1 2449 121 EPIGENETIC SUPPRESSION OF HIPPOCAMPAL CALBINDIN-D28K BY DELTAFOSB DRIVES SEIZURE-RELATED COGNITIVE DEFICITS. THE CALCIUM-BINDING PROTEIN CALBINDIN-D28K IS CRITICAL FOR HIPPOCAMPAL FUNCTION AND COGNITION, BUT ITS EXPRESSION IS MARKEDLY DECREASED IN VARIOUS NEUROLOGICAL DISORDERS ASSOCIATED WITH EPILEPTIFORM ACTIVITY AND SEIZURES. IN ALZHEIMER'S DISEASE (AD) AND EPILEPSY, BOTH OF WHICH ARE ACCOMPANIED BY RECURRENT SEIZURES, THE SEVERITY OF COGNITIVE DEFICITS REFLECTS THE DEGREE OF CALBINDIN REDUCTION IN THE HIPPOCAMPAL DENTATE GYRUS (DG). HOWEVER, DESPITE THE IMPORTANCE OF CALBINDIN IN BOTH NEURONAL PHYSIOLOGY AND PATHOLOGY, THE REGULATORY MECHANISMS THAT CONTROL ITS EXPRESSION IN THE HIPPOCAMPUS ARE POORLY UNDERSTOOD. HERE WE REPORT AN EPIGENETIC MECHANISM THROUGH WHICH SEIZURES CHRONICALLY SUPPRESS HIPPOCAMPAL CALBINDIN EXPRESSION AND IMPAIR COGNITION. WE DEMONSTRATE THAT DELTAFOSB, A HIGHLY STABLE TRANSCRIPTION FACTOR, IS INDUCED IN THE HIPPOCAMPUS IN MOUSE MODELS OF AD AND SEIZURES, IN WHICH IT BINDS AND TRIGGERS HISTONE DEACETYLATION AT THE PROMOTER OF THE CALBINDIN GENE (CALB1) AND DOWNREGULATES CALB1 TRANSCRIPTION. NOTABLY, INCREASING DG CALBINDIN LEVELS, EITHER BY DIRECT VIRUS-MEDIATED EXPRESSION OR INHIBITION OF DELTAFOSB SIGNALING, IMPROVES SPATIAL MEMORY IN A MOUSE MODEL OF AD. MOREOVER, LEVELS OF DELTAFOSB AND CALBINDIN EXPRESSION ARE INVERSELY RELATED IN THE DG OF INDIVIDUALS WITH TEMPORAL LOBE EPILEPSY (TLE) OR AD AND CORRELATE WITH PERFORMANCE ON THE MINI-MENTAL STATE EXAMINATION (MMSE). WE PROPOSE THAT CHRONIC SUPPRESSION OF CALBINDIN BY DELTAFOSB IS ONE MECHANISM THROUGH WHICH INTERMITTENT SEIZURES DRIVE PERSISTENT COGNITIVE DEFICITS IN CONDITIONS ACCOMPANIED BY RECURRENT SEIZURES. 2017 2 1317 51 DELTAFOSB REGULATES GENE EXPRESSION AND COGNITIVE DYSFUNCTION IN A MOUSE MODEL OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS CHARACTERIZED BY COGNITIVE DECLINE AND 5- TO 10-FOLD INCREASED SEIZURE INCIDENCE. HOW SEIZURES CONTRIBUTE TO COGNITIVE DECLINE IN AD OR OTHER DISORDERS IS UNCLEAR. WE SHOW THAT SPONTANEOUS SEIZURES INCREASE EXPRESSION OF DELTAFOSB, A HIGHLY STABLE FOS-FAMILY TRANSCRIPTION FACTOR, IN THE HIPPOCAMPUS OF AN AD MOUSE MODEL. DELTAFOSB SUPPRESSED EXPRESSION OF THE IMMEDIATE EARLY GENE C-FOS, WHICH IS CRITICAL FOR PLASTICITY AND COGNITION, BY BINDING ITS PROMOTER AND TRIGGERING HISTONE DEACETYLATION. ACUTE HISTONE DEACETYLASE (HDAC) INHIBITION OR INHIBITION OF DELTAFOSB ACTIVITY RESTORED C-FOS INDUCTION AND IMPROVED COGNITION IN AD MICE. ADMINISTRATION OF SEIZURE-INDUCING AGENTS TO NONTRANSGENIC MICE ALSO RESULTED IN DELTAFOSB-MEDIATED SUPPRESSION OF C-FOS, SUGGESTING THAT THIS MECHANISM IS NOT CONFINED TO AD MICE. THESE RESULTS EXPLAIN OBSERVATIONS THAT C-FOS EXPRESSION INCREASES AFTER ACUTE NEURONAL ACTIVITY BUT DECREASES WITH CHRONIC ACTIVITY. MOREOVER, THESE RESULTS INDICATE A GENERAL MECHANISM BY WHICH SEIZURES CONTRIBUTE TO PERSISTENT COGNITIVE DEFICITS, EVEN DURING SEIZURE-FREE PERIODS. 