1 3318 134 HISTONE ACETYLATION AND EXPRESSION OF MONO-AMINERGIC TRANSMITTERS SYNTHETASES INVOLVED IN CUS-INDUCED DEPRESSIVE RATS. HISTONE ACETYLATION HAS BEEN LINKED TO DEPRESSION, THE ETIOLOGY OF WHICH INVOLVES MANY FACTORS SUCH AS GENETICS, ENVIRONMENTS, AND EPIGENETICS. THE AIM OF THE PRESENT STUDY WAS TO INVESTIGATE WHETHER IT WAS ASSOCIATED WITH EPIGENETIC HISTONE MODIFICATION AND GENE EXPRESSION OF ENZYMES RESPONSIBLE FOR THE BIOSYNTHESIS OF NOREPINEPHRINE AND SEROTONIN IN RAT DEPRESSION MODEL INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS). EIGHT-WEEK-OLD MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO CUS OVER 28 DAYS. IT WAS SHOWN THAT THE CUS-INDUCED RATS DISPLAYED REMARKED ANXIETY- AND DEPRESSION-LIKE BEHAVIOR WITH WEAKENED LOCOMOTOR ACTIVITY IN OPEN FIELD TEST AND PROLONGED IMMOBILITY IN FORCED SWIMMING TEST. WESTERN BLOT REVEALED THAT CUS LED TO SIGNIFICANT DECREASE IN ACETYLATION OF H3 AT LYSINE 9 (K9) AND H4 AT LYSINE 12 (K12) WITH OBVIOUSLY INCREASING HISTONE DEACETYLASES 5 (HDAC5) EXPRESSION IN HIPPOCAMPUS OF CUS-INDUCED RATS. MEANWHILE, THERE WAS AN OBVIOUSLY DECREASED EXPRESSION OF TYROSINE HYDROXYLASE (TH) AND TRYPTOPHAN HYDROXYLASE (TPH) BOTH AT PROTEIN AND MRNA LEVELS. ADMINISTRATION OF SODIUM VALPROATE (VPA), A HISTONE DEACETYLASE 5 (HDAC5) INHIBITOR, NOT ONLY SIGNIFICANTLY RELIEVED THE ANXIETY- AND DEPRESSION-LIKE BEHAVIORS OF CUS-INDUCED RATS BUT ALSO CLEARLY BLUNTED DECREASE OF H3(K9) AND H4(K12) ACETYLATION AND EXPRESSION OF TH AND TPH, AND PREVENTED INCREASE OF HDAC5 EXPRESSION. THE RESULTS INDICATE THAT THERE EXISTS POSSIBLE INTERRELATION BETWEEN TH AND TPH GENE EXPRESSION AND EPIGENETIC HISTONE ACETYLATION IN CUS-INDUCED DEPRESSIVE RATS, WHICH AT LEAST PARTLY CONTRIBUTES TO THE ETIOLOGY OF DEPRESSION. 2014 2 5339 36 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 3 1808 40 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 4 2705 38 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 5 2672 32 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 6 6804 45 [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 7 3328 39 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 8 2152 38 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 9 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 10 3370 36 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 11 4299 28 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 12 4173 38 MELATONIN INDUCES HISTONE HYPERACETYLATION IN THE RAT BRAIN. WE HAVE REPORTED THAT MELATONIN INDUCES HISTONE HYPERACETYLATION IN MOUSE NEURAL STEM CELLS, SUGGESTING AN EPIGENETIC ROLE FOR THIS PLEIOTROPIC HORMONE. TO SUPPORT SUCH A ROLE, IT IS NECESSARY TO DEMONSTRATE THAT MELATONIN PRODUCES SIMILAR EFFECTS IN VIVO. HISTONE ACETYLATION, FOLLOWING CHRONIC TREATMENT