1 2773 138 EXTRACELLULAR SIGNAL-REGULATED PROTEIN KINASES 1 AND 2 ACTIVATION BY ADDICTIVE DRUGS: A SIGNAL TOWARD PATHOLOGICAL ADAPTATION. ADDICTION IS A CHRONIC AND RELAPSING PSYCHIATRIC DISORDER THAT IS THOUGHT TO OCCUR IN VULNERABLE INDIVIDUALS. SYNAPTIC PLASTICITY EVOKED BY DRUGS OF ABUSE IN THE SO-CALLED NEURONAL CIRCUITS OF REWARD HAS BEEN PROPOSED TO UNDERLIE BEHAVIORAL ADAPTATIONS THAT CHARACTERIZE ADDICTION. BY INCREASING DOPAMINE IN THE STRIATUM, ADDICTIVE DRUGS ALTER THE BALANCE OF DOPAMINE AND GLUTAMATE SIGNALS CONVERGING ONTO STRIATAL MEDIUM-SIZED SPINY NEURONS (MSNS) AND ACTIVATE INTRACELLULAR EVENTS INVOLVED IN LONG-TERM BEHAVIORAL ALTERATIONS. OUR LABORATORY CONTRIBUTED TO THE IDENTIFICATION OF SALIENT MOLECULAR CHANGES INDUCED BY ADMINISTRATION OF ADDICTIVE DRUGS TO RODENTS. WE PIONEERED THE OBSERVATION THAT A COMMON FEATURE OF ADDICTIVE DRUGS IS TO ACTIVATE, BY A DOUBLE TYROSINE/THREONINE PHOSPHORYLATION, THE EXTRACELLULAR SIGNAL-REGULATED KINASES 1 AND 2 (ERK1/2) IN THE STRIATUM, WHICH CONTROL A PLETHORA OF SUBSTRATES, SOME OF THEM BEING CRITICALLY INVOLVED IN COCAINE-MEDIATED MOLECULAR AND BEHAVIORAL ADAPTATIONS. HEREIN, WE REVIEW HOW THE INTERPLAY BETWEEN DOPAMINE AND GLUTAMATE SIGNALING CONTROLS COCAINE-INDUCED ERK1/2 ACTIVATION IN MSNS. WE EMPHASIZE THE KEY ROLE OF N-METHYL-D-ASPARTATE RECEPTOR POTENTIATION BY D1 RECEPTOR TO TRIGGER ERK1/2 ACTIVATION AND ITS SUBSEQUENT NUCLEAR TRANSLOCATION WHERE IT MODULATES BOTH EPIGENETIC AND GENETIC PROCESSES ENGAGED BY COCAINE. WE DISCUSS HOW COCAINE-INDUCED LONG-TERM SYNAPTIC AND STRUCTURAL PLASTICITY OF MSNS, AS WELL AS BEHAVIORAL ADAPTATIONS, ARE INFLUENCED BY ERK1/2-CONTROLLED TARGETS. WE CONCLUDE THAT A BETTER KNOWLEDGE OF MOLECULAR MECHANISMS UNDERLYING ERK1/2 ACTIVATION BY DRUGS OF ABUSE AND/OR ITS ROLE IN LONG-TERM NEURONAL PLASTICITY IN THE STRIATUM MAY PROVIDE A NEW ROUTE FOR THERAPEUTIC TREATMENT IN ADDICTION. 2014 2 5820 35 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 3 1339 25 DESIGN, SYNTHESIS, BIOLOGICAL EVALUATION, AND STRUCTURAL CHARACTERIZATION OF POTENT HISTONE DEACETYLASE INHIBITORS BASED ON CYCLIC ALPHA/BETA-TETRAPEPTIDE ARCHITECTURES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF ENZYMES FOUND IN BACTERIA, FUNGI, PLANTS, AND ANIMALS THAT PROFOUNDLY AFFECT CELLULAR FUNCTION BY CATALYZING THE REMOVAL OF ACETYL GROUPS FROM -N-ACETYLATED LYSINE RESIDUES OF VARIOUS PROTEIN SUBSTRATES INCLUDING HISTONES, TRANSCRIPTION FACTORS, ALPHA-TUBULIN, AND NUCLEAR IMPORTERS. ALTHOUGH THE PRECISE ROLES OF HDAC ISOFORMS IN CELLULAR FUNCTION ARE NOT YET COMPLETELY