFEAT STRESS, AND LPM570065 COULD REVERSE THESE CHANGES. COMBINED, THESE RESULTS SUGGEST THAT METHYLATION SPECIFICITY OF THE GENE OXTR IN THE HIPPOCAMPUS MAY PLAY AN IMPORTANT ROLE IN EARLY LIFE STRESS-INDUCED SUSCEPTIBILITY TO DEPRESSION AND THAT THE5-HT/NE/DA TRIPLE REUPTAKE INHIBITOR LPM570065 MAY REDUCE DEPRESSION SUSCEPTIBILITY VIA THE REVERSAL OF THE METHYLATION OF THE GENE OXTR. 2022 14 3370 38 HISTONE MODIFICATION OF NEDD4 UBIQUITIN LIGASE CONTROLS THE LOSS OF AMPA RECEPTORS AND COGNITIVE IMPAIRMENT INDUCED BY REPEATED STRESS. STRESS AND THE MAJOR STRESS HORMONE CORTICOSTERONE INDUCE PROFOUND INFLUENCES IN THE BRAIN. ALTERED HISTONE MODIFICATION AND TRANSCRIPTIONAL DYSFUNCTION HAVE BEEN IMPLICATED IN STRESS-RELATED MENTAL DISORDERS. WE PREVIOUSLY FOUND THAT REPEATED STRESS CAUSED AN IMPAIRMENT OF PREFRONTAL CORTEX (PFC)-MEDIATED COGNITIVE FUNCTIONS BY INCREASING THE UBIQUITINATION AND DEGRADATION OF AMPA-TYPE GLUTAMATE RECEPTORS VIA A MECHANISM DEPENDING ON THE E3 UBIQUITIN LIGASE NEDD4. HERE, WE DEMONSTRATED THAT IN PFC OF REPEATEDLY STRESSED RATS, ACTIVE GLUCOCORTICOID RECEPTOR HAD THE INCREASED BINDING TO THE GLUCOCORTICOID RESPONSE ELEMENT OF HISTONE DEACETYLASE 2 (HDAC2) PROMOTER, RESULTING IN THE UPREGULATION OF HDAC2. INHIBITION OR KNOCK-DOWN OF HDAC2 BLOCKED THE STRESS-INDUCED IMPAIRMENT OF SYNAPTIC TRANSMISSION, AMPAR EXPRESSION, AND RECOGNITION MEMORY. FURTHERMORE, WE FOUND THAT, IN STRESSED ANIMALS, THE HDAC2-DEPENDENT DOWNREGULATION OF HISTONE METHYLTRANSFERASE EHMT2 (G9A) LED TO THE LOSS OF REPRESSIVE HISTONE METHYLATION AT THE NEDD4-1 PROMOTER AND THE TRANSCRIPTIONAL ACTIVATION OF NEDD4. THESE RESULTS HAVE PROVIDED AN EPIGENETIC MECHANISM AND A POTENTIAL TREATMENT STRATEGY FOR THE DETRIMENTAL EFFECTS OF CHRONIC STRESS. SIGNIFICANCE STATEMENT: PROLONGED STRESS EXPOSURE CAN INDUCE ALTERED HISTONE MODIFICATION AND TRANSCRIPTIONAL DYSFUNCTION, WHICH MAY UNDERLIE THE PROFOUND INFLUENCE OF STRESS IN REGULATING BRAIN FUNCTIONS. WE REPORT AN IMPORTANT FINDING ABOUT THE EPIGENETIC MECHANISM CONTROLLING THE DETRIMENTAL EFFECTS OF REPEATED STRESS ON SYNAPTIC TRANSMISSION AND COGNITIVE FUNCTION. FIRST, IT HAS REVEALED THE STRESS-INDUCED ALTERATION OF KEY EPIGENETIC REGULATORS HDAC2 AND EHMT2, WHICH DETERMINES THE SYNAPTIC AND BEHAVIORAL EFFECTS OF REPEATED STRESS. SECOND, IT HAS UNCOVERED THE STRESS-INDUCED HISTONE MODIFICATION OF THE TARGET GENE NEDD4, AN E3 LIGASE THAT IS CRITICALLY INVOLVED IN THE UBIQUITINATION AND DEGRADATION OF AMPA RECEPTORS AND COGNITION. THIRD, IT HAS PROVIDED THE EPIGENETIC APPROACH, HDAC2 INHIBITION OR KNOCK-DOWN, TO RESCUE SYNAPTIC AND COGNITIVE FUNCTIONS IN STRESSED ANIMALS. 