WITH MELATONIN (4MUG/ML IN DRINKING WATER FOR 17 DAYS), WAS EXAMINED BY WESTERN BLOTTING IN SELECTED RAT BRAIN REGIONS. MELATONIN INDUCED SIGNIFICANT INCREASES IN HISTONE H3 AND HISTONE H4 ACETYLATION IN THE HIPPOCAMPUS. HISTONE H4 WAS ALSO HYPERACETYLATED IN THE STRIATUM, BUT THERE WERE NO SIGNIFICANT CHANGES IN HISTONE H3 ACETYLATION IN THIS BRAIN REGION. NO SIGNIFICANT CHANGES IN THE ACETYLATION OF EITHER HISTONE H3 OR H4 WERE OBSERVED IN THE MIDBRAIN AND CEREBELLUM. AN EXAMINATION OF KINASE ACTIVATION, WHICH MAY BE RELATED TO THESE CHANGES, REVEALED THAT MELATONIN TREATMENT INCREASED THE LEVELS OF PHOSPHO-ERK (EXTRACELLULAR SIGNAL-REGULATED KINASE) IN THE HIPPOCAMPUS AND STRIATUM, BUT PHOSPHO-AKT (PROTEIN KINASE B) LEVELS WERE UNCHANGED. THESE FINDINGS SUGGEST THAT CHROMATIN REMODELING AND ASSOCIATED CHANGES IN THE EPIGENETIC REGULATION OF GENE EXPRESSION UNDERLIE THE MULTIPLE PHYSIOLOGICAL EFFECTS OF MELATONIN. 2013 13 1328 39 DEPRESSION AND STRESS LEVELS INCREASE RISK OF LIVER CANCER THROUGH EPIGENETIC DOWNREGULATION OF HYPOCRETIN. RECENT STUDIES SUGGEST THAT HYPOCRETIN (HCRT, OREXIN) ARE INVOLVED IN STRESS REGULATION OF DEPRESSION THROUGH THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. HOWEVER, THE MOLECULAR MECHANISM BY WHICH HYPOCRETIN REGULATE NEUROBIOLOGICAL RESPONSES IS UNKNOWN. HEREIN, THE EFFECTS OF CHRONIC STRESS ON THE EPIGENETIC MODIFICATION OF HCRT AND ITS ASSOCIATION WITH DEPRESSION WERE EXPLORED WITH REGARD TO A POTENTIAL ROLE IN CANCER PROGRESSION. IN THE STUDY, SPRAGUE DAWLEY (SD) RATS WERE USED TO ESTABLISH AN ANIMAL MODEL OF CANCER WITH DEPRESSION BY ADMINISTRATING N-NITROSODIETHYLAMINE (DEN) AND CHRONIC UNPREDICTABLE MILD STRESS (CUMS). RNA-SEQUENCING WAS USED TO DETECT DIFFERENTIALLY EXPRESSED GENES IN THE HIPPOCAMPUS OF RATS AND QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR) WAS USED TO VALIDATE THE RESULTS OF RNA-SEQUENCING. THE STATUS OF HCRT PROMOTER METHYLATION WAS ASSESSED BY METHYLATION SPECIFIC POLYMERASE CHAIN REACTION. BEHAVIORAL TESTS SHOWED THAT RATS EXPOSED TO CUMS HAD SIGNIFICANT DEPRESSIVE-LIKE BEHAVIORS. THE NUMBER OF LIVER TUMORS AND TUMOR LOAD IN DEPRESSED RATS EXPOSED TO CUMS WAS HIGHER THAN IN SD RATS WITHOUT CUMS. RNA-SEQUENCING REVEALED THAT HCRT WAS ONE OF THE MOST SIGINIFICANTLY DOWNREGULATED GENE IN THE HIPPOCAMPUS OF SD RATS WITH CUMS COMPARED TO NON-STRESSED GROUP, WHICH WAS VALIDATED BY QRT-PCR. HCRT MRNA EXPRESSION WAS DOWNREGULATED AND THE PROMOTER FOR HCRT WAS HYPER-METHYLATED IN THOSE WITH DEPRESSION. THESE RESULTS IDENTIFIED A CRITICAL ROLE FOR CHRONIC PSYCHOLOGICAL STRESSORS IN TUMORIGENESIS AND CANCER PROGRESSION, VIA EPIGENETIC HCRT DOWNREGULATION. SUCH EPIGENETIC DOWNREGULATION MAY BE THE MOLECULAR BASIS FOR THE ASSOCIATION OF CANCER WITH DEPRESSION. 