2017 3 2325 40 EPIGENETIC REGULATION OF HIPPOCAMPAL FOSB EXPRESSION CONTROLS BEHAVIORAL RESPONSES TO COCAINE. DRUG ADDICTION RESULTS IN PART FROM MALADAPTIVE LEARNING, INCLUDING THE FORMATION OF STRONG ASSOCIATIONS BETWEEN THE DRUG AND THE CIRCUMSTANCES OF CONSUMPTION. HOWEVER, DRUG-INDUCED CHANGES IN GENE EXPRESSION UNDERLYING THE SALIENCY OF THESE ASSOCIATIONS REMAIN UNDERSTUDIED. CONSOLIDATION OF EXPLICIT MEMORIES OCCURS WITHIN THE HIPPOCAMPUS, AND WE HAVE SHOWN THAT SPATIAL LEARNING INDUCES EXPRESSION OF THE TRANSCRIPTION FACTOR DELTAFOSB IN HIPPOCAMPUS AND THAT THIS INDUCTION IS CRITICAL FOR LEARNING. DRUGS OF ABUSE ALSO UPREGULATE DELTAFOSB IN HIPPOCAMPUS, BUT THE MECHANISM OF ITS INDUCTION BY COCAINE AND ITS ROLE IN HIPPOCAMPUS-DEPENDENT COCAINE RESPONSES IS UNKNOWN. WE INVESTIGATED DIFFERENCES IN MOUSE DORSAL AND VENTRAL HIPPOCAMPAL DELTAFOSB EXPRESSION IN RESPONSE TO CHRONIC COCAINE, BECAUSE THESE REGIONS APPEAR TO REGULATE DISTINCT COCAINE-RELATED BEHAVIORS. WE FOUND THAT COCAINE-MEDIATED INDUCTION OF DELTAFOSB WAS SUBREGION-SPECIFIC, AND THAT DELTAFOSB TRANSCRIPTIONAL ACTIVITY IN BOTH THE DORSAL AND VENTRAL HIPPOCAMPUS IS NECESSARY FOR COCAINE CONDITIONED PLACE PREFERENCE. FURTHER, WE CHARACTERIZE CHANGES IN HISTONE MODIFICATIONS AT THE FOSB PROMOTER IN HIPPOCAMPUS IN RESPONSE TO CHRONIC COCAINE AND FOUND THAT LOCUS-SPECIFIC EPIGENETIC MODIFICATION IS ESSENTIAL FOR FOSB INDUCTION AND MULTIPLE HIPPOCAMPUS-DEPENDENT BEHAVIORS, INCLUDING COCAINE PLACE PREFERENCE. COLLECTIVELY, THESE FINDINGS SUGGEST THAT EXPOSURE TO COCAINE INDUCES HISTONE MODIFICATION AT THE HIPPOCAMPAL FOSB GENE PROMOTER TO CAUSE DELTAFOSB INDUCTION CRITICAL FOR COCAINE-RELATED LEARNING.SIGNIFICANCE STATEMENT ALTHOUGH COCAINE ADDICTION IS DRIVEN IN PART BY THE FORMATION OF INDELIBLE ASSOCIATIONS BETWEEN THE DRUG AND THE ENVIRONMENT, PARAPHERNALIA, AND CIRCUMSTANCES OF USE, AND ALTHOUGH THIS TYPE OF ASSOCIATIVE LEARNING IS DEPENDENT UPON CHANGES IN GENE EXPRESSION IN A BRAIN REGION CALLED THE HIPPOCAMPUS, THE MECHANISMS BY WHICH COCAINE ALTERS HIPPOCAMPAL GENE EXPRESSION TO DRIVE FORMATION OF THESE ASSOCIATIONS IS POORLY UNDERSTOOD. HERE, WE DEMONSTRATE THAT CHRONIC COCAINE ENGAGES LOCUS-SPECIFIC CHANGES IN THE EPIGENETIC PROFILE OF THE FOSB GENE IN THE HIPPOCAMPUS, AND THAT THESE ALTERATIONS ARE REQUIRED FOR COCAINE-DEPENDENT GENE EXPRESSION AND COCAINE-ENVIRONMENT ASSOCIATIONS. THIS WORK PROVIDES NOVEL INSIGHT INTO ADDICTION ETIOLOGY AND POTENTIAL INROADS FOR THERAPEUTIC INTERVENTION IN COCAINE ADDICTION. 