2016 15 1004 42 CHRONIC TREATMENT WITH HORMONAL CONTRACEPTIVES ALTERS HIPPOCAMPAL BDNF AND HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS BUT NOT LEARNING AND MEMORY IN FEMALE RATS. HORMONAL CONTRACEPTIVES PREVENT OVULATION WITH SUBSEQUENT REDUCTION IN ENDOGENOUS LEVELS OF ESTRADIOL, PROGESTERONE AND ITS NEUROACTIVE METABOLITE ALLOPREGNANOLONE. THESE NEUROSTEROIDS MODULATE SEVERAL BRAIN FUNCTIONS, INCLUDING NEURONAL PLASTICITY, COGNITION AND MEMORY. WE HYPOTHESIZED THAT HORMONAL CONTRACEPTIVES MIGHT AFFECT SYNAPTIC PLASTICITY, LEARNING AND MEMORY, AS A CONSEQUENCE OF SUPPRESSED ENDOGENOUS HORMONES LEVELS. FEMALE RATS WERE ORALLY TREATED WITH A COMBINATION OF ETHINYL ESTRADIOL (EE, 0.020 MG) AND LEVONORGESTREL (LNG, 0.060 MG) ONCE DAILY FOR FOUR WEEKS. DECREASED HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND ALTERED HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS (PTMS) WERE OBSERVED 14 DAYS AFTER DISCONTINUATION FROM CHRONIC EE-LNG TREATMENT. THESE EFFECTS WERE NOT ACCOMPANIED BY ALTERATIONS IN LONG-TERM PLASTICITY AT GLUTAMATERGIC SYNAPSES, RECOGNITION MEMORY IN THE NOVEL OBJECT AND NOVEL PLACE LOCATION TESTS, OR SPATIAL LEARNING, MEMORY, AND BEHAVIORAL FLEXIBILITY IN THE MORRIS WATER MAZE TEST. THUS, DECREASED BDNF CONTENT DOES NOT AFFECT SYNAPTIC PLASTICITY AND COGNITIVE PERFORMANCE; RATHER IT MIGHT BE RELEVANT FOR THE OCCURRENCE OF CERTAIN PSYCHIATRIC SYMPTOMS, REPORTED BY SOME WOMEN USING HORMONAL CONTRACEPTIVES. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF HIPPOCAMPAL EPIGENETIC CHANGES INDUCED BY HORMONAL CONTRACEPTIVES AND COMPLEMENT PREVIOUS STUDIES ON THE NEUROBIOLOGICAL ACTIONS OF HORMONAL CONTRACEPTIVES; THE FINDING THAT EFFECTS OF CHRONIC EE-LNG TREATMENT ON BDNF CONTENT AND HISTONE PTMS ARE OBSERVED 14 DAYS AFTER DRUG DISCONTINUATION WARRANTS FURTHER INVESTIGATION TO BETTER UNDERSTAND THE IMPLICATIONS OF SUCH LONG-TERM CONSEQUENCES FOR WOMEN'S HEALTH. 2022 16 6804 39 [EPIGENETIC REGULATION IN DEPRESSION]. RECENT RESEARCH HAS RAISED THE NOTION THAT EPIGENETIC MECHANISMS (E.G., DNA METHYLATION AND HISTONE MODIFICATIONS), WHICH EXERT LASTING CONTROL OVER GENE EXPRESSION WITHOUT ALTERING THE GENETIC CODE, COULD MEDIATE STABLE CHANGES IN BRAIN FUNCTION. HOWEVER, THE ROLE OF ENVIRONMENTAL FACTORS ALONG WITH GENETIC FACTORS IN THE EPIGENETIC REGULATION OF THE PATHOGENESIS OF DEPRESSION IS LARGELY UNKNOWN. TWO GENETICALLY DISTINCT MICE STRAINS, BALB/C (BALB) AND C57BL/6 (B6), EXHIBIT DIFFERENT BEHAVIORAL RESPONSES TO CHRONIC STRESS. WITH CHRONIC STRESS, BALB MICE SHOWED DEPRESSIVE-LIKE BEHAVIORS, BUT NOT B6 MICE, AND GLIAL CELL-DERIVED NEUROTROPHIC FACTOR (GDNF) EXPRESSION LEVEL WAS DECREASED IN THE VENTRAL STRIATUM OF BALB MICE BUT INCREASED IN B6 MICE. IN BALB MICE, DEPRESSIVE-LIKE BEHAVIORS AND DECREASED GDNF EXPRESSION WERE RECOVERED BY CHRONIC ANTIDEPRESSANT TREATMENT. THEREFORE, WE USED THESE TWO MICE STRAINS TO INVESTIGATE HOW THE EPIGENETIC STATUS OF THE GDNF GENE IN THE VENTRAL STRIATUM MODULATES STRESS VULNERABILITY. BOTH MICE STRAINS SHOWED INCREASED DNA METHYLATION LEVELS AND MECP2 RECRUITMENT IN THE GDNF PROMOTER REGION. HOWEVER, HISTONE H3 ACETYLATION LEVEL WAS DECREASED IN BALB MICE, BUT INCREASED IN B6 MICE. FURTHERMORE, BALB MICE SHOWED INCREASED HISTONE DEACETYLASE2 (HDAC2) EXPRESSION LEVEL AND RE-CHIP ASSAY REVEALED HDAC2-MECP2 COMPLEX IN BALB MICE. OUR RESULTS INDICATE THE CRUCIAL ROLE OF HISTONE MODIFICATION BY HDAC2 AND MECP2 COMPLEX FOR THE CONTROL OF GDNF EXPRESSION AND SUBSEQUENT BEHAVIORAL RESPONSES TO CHRONIC STRESS, IN OTHER WORDS, THE SUSCEPTIBILITY TO STRESS. IN ADDITION, WE INVESTIGATED THE EFFECT OF ANTIDEPRESSANTS ON THE EPIGENETIC REGULATION OF GDNF EXPRESSION. WE FOUND A REDUCED LEVEL OF HDAC4 RECRUITMENT AT THE GDNF PROMOTER REGION WITH ANTIDEPRESSANTS. THUS, OUR DATA SUGGEST THAT ANTIDEPRESSANTS INCREASE TRANSCRIPTIONAL ACTIVITY OF THE GDNF GENE THROUGH THE MODULATION OF HISTONE ACETYLATION BY HDAC4. FINALLY, WE EXAMINED THE EXPRESSIONS OF GDNF AND EPIGENETIC-RELATED MOLECULES MRNAS WITH MAJOR DEPRESSIVE AND BIPOLAR DISORDER PATIENTS BY USING QUANTITATIVE REAL-TIME PCR. WE FOUND THE ABERRANT EXPRESSION OF GDNF AND EPIGENETIC-RELATED GENES INCLUDING HDAC2 AND HDAC4 IN MOOD DISORDER PATIENTS. THUS, OUR DATA PROVIDE NOVEL INSIGHTS SUGGESTING THAT EPIGENETIC MECHANISMS OF GDNF EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OR PATHOPHYSIOLOGY OF DEPRESSION. 2012 17 3590 28 IMPAIRED LATENT INHIBITION IN GDNF-DEFICIENT MICE EXPOSED TO CHRONIC STRESS. INCREASED REACTIVITY TO STRESS IS MALADAPTIVE AND LINKED TO ABNORMAL BEHAVIORS AND PSYCHOPATHOLOGY. CHRONIC UNPREDICTABLE STRESS (CUS) ALTERS CATECHOLAMINERGIC NEUROTRANSMISSION AND REMODELS NEURONAL CIRCUITS INVOLVED IN LEARNING, ATTENTION AND DECISION MAKING. GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) IS ESSENTIAL FOR THE PHYSIOLOGY AND SURVIVAL OF DOPAMINERGIC NEURONS IN SUBSTANTIA NIGRA AND OF NORADRENERGIC NEURONS IN THE LOCUS COERULEUS. UP-REGULATION OF GDNF EXPRESSION DURING STRESS IS LINKED TO RESILIENCE; ON THE OTHER HAND, THE INABILITY TO UP-REGULATE GDNF IN RESPONSE TO STRESS, AS A RESULT OF EITHER GENETIC OR EPIGENETIC MODIFICATIONS, INDUCES BEHAVIORAL ALTERATIONS. FOR EXAMPLE, GDNF-DEFICIENT MICE EXPOSED TO CHRONIC STRESS EXHIBIT ALTERATIONS OF