2022 14 3969 39 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 15 3590 33 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 16 989 27 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 17 3325 43 HISTONE DEACETYLASE 2-MEDIATED EPIGENETIC REGULATION IS INVOLVED IN THE EARLY ISOFLURANE EXPOSURE-RELATED INCREASE IN SUSCEPTIBILITY TO ANXIETY-LIKE BEHAVIOUR EVOKED BY CHRONIC VARIABLE STRESS IN MICE. INCREASING STUDIES REPORT THAT PROLONGED OR MULTIPLE ANAESTHETIC EXPOSURES EARLY IN LIFE ARE ASSOCIATED WITH DETRIMENTAL EFFECTS ON BRAIN FUNCTION. ALTHOUGH STUDIES HAVE EVALUATED THE DETRIMENTAL EFFECTS ON NEUROCOGNITIVE FUNCTION, FEW HAVE FOCUSED ON LONG-TERM NEUROPSYCHIATRIC EFFECTS. IN THE PRESENT STUDY, C57BL/6 MICE RECEIVED EITHER THREE NEONATAL ISOFLURANE EXPOSURES OR CONTROL EXPOSURE. STARTING ON POSTNATAL DAY 45, THE MICE WERE EITHER EXPOSED OR NOT TO A CHRONIC VARIABLE STRESS (CVS) PARADIGM, AND CVS-RELATED NEUROPSYCHIATRIC PERFORMANCE WAS EVALUATED USING A SERIES OF BEHAVIOURAL TESTS. THE EXPRESSION LEVELS OF HISTONE 3 LYSINE 9 ACETYLATION (ACETYL-H3K9), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN, AND HISTONE DEACETYLASES 1-4 IN THE AMYGDALA WERE MEASURED BY IMMUNOBLOTTING OR IMMUNOHISTOCHEMISTRY ANALYSIS. IN MICE WITH NEONATAL ISOFLURANE EXPOSURE, THE EFFECTS OF SODIUM BUTYRATE (NAB), A COMMONLY USED HDAC INHIBITOR, WERE EXAMINED ON CVS-RELATED BEHAVIOURAL AND MOLECULAR ALTERATIONS. THE RESULTS SHOWED THAT REPEATED NEONATAL ISOFLURANE EXPOSURE DID NOT AFFECT INNATE DEPRESSION-LIKE AND ANXIETY-LIKE BEHAVIOURS UNDER NON-STRESS CONDITIONS BUT FACILITATED THE CVS-INDUCED ANXIETY-LIKE BEHAVIOURAL PHENOTYPE. INCREASED HDAC2 EXPRESSION IN THE AMYGDALA WAS ASSOCIATED WITH AN INCREASE IN THE CVS-INDUCED REPRESSION OF ACETYL-H3K9 AND BDNF EXPRESSION AND AN ENHANCED CVS-EVOKED ANXIETY-LIKE BEHAVIOURAL PHENOTYPE IN MICE NEONATAL ISOFLURANE EXPOSURE. NAB SIGNIFICANTLY DECREASED THE CVS-INDUCED ANXIETY LEVEL BY ELEVATING ACETYL-H3K9 AND BDNF EXPRESSION. THESE RESULTS SUGGESTED THAT EARLY ANAESTHESIA EXPOSURE FACILITATED CHRONIC STRESS-INDUCED NEUROPSYCHIATRIC OUTCOMES, AND THE HDAC2-RELATED EPIGENETIC DYSREGULATION OF BDNF GENE EXPRESSION IS INVOLVED IN THE UNDERLYING MECHANISM. 2021 18 1903 39 ENHANCED NEUROINFLAMMATION MEDIATED BY DNA METHYLATION OF THE GLUCOCORTICOID RECEPTOR TRIGGERS COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS SUBJECTED TO MATERNAL SEPARATION DURING THE NEONATAL PERIOD. BACKGROUND: MOUNTING EVIDENCE INDICATES THAT CHILDREN WHO EXPERIENCE ABUSE AND NEGLECT ARE PRONE TO CHRONIC DISEASES AND PREMATURE MORTALITY LATER IN LIFE. ONE MECHANISTIC HYPOTHESIS FOR THIS PHENOMENON IS THAT EARLY LIFE ADVERSITY ALTERS THE EXPRESSION OR FUNCTIONING OF THE GLUCOCORTICOID RECEPTOR (GR) THROUGHOUT THE COURSE OF LIFE AND THEREBY INCREASES