2019 4 2057 33 EPIGENETIC CONTROL OF EPILEPSY TARGET GENES CONTRIBUTES TO A CELLULAR MEMORY OF EPILEPTOGENESIS IN CULTURED RAT HIPPOCAMPAL NEURONS. HYPERSYNCHRONOUS NEURONAL EXCITATION MANIFESTS CLINICALLY AS SEIZURE (ICTOGENESIS), AND MAY RECUR SPONTANEOUSLY AND REPETITIVELY AFTER A VARIABLE LATENCY PERIOD (EPILEPTOGENESIS). DESPITE TREMENDOUS RESEARCH EFFORTS TO DESCRIBE MOLECULAR PATHWAYS AND SIGNATURES OF EPILEPTOGENESIS, MOLECULAR PATHOMECHANISMS LEADING TO CHRONIC EPILEPSY REMAIN TO BE CLARIFIED. WE HYPOTHESIZED THAT EPIGENETIC MODIFICATIONS MAY FORM THE BASIS FOR A CELLULAR MEMORY OF EPILEPTOGENESIS, AND USED A PRIMARY NEURONAL CELL CULTURE MODEL OF THE RAT HIPPOCAMPUS TO STUDY THE TRANSLATION OF MASSIVE NEURONAL EXCITATION INTO PERSISTING CHANGES OF EPIGENETIC SIGNATURES AND PRO-EPILEPTOGENIC TARGET GENE EXPRESSION. INCREASED SPONTANEOUS ACTIVATION OF CULTURED NEURONS WAS DETECTED 3 AND 7 DAYS AFTER STIMULATION WITH 10 MUM GLUTAMATE WHEN COMPARED TO SHAM-TREATED TIME-MATCHED CONTROLS USING CALCIUM-IMAGING IN VITRO. CHROMATIN-IMMUNOPRECIPITATION EXPERIMENTS REVEALED SHORT-TERM (3 H, 7 H, AND 24 H) AND LONG-TERM (3 D AND 2 WEEKS) CHANGES IN HISTONE MODIFICATIONS, WHICH WERE DIRECTLY LINKED TO DECREASED EXPRESSION OF TWO SELECTED EPILEPSY TARGET GENES, E.G. EXCITATORY GLUTAMATE RECEPTOR GENES GRIA2 AND GRIN2A. INCREASED PROMOTER METHYLATION OBSERVED 4 WEEKS AFTER GLUTAMATE STIMULATION AT RESPECTIVE GENES SUGGESTED LONG-TERM REPRESSION OF GRIA2 AND GRIN2A GENES. INHIBITION OF GLUTAMATERGIC ACTIVATION OR BLOCKING THE PROPAGATION OF ACTION POTENTIALS IN CULTURED NEURONS RESCUED ALTERED GENE EXPRESSION AND REGULATORY EPIGENETIC MODIFICATIONS. OUR DATA SUPPORT THE CONCEPT OF A CELLULAR MEMORY OF EPILEPTOGENESIS AND PERSISTING EPIGENETIC MODIFICATIONS OF EPILEPSY TARGET GENES, WHICH ARE ABLE TO TURN NORMAL INTO PRO-EPILEPTIC NEURONS AND CIRCUITS. 2017 5 5820 32 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 6 2116 40 EPIGENETIC HISTONE DEACETYLATION INHIBITION PREVENTS THE DEVELOPMENT AND PERSISTENCE OF TEMPORAL LOBE EPILEPSY. EPILEPSY IS A CHRONIC BRAIN DISEASE CHARACTERIZED BY REPEATED UNPROVOKED SEIZURES. CURRENTLY, NO DRUG THERAPY EXISTS FOR CURING EPILEPSY OR DISEASE MODIFICATION IN PEOPLE AT RISK. DESPITE SEVERAL EMERGING MECHANISMS, THERE HAVE BEEN FEW STUDIES OF EPIGENETIC SIGNALING IN EPILEPTOGENESIS, THE PROCESS WHEREBY A NORMAL BRAIN BECOMES PROGRESSIVELY EPILEPTIC BECAUSE OF PRECIPITATING FACTORS. HERE, WE REPORT A NOVEL ROLE OF HISTONE DEACETYLATION AS A CRITICAL EPIGENETIC MECHANISM IN EPILEPTOGENESIS. EXPERIMENTS WERE CONDUCTED USING THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE IN THE HIPPOCAMPUS KINDLING MODEL OF TEMPORAL LOBE EPILEPSY (TLE), A CLASSIC MODEL HEAVILY USED TO APPROVE DRUGS FOR TREATMENT OF EPILEPSY. DAILY TREATMENT WITH BUTYRATE SIGNIFICANTLY INHIBITED HDAC ACTIVITY AND RETARDED THE DEVELOPMENT OF LIMBIC EPILEPTOGENESIS WITHOUT AFFECTING AFTER-DISCHARGE SIGNAL. HDAC INHIBITION MARKEDLY IMPAIRED THE PERSISTENCE OF SEIZURE EXPRESSION MANY WEEKS AFTER EPILEPSY DEVELOPMENT. MOREOVER, SUBCHRONIC HDAC INHIBITION FOR 2 WEEKS RESULTED IN A STRIKING RETARDATION OF EPILEPTOGENESIS. HDAC INHIBITION, UNEXPECTEDLY, ALSO SHOWED ERASURE OF THE EPILEPTOGENIC STATE IN EPILEPTIC ANIMALS. FINALLY, BUTYRATE-TREATED ANIMALS EXHIBITED A POWERFUL REDUCTION IN MOSSY FIBER SPROUTING, A MORPHOLOGIC INDEX OF EPILEPTOGENESIS. TOGETHER THESE RESULTS UNDERSCORE THAT HDAC INHIBITION PREVENTS THE DEVELOPMENT OF TLE, INDICATING HDAC'S CRITICAL SIGNALING ROLE IN EPILEPTOGENESIS. THESE FINDINGS, THEREFORE, ENVISAGE A UNIQUE NOVEL THERAPY FOR PREVENTING OR CURING EPILEPSY BY TARGETING THE EPIGENETIC HDAC PATHWAY. 