EXECUTIVE FUNCTION, SUCH AS INCREASED TEMPORAL DISCOUNTING. HERE WE INVESTIGATED THE EFFECTS OF CUS ON LATENT INHIBITION (LI), A MEASURE OF SELECTIVE ATTENTION AND LEARNING, IN GDNF-HETEROZYGOUS (HET) MICE AND THEIR WILD-TYPE (WT) LITTERMATE CONTROLS. NO DIFFERENCES IN LI WERE FOUND BETWEEN GDNF HET AND WT MICE UNDER BASELINE EXPERIMENTAL CONDITIONS. HOWEVER, FOLLOWING CUS, GDNF-DEFICIENT MICE FAILED TO EXPRESS LI. MOREOVER, STRESSED GDNF-HET MICE, BUT NOT THEIR WT CONTROLS, SHOWED DECREASED NEURONAL ACTIVATION (NUMBER OF C-FOS POSITIVE NEURONS) IN THE NUCLEUS ACCUMBENS SHELL AND INCREASED ACTIVATION IN THE NUCLEUS ACCUMBENS CORE, BOTH KEY REGIONS IN THE EXPRESSION OF LI. OUR RESULTS ADD LI TO THE LIST OF BEHAVIORS AFFECTED BY CHRONIC STRESS AND SUPPORT A ROLE FOR GDNF DEFICITS IN STRESS-INDUCED PATHOLOGICAL BEHAVIORS RELEVANT TO SCHIZOPHRENIA AND OTHER PSYCHIATRIC DISORDERS. 2017 18 5820 34 STRESS DYNAMICALLY REGULATES BEHAVIOR AND GLUTAMATERGIC GENE EXPRESSION IN HIPPOCAMPUS BY OPENING A WINDOW OF EPIGENETIC PLASTICITY. EXCITATORY AMINO ACIDS PLAY A KEY ROLE IN BOTH ADAPTIVE AND DELETERIOUS EFFECTS OF STRESSORS ON THE BRAIN, AND DYSREGULATED GLUTAMATE HOMEOSTASIS HAS BEEN ASSOCIATED WITH PSYCHIATRIC AND NEUROLOGICAL DISORDERS. HERE, WE ELUCIDATE MECHANISMS OF EPIGENETIC PLASTICITY IN THE HIPPOCAMPUS IN THE INTERACTIONS BETWEEN A HISTORY OF CHRONIC STRESS AND FAMILIAR AND NOVEL ACUTE STRESSORS THAT ALTER EXPRESSION OF ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. WE DEMONSTRATE THAT ACUTE RESTRAINT AND ACUTE FORCED SWIM STRESSORS INDUCE DIFFERENTIAL EFFECTS ON THESE BEHAVIORS IN NAIVE MICE AND IN MICE WITH A HISTORY OF CHRONIC-RESTRAINT STRESS (CRS). THEY REVEAL A KEY ROLE FOR EPIGENETIC UP- AND DOWN-REGULATION OF THE PUTATIVE PRESYNAPTIC TYPE 2 METABOTROPIC GLUTAMATE (MGLU2) RECEPTORS AND THE POSTSYNAPTIC NR1/NMDA RECEPTORS IN THE HIPPOCAMPUS AND PARTICULARLY IN THE DENTATE GYRUS (DG), A REGION OF ACTIVE NEUROGENESIS AND A TARGET OF ANTIDEPRESSANT TREATMENT. WE SHOW CHANGES IN DG LONG-TERM POTENTIATION (LTP) THAT PARALLEL BEHAVIORAL RESPONSES, WITH HABITUATION TO THE SAME ACUTE RESTRAINT STRESSOR AND SENSITIZATION TO A NOVEL FORCED-SWIM STRESSOR. IN WT MICE AFTER CRS AND IN UNSTRESSED MICE WITH A BDNF LOSS-OF-FUNCTION ALLELE (BDNF VAL66MET), WE SHOW THAT THE EPIGENETIC ACTIVATOR OF HISTONE ACETYLATION, P300, PLAYS A PIVOTAL ROLE IN THE DYNAMIC UP- AND DOWN-REGULATION OF MGLU2 IN HIPPOCAMPUS VIA HISTONE-3-LYSINE-27-ACETYLATION (H3K27AC) WHEN ACUTE STRESSORS ARE APPLIED. THESE HIPPOCAMPAL RESPONSES REVEAL A WINDOW OF EPIGENETIC PLASTICITY THAT MAY BE USEFUL FOR TREATMENT OF DISORDERS IN WHICH GLUTAMATERGIC TRANSMISSION IS DYSREGULATED. 