SENSITIVITY TO INFLAMMATORY STIMULATION. AN EXAGGERATED PRO-INFLAMMATORY RESPONSE IS GENERALLY CONSIDERED TO BE A KEY CAUSE OF POSTOPERATIVE COGNITIVE DYSFUNCTION (POCD). THE AIM OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF EARLY LIFE ADVERSITY ON COGNITIVE FUNCTION AND NEUROINFLAMMATION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS AND TO DETERMINE WHETHER SUCH EFFECTS ARE ASSOCIATED WITH THE EPIGENETIC REGULATION OF GR. METHODS: WISTAR RAT PUPS WERE REPEATEDLY SUBJECTED TO INFANT MATERNAL SEPARATION (EARLY LIFE STRESS) FROM POSTNATAL DAYS 2-21. IN ADULTHOOD, THEIR BEHAVIOR AND THE SIGNALING OF HIPPOCAMPAL PRO-INFLAMMATORY FACTORS AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AFTER SEVOFLURANE ANESTHESIA WERE EVALUATED. WE ALSO EXAMINED THE EFFECTS OF MATERNAL SEPARATION (MS) ON THE EXPRESSION OF GR AND THE DNA METHYLATION STATUS OF THE PROMOTER REGION OF EXON 1(7) OF GR AND WHETHER BEHAVIORAL CHANGES AND NEUROINFLAMMATION AFTER ANESTHESIA WERE REVERSIBLE WHEN THE EXPRESSION OF GR WAS INCREASED BY ALTERING DNA METHYLATION. RESULTS: MS INDUCED COGNITIVE DECLINE AFTER SEVOFLURANE INHALATION IN THE MORRIS WATER MAZE AND CONTEXT FEAR CONDITIONING TESTS AND ENHANCED THE RELEASE OF CYTOKINES AND THE ACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING INDUCED BY SEVOFLURANE IN THE HIPPOCAMPUS OF ADULT RATS. BLOCKING NF-KAPPAB SIGNALING BY PYRROLIDINE DITHIOCARBAMATE (PDTC) INHIBITED THE RELEASE OF CYTOKINES. MS ALSO REDUCED THE EXPRESSION OF GR AND UPREGULATED THE METHYLATION LEVELS OF THE PROMOTER REGION OF GR EXON 1(7), AND SUCH EFFECTS WERE REVERSED BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) IN ADULT RATS. MOREOVER, TSA TREATMENT IN ADULT MS RATS INHIBITED THE OVERACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING AND THE RELEASE OF CYTOKINES AND ALLEVIATED COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA. CONCLUSIONS: EARLY LIFE STRESS INDUCES COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA, PERHAPS DUE TO THE ABERRANT METHYLATION OF THE GR GENE PROMOTER, WHICH REDUCES THE EXPRESSION OF THE GR GENE AND FACILITATES EXAGGERATED INFLAMMATORY RESPONSES. 2017 19 2318 31 EPIGENETIC REGULATION OF GABAERGIC DIFFERENTIATION IN THE DEVELOPING BRAIN. IN THE VERTEBRATE BRAIN, GABAERGIC CELL DEVELOPMENT AND NEUROTRANSMISSION ARE IMPORTANT FOR THE ESTABLISHMENT OF NEURAL CIRCUITS. VARIOUS INTRINSIC AND EXTRINSIC FACTORS HAVE BEEN IDENTIFIED TO AFFECT GABAERGIC NEUROGENESIS. HOWEVER, LITTLE IS KNOWN ABOUT THE EPIGENETIC CONTROL OF GABAERGIC DIFFERENTIATION IN THE DEVELOPING BRAIN. HERE, WE REPORT THAT THE NUMBER OF GABAERGIC NEURONS DYNAMICALLY CHANGES DURING THE EARLY TECTAL DEVELOPMENT IN THE XENOPUS BRAIN. THE PERCENTAGE OF GABAERGIC NEURONS IS RELATIVELY UNCHANGED DURING THE EARLY STAGES FROM