2018 7 213 27 ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURES (ECS) DIFFERENTIALLY REGULATE THE EXPRESSION OF EPIGENETIC MACHINERY IN THE ADULT RAT HIPPOCAMPUS. BACKGROUND: ELECTROCONVULSIVE SEIZURE TREATMENT IS A FAST-ACTING ANTIDEPRESSANT THERAPY THAT EVOKES RAPID TRANSCRIPTIONAL, NEUROGENIC, AND BEHAVIORAL CHANGES. EPIGENETIC MECHANISMS CONTRIBUTE TO ALTERED GENE REGULATION, WHICH UNDERLIES THE NEUROGENIC AND BEHAVIORAL EFFECTS OF ELECTROCONVULSIVE SEIZURE. WE HYPOTHESIZED THAT ELECTROCONVULSIVE SEIZURE MAY MODULATE THE EXPRESSION OF EPIGENETIC MACHINERY, THUS ESTABLISHING POTENTIAL ALTERATIONS IN THE EPIGENETIC LANDSCAPE. METHODS: WE EXAMINED THE INFLUENCE OF ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE ON THE GENE EXPRESSION OF HISTONE MODIFIERS, NAMELY HISTONE ACETYLTRANSFERASES, HISTONE DEACETYLASES, HISTONE METHYLTRANSFERASES, AND HISTONE (LYSINE) DEMETHYLASES AS WELL AS DNA MODIFYING ENZYMES, INCLUDING DNA METHYLTRANSFERASES, DNA DEMETHYLASES, AND METHYL-CPG-BINDING PROTEINS IN THE HIPPOCAMPI OF ADULT MALE WISTAR RATS USING QUANTITATIVE REAL TIME-PCR ANALYSIS. FURTHER, WE EXAMINED THE INFLUENCE OF ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE ON GLOBAL AND RESIDUE-SPECIFIC HISTONE ACETYLATION AND METHYLATION LEVELS WITHIN THE HIPPOCAMPUS, A BRAIN REGION IMPLICATED IN THE CELLULAR AND BEHAVIORAL EFFECTS OF ELECTROCONVULSIVE SEIZURE. RESULTS: ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE INDUCED A PRIMARILY UNIQUE, AND IN CERTAIN CASES BIDIRECTIONAL, REGULATION OF HISTONE AND DNA MODIFIERS, AND METHYL-CPG-BINDING PROTEINS, WITH AN OVERLAPPING PATTERN OF GENE REGULATION RESTRICTED TO SIRT4, MLL3, JMJD3, GADD45B, TET2, AND TET3. GLOBAL HISTONE ACETYLATION AND METHYLATION LEVELS WERE PREDOMINANTLY UNCHANGED, WITH THE EXCEPTION OF A SIGNIFICANT DECLINE IN H3K9 ACETYLATION IN THE HIPPOCAMPUS FOLLOWING CHRONIC ELECTROCONVULSIVE SEIZURE. CONCLUSIONS: ELECTROCONVULSIVE SEIZURE TREATMENT EVOKES THE TRANSCRIPTIONAL REGULATION OF SEVERAL HISTONE AND DNA MODIFIERS, AND METHYL-CPG-BINDING PROTEINS WITHIN THE HIPPOCAMPUS, WITH A PREDOMINANTLY DISTINCT PATTERN OF REGULATION INDUCED BY ACUTE AND CHRONIC ELECTROCONVULSIVE SEIZURE. 2016 8 3341 29 HISTONE DEACETYLASE-2 IS INVOLVED IN STRESS-INDUCED COGNITIVE IMPAIRMENT VIA HISTONE DEACETYLATION AND PI3K/AKT SIGNALING PATHWAY MODIFICATION. EXPOSURE TO CHRONIC STRESS UPREGULATES BLOOD GLUCOCORTICOID LEVELS AND IMPAIRS COGNITION VIA DIVERSE EPIGENETIC MECHANISMS, SUCH AS HISTONE DEACETYLATION. HISTONE DEACETYLATION CAN LEAD TO TRANSCRIPTIONAL SILENCING OF MANY PROTEINS INVOLVED IN COGNITION AND MAY ALSO CAUSE LEARNING AND MEMORY DYSFUNCTION. HISTONE DEACETYLASE?2 (HDAC2) HAS BEEN DEMONSTRATED