2015 19 1907 43 ENRICHED ENVIRONMENT PRIORS TO TET1 HIPPOCAMPAL ADMINISTRATION FOR REGULATING PSYCHIATRIC BEHAVIORS VIA GLIAL REACTIVITY IN CHRONIC CEREBRAL HYPOPERFUSION MODELS. BACKGROUND: CHRONIC CEREBRAL HYPOPERFUSION (CCH) HAS BEEN GRADUALLY REGARDED AS A COMMON ETIOLOGIC MECHANISM FOR COGNITIVE AND PSYCHIATRIC DISTURBANCES. TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1) PLAYED AN IMPORTANT ROLE IN ADULT HIPPOCAMPAL NEUROGENESIS (AHN), NEURONAL CIRCUITS FORMATION, COGNITION AND PSYCHIATRIC DISORDERS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON COGNITION AND DEPRESSION VIA EFFECTIVELY REGULATING AHN AND GLIAL REACTIVITY. THIS STUDY AIMED TO ASSESS WHICH STRATEGY WAS FEASIBLE TO IMPROVE COGNITION AND PSYCHIATRIC DISTURBANCES BY COMPARING THE TET1 HIPPOCAMPAL MICROINJECTION AND EE IN CCH MODELS AND TO INVESTIGATE THE POSSIBLE MECHANISMS. METHOD: CCH RATS WERE ESTABLISHED VIA PERMANENT BILATERAL COMMON CAROTID ARTERY OCCLUSION (2-VO). RATS WERE STEREOTAXICALLY INJECTED WITH THE HUMAN CATALYTIC DOMAIN OF TET1 (HTET1) TO OVEREXPRESS THE HTET1 IN THE HIPPOCAMPUS 10 DAYS BEFORE 2-VO. 3 DAYS AFTER 2-VO, RATS WERE SUBJECTED TO STANDARD ENVIRONMENT OR EE WITH FREE ACCESS TO FOOD AND WATER. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION BEFORE SACRIFICE. EPIGENETIC MOLECULES, ADULT NEUROGENESIS, SYNAPTIC PROTEINS EXPRESSION, AND GLIAL ACTIVATION WERE ANALYZED USING IMMUNOFLUORESCENT STAINING, QRT-PCR AND WESTERN BLOT. RESULTS: IN THE PRESENT STUDY, WE FOUND BOTH EE AND GENETICAL TREATMENT WITH OVEREXPRESSING HTET1 WERE SUFFICIENT FOR STIMULATING AHN. HOWEVER, PROMOTING ANH COULD NOT DEAL WITH THE COGNITIVE DYSFUNCTION AND DEPRESSIVE-LIKE BEHAVIORS IN CCH RATS. NOTABLY, A HEALTHY LOCAL BRAIN ENVIRONMENT WITH ELEVATED BDNF AND ASTROCYTES WAS CONDUCIVE TO IMPROVING COGNITIVE DYSFUNCTION. MEANWHILE, ASTROCYTES WERE INVOLVED IN THE COGNITIVE REGULATING PROCESS OF NEURONS, PRESYNAPTIC FUNCTION AND MICROGLIA. IN GENERAL, WE HELD THAT DEPRESSIVE DISTURBANCES WERE DETERMINED BY BDNF LEVELS, NEURONAL AND PRESYNAPTIC FUNCTION, AS WELL AS GLIAL ACTIVATION CONTAINING ASTROCYTES AND MICROGLIA. TO FURTHER SUPPORT THIS POINT, WE INVESTIGATED SEVERE DEPRESSIVE SYMPTOMS THAT WERE STRONGLY CORRELATED WITH THE ACTIVATION OF ASTROGLIA AND MICROGLIA. IMPORTANTLY, CAUSAL MEDIATION ANALYSIS SHOWED SIGNIFICANT MEDIATION BY THE PRESENCE OF REACTIVE GLIAL CELLS IN THE RELATION BETWEEN NEURAL PLASTICITY AND DEPRESSIVE SYMPTOMS. FINALLY, WE SHOWED EE PERFORMED BETTER THAN HTET1 TREATMENT FOR COGNITIVE DEFICITS AND DEPRESSION. EE WITH LESS GLIAL REACTIVITY WAS MUCH MORE RESISTANT