STAGE 40 TO 46 BUT SIGNIFICANTLY DECREASED FROM STAGE 46 TO 48 TADPOLES. INTERESTINGLY, THE HISTONE ACETYLATION OF H3K9 IS DEVELOPMENTALLY DECREASED FROM STAGE 42 TO 48 (ABOUT 3.5 DAYS). CHRONIC APPLICATION OF VALPROATE ACID (VPA), A BROAD-SPECTRUM HISTONE DEACETYLASE (HDAC) INHIBITOR, AT STAGE 46 FOR 48 H INCREASES THE ACETYLATION OF H3K9 AND THE NUMBER OF GABAERGIC CELLS IN THE OPTIC TECTUM. VPA TREATMENT ALSO REDUCES APOPTOTIC CELLS. ELECTROPHYSIOLOGICAL RECORDINGS SHOW THAT A VPA INDUCES AN INCREASE IN THE FREQUENCY OF MIPSCS AND NO CHANGES IN THE AMPLITUDE. BEHAVIORAL STUDIES REVEAL THAT VPA DECREASES SWIMMING ACTIVITY AND VISUALLY GUIDED AVOIDANCE BEHAVIOR. THESE FINDINGS EXTEND OUR UNDERSTANDING OF HISTONE MODIFICATION IN THE GABAERGIC DIFFERENTIATION AND NEUROTRANSMISSION DURING EARLY BRAIN DEVELOPMENT. 2022 20 433 31 ANTIDEPRESSANT TREATMENT IS ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER IN A MOUSE MODEL OF CHRONIC DEPRESSION. BACKGROUND: UNDERSTANDING THE NEUROBIOLOGY OF DEPRESSION AND THE MECHANISM OF ACTION OF THERAPEUTIC MEASURES IS CURRENTLY A RESEARCH PRIORITY. WE HAVE SHOWN THAT THE EXPRESSION OF THE SYNAPTIC PROTEIN HOMER1A CORRELATES WITH DEPRESSION-LIKE BEHAVIOR AND ITS INDUCTION IS A COMMON MECHANISM OF ACTION OF DIFFERENT ANTIDEPRESSANT TREATMENTS. HOWEVER, THE MECHANISM OF HOMER1A REGULATION IS STILL UNKNOWN. METHODS: WE COMBINED THE CHRONIC DESPAIR MOUSE MODEL (CDM) OF CHRONIC DEPRESSION WITH DIFFERENT ANTIDEPRESSANT TREATMENTS. DEPRESSION-LIKE BEHAVIOR WAS CHARACTERIZED BY FORCED SWIM AND TAIL SUSPENSION TESTS, AND VIA AUTOMATIC MEASUREMENT OF SUCROSE PREFERENCE IN INTELLICAGE. THE HOMER1 MRNA EXPRESSION AND PROMOTER DNA METHYLATION WERE ANALYZED IN CORTEX AND PERIPHERAL BLOOD BY QRT-PCR AND PYROSEQUENCING. RESULTS: CDM MICE SHOW DECREASED HOMER1A AND HOMER1B/C MRNA EXPRESSION IN CORTEX AND BLOOD SAMPLES, WHILE CHRONIC TREATMENT WITH IMIPRAMINE AND FLUOXETINE OR ACUTE KETAMINE APPLICATION INCREASES THEIR LEVEL ONLY IN THE CORTEX. THE QUANTITATIVE ANALYSES OF THE METHYLATION OF 7 CPG SITES, LOCATED ON THE HOMER1 PROMOTER REGION CONTAINING SEVERAL CRE BINDING SITES, SHOW A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE CORTEX OF CDM MICE. IN CONTRAST, ANTIDEPRESSANT TREATMENTS REDUCE THE METHYLATION LEVEL. LIMITATIONS: HOMER1 EXPRESSION AND PROMOTOR METHYLATION WERE NOT ANALYZED IN DIFFERENT BLOOD CELL TYPES. OTHER CPG SITES OF HOMER1 PROMOTER SHOULD BE INVESTIGATED IN FUTURE STUDIES. OUR EXPERIMENTAL APPROACH DOES NOT DISTINGUISH BETWEEN METHYLATION AND HYDROXYMETHYLATION. CONCLUSIONS: WE DEMONSTRATE THAT STRESS-INDUCED DEPRESSION-LIKE BEHAVIOR AND ANTIDEPRESSANT TREATMENTS ARE ASSOCIATED WITH EPIGENETIC ALTERATIONS OF HOMER1 PROMOTER, PROVIDING NEW INSIGHTS INTO THE MECHANISM OF ANTIDEPRESSANT TREATMENT. 2021