TO EPIGENETICALLY BLOCK COGNITION VIA A REDUCTION IN THE HISTONE ACETYLATION LEVEL; HOWEVER, IT IS UNKNOWN WHETHER HDAC2 IS INVOLVED IN THE COGNITIVE DECLINE INDUCED BY CHRONIC STRESS. TO THE BEST OF AUTHORS' KNOWLEDGE, THIS IS THE FIRST STUDY TO DEMONSTRATE THAT THE STRESS HORMONE CORTICOSTEROID UPREGULATE HDAC2 PROTEIN LEVELS IN NEURO?2A CELLS AND CAUSE CELL INJURIES. HDAC2 KNOCKDOWN RESULTED IN A SIGNIFICANT AMELIORATION OF THE PATHOLOGICAL CHANGES IN N2A CELLS VIA THE UPREGULATION OF HISTONE ACETYLATION AND MODIFICATIONS IN THE PHOSPHOINOSITIDE 3?KINASE/PROTEIN KINASE B SIGNALING PATHWAY. IN ADDITION, THE HDAC2 PROTEIN LEVELS WERE UPREGULATED IN 12?MONTH?OLD FEMALE C57BL/6J MICE UNDER CHRONIC STRESS IN VIVO. TAKEN TOGETHER, THESE FINDINGS SUGGESTED THAT HDAC2 MAY BE AN IMPORTANT NEGATIVE REGULATOR INVOLVED IN CHRONIC STRESS?INDUCED COGNITIVE IMPAIRMENT. 2017 9 5219 35 PREVIOUS HISTORY OF CHRONIC STRESS CHANGES THE TRANSCRIPTIONAL RESPONSE TO GLUCOCORTICOID CHALLENGE IN THE DENTATE GYRUS REGION OF THE MALE RAT HIPPOCAMPUS. CHRONIC STRESS IS A RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISEASES, SUCH AS DEPRESSION AND PSYCHOSIS. IN RESPONSE TO STRESS GLUCOCORTICOIDS (GCS) ARE SECRETED THAT BIND TO MINERALOCORTICOID AND GLUCOCORTICOID RECEPTORS, LIGAND-ACTIVATED TRANSCRIPTION FACTORS THAT REGULATE THE TRANSCRIPTION OF GENE NETWORKS IN THE BRAIN NECESSARY FOR COPING WITH STRESS, RECOVERY, AND ADAPTATION. CHRONIC STRESS PARTICULARLY AFFECTS THE DENTATE GYRUS (DG) SUBREGION OF THE HIPPOCAMPUS, CAUSING SEVERAL FUNCTIONAL AND MORPHOLOGICAL CHANGES WITH CONSEQUENCES FOR LEARNING AND MEMORY, WHICH ARE LIKELY ADAPTIVE BUT AT THE SAME TIME MAKE DG NEURONS MORE VULNERABLE TO SUBSEQUENT CHALLENGES. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE TRANSCRIPTIONAL RESPONSE OF DG NEURONS TO A GC CHALLENGE IN MALE RATS PREVIOUSLY EXPOSED TO CHRONIC RESTRAINT STRESS (CRS). AN INTRIGUING FINDING OF THE CURRENT STUDY WAS THAT HAVING A HISTORY OF CRS HAD PROFOUND CONSEQUENCES FOR THE SUBSEQUENT RESPONSE TO ACUTE GC CHALLENGE, DIFFERENTIALLY AFFECTING THE EXPRESSION OF SEVERAL HUNDREDS OF GENES IN THE DG COMPARED WITH CHALLENGED NONSTRESSED CONTROL ANIMALS. THIS ENDURING EFFECT OF PREVIOUS STRESS EXPOSURE SUGGESTS THAT EPIGENETIC PROCESSES MAY BE INVOLVED. IN LINE WITH THIS, CRS INDEED AFFECTED THE EXPRESSION OF SEVERAL GENES INVOLVED IN CHROMATIN STRUCTURE AND EPIGENETIC PROCESSES, INCLUDING ASF1, ASH1L, HIST1H3F, AND TP63. THE DATA PRESENTED HERE INDICATE THAT CRS ALTERS THE TRANSCRIPTIONAL RESPONSE TO A SUBSEQUENT GC INJECTION. WE PROPOSE THAT THIS ALTERED TRANSCRIPTIONAL POTENTIAL FORMS PART OF THE MOLECULAR MECHANISM UNDERLYING THE ENHANCED VULNERABILITY FOR STRESS-RELATED DISORDERS LIKE DEPRESSION CAUSED BY CHRONIC STRESS. 