TO DEPRESSION, WHILE HTET1 WITH MORE GLIAL ACTIVATION WAS MORE VULNERABLE TO DEPRESSIVE DISORDERS. CONCLUSIONS: EE WAS LIKELY TO BE SUPERIOR TO TET1 HIPPOCAMPAL ADMINISTRATION FOR COGNITION AND PSYCHIATRIC BEHAVIORS IN CCH RATS. FURTHERMORE, A HEALTHY LOCAL BRAIN ENVIRONMENT WITH ELEVATED BDNF AND ASTROCYTES WAS CONDUCIVE TO IMPROVING COGNITIVE DYSFUNCTION. MORE GLIAL ACTIVATION, AND MORE VULNERABLE TO DEPRESSIVE DISORDERS. THESE RESULTS WERE IMPORTANT FOR OUR UNDERSTANDING OF DISEASE MECHANISMS AND PROVIDED VALUABLE TOOLS FOR THE OVERALL MANAGEMENT OF CCH PATIENTS. 2022 20 3328 40 HISTONE DEACETYLASE 5 MODULATES THE EFFECTS OF SOCIAL ADVERSITY IN EARLY LIFE ON COCAINE-INDUCED BEHAVIOR. PSYCHOSTIMULANTS INDUCE STABLE CHANGES IN NEURAL PLASTICITY AND BEHAVIOR IN A TRANSCRIPTION-DEPENDENT MANNER. FURTHER, STABLE CELLULAR CHANGES REQUIRE TRANSCRIPTION THAT IS REGULATED BY EPIGENETIC MECHANISMS THAT ALTER CHROMATIN STRUCTURE, SUCH AS HISTONE ACETYLATION. THIS MECHANISM IS TYPICALLY CATALYZED BY ENZYMES WITH HISTONE ACETYLTRANSFERASE OR HISTONE DEACETYLASE (HDAC) ACTIVITY. CLASS IIA HDACS ARE NOTABLE FOR THEIR HIGH EXPRESSION IN IMPORTANT REGIONS OF THE BRAIN REWARD CIRCUITRY AND THEIR NEURAL ACTIVITY-DEPENDENT SHUTTLING IN AND OUT OF THE CELL NUCLEUS. IN PARTICULAR, HDAC5 HAS AN IMPORTANT MODULATORY FUNCTION IN COCAINE-INDUCED BEHAVIORS AND SOCIAL DEFEAT STRESS-INDUCED EFFECTS. ALTHOUGH A MUTATION IN HDAC5 HAS BEEN SHOWN TO CAUSE HYPERSENSITIVE RESPONSES TO CHRONIC COCAINE USE WHETHER THIS RESPONSE WORSENS DURING CHRONIC EARLY LIFE STRESS HAS NOT BEEN EXAMINED YET. IN THIS STUDY, WE EXPOSED MOUSE PUPS TO TWO DIFFERENT EARLY LIFE STRESS PARADIGMS (SOCIAL ISOLATION, ESI, AND SOCIAL THREAT, EST) TO DETERMINE WHETHER THE HETEROZYGOUS NULL MUTATION IN HDAC5 (HDAC5+/-) MODERATED THE EFFECTS OF EXPOSURE TO STRESS IN EARLY LIFE ON ADULT COCAINE-INDUCED CONDITIONED PLACE PREFERENCE (CPP). NOTABLY, HDAC5+/- MICE THAT HAD BEEN EXPOSED TO ESI WERE MORE SUSCEPTIBLE TO DEVELOPING COCAINE-INDUCED CPP AND MORE RESISTANT TO EXTINGUISHING THIS BEHAVIOR. THE SAME EFFECT WAS NOT OBSERVED FOR HDAC5+/- MICE EXPERIENCING EST, SUGGESTING THAT ONLY ESI INDUCES BEHAVIORAL CHANGES BY ACTING PRECISELY THROUGH HDAC5-RELATED BIOLOGICAL PATHWAYS. FINALLY, AN ANALYSIS OF C-FOS EXPRESSION PERFORMED TO DISCOVER THE NEUROBIOLOGICAL SUBSTRATES THAT MEDIATED THIS PHENOTYPE, IDENTIFIED THE DORSOLATERAL STRIATUM AS AN IMPORTANT STRUCTURE THAT MEDIATES THE INTERACTION BETWEEN HDAC5 MUTATION AND ESI. OUR DATA DEMONSTRATE THAT DECREASED HDAC5 FUNCTION IS ABLE TO EXACERBATE THE LONG-TERM BEHAVIORAL EFFECTS OF ADVERSE REARING ENVIRONMENT IN MOUSE. 2017