2013 10 4299 32 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 11 3370 40 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 12 1315 36 DELTA FOSB MEDIATES EPIGENETIC DESENSITIZATION OF THE C-FOS GENE AFTER CHRONIC AMPHETAMINE EXPOSURE. THE MOLECULAR MECHANISMS UNDERLYING THE TRANSITION FROM RECREATIONAL DRUG USE TO CHRONIC ADDICTION REMAIN POORLY UNDERSTOOD. ONE MOLECULE IMPLICATED IN THIS PROCESS IS DELTAFOSB, A TRANSCRIPTION FACTOR THAT ACCUMULATES IN STRIATUM AFTER REPEATED DRUG EXPOSURE AND MEDIATES SENSITIZED BEHAVIORAL RESPONSES TO PSYCHOSTIMULANTS AND OTHER DRUGS OF ABUSE. THE DOWNSTREAM TRANSCRIPTIONAL MECHANISMS BY WHICH DELTAFOSB REGULATES DRUG-INDUCED BEHAVIORS ARE INCOMPLETELY UNDERSTOOD. WE REPORTED PREVIOUSLY THE CHROMATIN REMODELING MECHANISMS BY WHICH DELTAFOSB ACTIVATES THE EXPRESSION OF CERTAIN GENES; HOWEVER, THE MECHANISMS UNDERLYING DELTAFOSB-MEDIATED GENE REPRESSION REMAIN UNKNOWN. HERE, WE IDENTIFY C-FOS, AN IMMEDIATE EARLY GENE RAPIDLY INDUCED IN STRIATUM AFTER ACUTE PSYCHOSTIMULANT EXPOSURE, AS A NOVEL DOWNSTREAM TARGET THAT IS REPRESSED CHRONICALLY BY DELTAFOSB. WE SHOW THAT ACCUMULATION OF DELTAFOSB IN STRIATUM AFTER CHRONIC AMPHETAMINE TREATMENT DESENSITIZES C-FOS MRNA INDUCTION TO A SUBSEQUENT DRUG DOSE. DELTAFOSB DESENSITIZES C-FOS EXPRESSION BY RECRUITING HISTONE DEACETYLASE 1 (HDAC1) TO THE C-FOS GENE PROMOTER, WHICH, IN TURN, DEACETYLATES SURROUNDING HISTONES AND ATTENUATES GENE ACTIVITY. ACCORDINGLY, LOCAL KNOCK-OUT OF HDAC1 IN STRIATUM ABOLISHES AMPHETAMINE-INDUCED DESENSITIZATION OF THE C-FOS GENE. IN CONCERT, CHRONIC AMPHETAMINE INCREASES HISTONE H3 METHYLATION ON THE C-FOS PROMOTER, A CHROMATIN MODIFICATION ALSO KNOWN TO REPRESS GENE ACTIVITY, AS WELL AS EXPRESSION LEVELS OF THE H3 HISTONE METHYLTRANSFERASE, KMT1A (LYSINE METHYLTRANSFERASE 1A, FORMERLY SUV39H1). THIS STUDY REVEALS A NOVEL EPIGENETIC PATHWAY THROUGH WHICH DELTAFOSB MEDIATES DISTINCT TRANSCRIPTIONAL PROGRAMS THAT MAY ULTIMATELY ALTER BEHAVIORAL PLASTICITY TO CHRONIC AMPHETAMINE EXPOSURE. 2008 13 3969 35 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 14 2442 29 EPIGENETIC STABILITY IN THE ADULT MOUSE CORTEX UNDER CONDITIONS OF PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION. HISTONE ACETYLATION IS CONSIDERED A MAJOR EPIGENETIC PROCESS THAT AFFECTS BRAIN DEVELOPMENT AND SYNAPTIC PLASTICITY, AS WELL AS LEARNING AND MEMORY. THE TRANSCRIPTIONAL EFFECTORS AND MORPHOLOGICAL CHANGES RESPONSIBLE FOR PLASTICITY AS A RESULT OF LONG-TERM MODIFICATIONS TO HISTONE ACETYLATION ARE NOT FULLY UNDERSTOOD. TO THIS END, WE PHARMACOLOGICALLY INHIBITED HISTONE DEACETYLATION USING TRICHOSTATIN A IN ADULT (6-MONTH-OLD) MICE AND FOUND SIGNIFICANT INCREASES IN THE LEVELS OF THE ACETYLATED HISTONE MARKS H3LYS9, H3LYS14 AND H4LYS12. HIGH-RESOLUTION TRANSCRIPTOME ANALYSIS OF DIVERSE BRAIN REGIONS UNCOVERED FEW DIFFERENCES IN GENE EXPRESSION BETWEEN TREATED AND CONTROL ANIMALS, NONE OF WHICH WERE PLASTICITY RELATED. INSTEAD, AFTER INCREASED HISTONE ACETYLATION, WE DETECTED A LARGE NUMBER OF NOVEL TRANSCRIPTIONALLY ACTIVE REGIONS, WHICH CORRESPOND TO LONG NON-CODING RNAS (LNCRNAS). WE ALSO SURPRISINGLY FOUND NO SIGNIFICANT CHANGES IN DENDRITIC SPINE PLASTICITY IN LAYERS 1 AND 2/3 OF THE VISUAL CORTEX USING LONG-TERM IN VIVO TWO-PHOTON IMAGING. OUR RESULTS INDICATE THAT CHRONIC PHARMACOLOGICALLY INDUCED HISTONE ACETYLATION CAN BE DECOUPLED FROM GENE EXPRESSION AND INSTEAD, MAY POTENTIALLY EXERT A POST-TRANSCRIPTIONAL EFFECT THROUGH THE DIFFERENTIAL PRODUCTION OF LNCRNAS. 2016 15 4173 34 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 16 5617 39 SARCOSINE SUPPRESSES EPILEPTOGENESIS IN RATS WITH EFFECTS ON HIPPOCAMPAL DNA METHYLATION. EPILEPTOGENESIS IS A COMMON CONSEQUENCE OF BRAIN INSULTS, HOWEVER, THE PREVENTION OR DELAY OF THE EPILEPTOGENIC PROCESS REMAINS AN IMPORTANT UNMET MEDICAL CHALLENGE. OVEREXPRESSION OF GLYCINE TRANSPORTER 1 (GLYT1) IS PROPOSED AS A PATHOLOGICAL HALLMARK IN THE HIPPOCAMPUS OF PATIENTS WITH TEMPORAL LOBE EPILEPSY (TLE), AND WE PREVIOUSLY DEMONSTRATED IN RODENT EPILEPSY MODELS THAT AUGMENTATION OF GLYCINE SUPPRESSED CHRONIC SEIZURES AND ALTERED ACUTE SEIZURE THRESHOLDS. IN THE PRESENT STUDY WE EVALUATED THE EFFECT OF THE GLYT1 INHIBITOR, SARCOSINE (AKA N-METHYLGLYCINE), ON EPILEPTOGENESIS AND ALSO INVESTIGATED POSSIBLE MECHANISMS. WE DEVELOPED A MODIFIED RAPID KINDLING MODEL OF EPILEPTOGENESIS IN RATS COMBINED WITH SEIZURE SCORE MONITORING TO EVALUATE THE ANTIEPILEPTOGENIC EFFECT OF SARCOSINE. WE USED IMMUNOHISTOCHEMISTRY AND WESTERN BLOT ANALYSIS FOR THE EVALUATION OF GLYT1 EXPRESSION AND EPIGENETIC CHANGES OF 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC) IN THE EPILEPTOGENIC HIPPOCAMPI OF RATS, AND FURTHER EVALUATED EXPRESSION CHANGES IN ENZYMES INVOLVED IN THE REGULATION OF DNA METHYLATION, TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1), DNA-METHYLTRANSFERASE 1 (DNMT1), AND DNMT3A. OUR RESULTS DEMONSTRATED: (I) EXPERIMENTAL EVIDENCE THAT SARCOSINE (3 G/KG, I.P. DAILY) SUPPRESSED KINDLING EPILEPTOGENESIS IN RATS; (II) THE SARCOSINE-INDUCED ANTIEPILEPTOGENIC EFFECT WAS ACCOMPANIED BY A SUPPRESSED HIPPOCAMPAL GLYT1 EXPRESSION AS WELL AS A REDUCTION OF HIPPOCAMPAL 5MC LEVELS AND A CORRESPONDING INCREASE IN 5HMC; AND (III) SARCOSINE TREATMENT CAUSED DIFFERENTIAL EXPRESSION CHANGES OF TET1 AND DNMTS. TOGETHER, THESE FINDINGS SUGGEST THAT SARCOSINE HAS UNPRECEDENTED DISEASE-MODIFYING PROPERTIES IN A KINDLING MODEL OF EPILEPTOGENESIS IN RATS, WHICH WAS ASSOCIATED WITH ALTERED HIPPOCAMPAL DNA METHYLATION. THUS, MANIPULATION OF THE GLYCINE SYSTEM IS A POTENTIAL THERAPEUTIC APPROACH TO ATTENUATE THE DEVELOPMENT OF EPILEPSY. 2020 17 989 31 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 18 5624 27 SELECTIVE BOOSTING OF TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES TO DRUGS OF ABUSE BY HISTONE DEACETYLASE INHIBITION. HISTONE ACETYLATION AND OTHER MODIFICATIONS OF THE CHROMATIN ARE IMPORTANT REGULATORS OF GENE EXPRESSION AND, CONSEQUENTLY, MAY CONTRIBUTE TO DRUG-INDUCED BEHAVIORS AND NEUROPLASTICITY. EARLIER STUDIES HAVE SHOWN THAT A REDUCTION IN HISTONE DEACETYLASE (HDAC) ACTIVITY RESULTS IN THE ENHANCEMENT OF SOME PSYCHOSTIMULANT-INDUCED BEHAVIORS. IN THIS STUDY, WE EXTEND THOSE SEMINAL FINDINGS BY SHOWING THAT THE ADMINISTRATION OF THE HDAC INHIBITOR SODIUM BUTYRATE ENHANCES MORPHINE-INDUCED LOCOMOTOR SENSITIZATION AND CONDITIONED PLACE PREFERENCE. IN CONTRAST, THIS COMPOUND HAS NO EFFECTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE. SIMILAR EFFECTS WERE OBSERVED FOR COCAINE AND ETHANOL-INDUCED BEHAVIORS. THESE BEHAVIORAL CHANGES WERE ACCOMPANIED BY A SELECTIVE BOOSTING OF A COMPONENT OF THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CHRONIC MORPHINE ADMINISTRATION THAT INCLUDED CIRCADIAN CLOCK GENES AND OTHER GENES RELEVANT TO ADDICTIVE BEHAVIOR. OUR RESULTS SUPPORT A SPECIFIC FUNCTION FOR HISTONE ACETYLATION AND THE EPIGENETIC MODULATION OF TRANSCRIPTION AT A REDUCED NUMBER OF BIOLOGICALLY RELEVANT LOCI ON NON-HOMEOSTATIC, LONG-LASTING, DRUG-INDUCED BEHAVIORAL PLASTICITY. 2009 19 2119 30 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 20 5467 34 RESILIENT PHENOTYPE IN CHRONIC MILD STRESS PARADIGM IS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF MIR-18A-5P AND SEROTONIN 5-HT(1A) RECEPTOR IN DORSAL PART OF THE HIPPOCAMPUS. DISTURBED SEROTONERGIC SIGNALING IN THE HIPPOCAMPUS OBSERVED IN MANY INDIVIDUALS VULNERABLE TO STRESS HAS BEEN SUGGESTED AS ONE OF THE PRIMARY FACTORS CONTRIBUTING TO THE DEVELOPMENT OF DEPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PHYSIOLOGY OF THE BRAIN IN THE RESILIENT PHENOTYPE. RESILIENT SUBJECTS MAINTAIN A POSITIVE MOOD AND PSYCHOLOGICAL BALANCE DESPITE BEING UNDER THE STRESS INFLUENCE. IN OUR STUDY, WE GENERATED STRESS-VULNERABLE AND RESILIENT RATS BY USING A CHRONIC MILD STRESS (CMS) PARADIGM. USING DIFFERENT MOLECULAR APPROACHES, WE REVEALED THAT RESILIENT ANIMALS EXHIBITED A SIGNIFICANTLY DECREASED EXPRESSION LEVEL OF MIR-18A-5P AND, IN THE SAME TIME, AN ELEVATED LEVEL OF 5-HT1AR IN DORSAL, BUT NOT VENTRAL, PART OF THE HIPPOCAMPUS. DESCRIBED BIOCHEMICAL CHANGES WERE NOT OBSERVED IN ANIMALS BEHAVIORALLY VULNERABLE TO STRESS. FURTHER, IN VITRO ANALYSIS SHOWED THAT MIR-18A-5P MAY BE A NEGATIVE EPIGENETIC REGULATOR OF 5-HT1AR SINCE THE TREATMENT OF ADULT HIPPOCAMPAL NEURONS WITH MIR-18A-5P MIMIC SIGNIFICANTLY LOWERED THE EXPRESSION LEVEL OF MRNA ENCODING 5-HT1AR. MOREOVER, BIOINFORMATIC ANALYSIS OF POTENTIAL TARGET GENES EXPRESSED IN THE HIPPOCAMPUS AND BEING REGULATED BY MIR-18A-5P SHOWED THAT THIS MICRORNA MAY REGULATE BIOLOGICAL PROCESSES, SUCH AS AXONOGENESIS, WHICH ARE IMPORTANT IN THE FUNCTIONING OF THE HIPPOCAMPUS IN BOTH RATS AND HUMANS. ALL THESE MOLECULAR FEATURES MAY CONTRIBUTE TO SEROTONERGIC HOMEOSTATIC BALANCE AT THE LEVEL OF SEROTONIN TURNOVER OBSERVED IN HIPPOCAMPI OF RESILIENT BUT NOT STRESS-VULNERABLE RATS. DELINEATION OF FURTHER MOLECULAR AND BIOCHEMICAL MARKERS UNDERLYING RESILIENCE TO STRESS MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW ANTIDEPRESSANT STRATEGIES WHICH WILL RESTORE RESILIENT PHENOTYPE IN DEPRESSED PATIENTS. 2019