UNDERSTOOD, INHIBITION OF HDAC ACTIVITY HAS EMERGED AS A PROMISING APPROACH FOR REVERSING THE ABERRANT EPIGENETIC STATES ASSOCIATED WITH CANCER AND OTHER CHRONIC DISEASES. POTENT NEW ISOFORM-SELECTIVE HDAC INHIBITORS WOULD THEREFORE HELP EXPAND OUR UNDERSTANDING OF THE HDAC ENZYMES AND REPRESENT ATTRACTIVE LEAD COMPOUNDS FOR DRUG DESIGN, ESPECIALLY IF COMBINED WITH HIGH-RESOLUTION STRUCTURAL ANALYSES OF SUCH INHIBITORS TO SHED LIGHT ON THE THREE-DIMENSIONAL PHARMACOPHORIC FEATURES NECESSARY FOR THE FUTURE DESIGN OF MORE POTENT AND SELECTIVE COMPOUNDS. HERE WE PRESENT STRUCTURAL AND FUNCTIONAL ANALYSES OF A SERIES OF BETA-AMINO-ACID-CONTAINING HDAC INHIBITORS INSPIRED BY CYCLIC TETRAPEPTIDE NATURAL PRODUCTS. TO SURVEY A DIVERSE ENSEMBLE OF PHARMACOPHORIC CONFIGURATIONS, WE SYSTEMATICALLY VARIED THE POSITION OF THE BETA-AMINO ACID, AMINO ACID CHIRALITY, FUNCTIONALIZATION OF THE ZN(2+)-COORDINATING AMINO ACID SIDE CHAIN, AND ALKYLATION OF THE BACKBONE AMIDE NITROGEN ATOMS AROUND THE MACROCYCLE. IN MANY CASES, THE COMPOUNDS WERE A SINGLE CONFORMATION IN SOLUTION AND EXHIBITED POTENT ACTIVITIES AGAINST A NUMBER OF HDAC ISOFORMS AS WELL AS EFFECTIVE ANTIPROLIFERATIVE AND CYTOTOXIC ACTIVITIES AGAINST HUMAN TUMOR CELLS. HIGH-RESOLUTION NMR SOLUTION STRUCTURES WERE DETERMINED FOR A SELECTION OF THE INHIBITORS, PROVIDING A USEFUL MEANS OF CORRELATING DETAILED STRUCTURAL INFORMATION WITH POTENCY. THE STRUCTURE-BASED APPROACH DESCRIBED HERE IS EXPECTED TO FURNISH VALUABLE INSIGHTS TOWARD THE FUTURE DESIGN OF MORE SELECTIVE HDAC INHIBITORS. 2009 4 5967 34 TERMINATION OF ACUTE STRESS RESPONSE BY THE ENDOCANNABINOID SYSTEM IS REGULATED THROUGH LYSINE-SPECIFIC DEMETHYLASE 1-MEDIATED TRANSCRIPTIONAL REPRESSION OF 2-AG HYDROLASES ABHD6 AND MAGL. ACUTE ENVIRONMENTAL STRESS RARELY IMPLIES LONG-LASTING NEUROPHYSIOLOGICAL AND BEHAVIORAL ALTERATIONS. ON THE CONTRARY, CHRONIC STRESS EXERTS A POTENT TOXIC EFFECT AT THE GLUTAMATERGIC SYNAPSE WHOSE ALTERED PHYSIOLOGY HAS BEEN RECOGNIZED AS A CORE TRAIT OF NEUROPSYCHIATRIC DISORDERS. THE ENDOCANNABINOID SYSTEM (ECS) PLAYS AN IMPORTANT ROLE IN THE HOMEOSTATIC RESPONSE TO ACUTE STRESS. IN PARTICULAR, STRESS INDUCES SYNTHESIS OF ENDOCANNABINOID (ECB) 2-ARACHIDONYL GLYCEROL (2-AG). 2-AG STIMULATES PRESYNAPTIC CANNABINOID 1 (CB1) RECEPTOR CONTRIBUTING TO STRESS RESPONSE TERMINATION THROUGH INHIBITION OF GLUTAMATE RELEASE, RESTRAINING THEREAFTER ANXIETY AROUSAL. WE EMPLOY MOUSE MODELS OF STRESS RESPONSE COUPLED TO GENE EXPRESSION ANALYSES, UNRAVELLING THAT IN RESPONSE TO ACUTE PSYCHOSOCIAL STRESS IN THE MOUSE HIPPOCAMPUS, ECS-MEDIATED SYNAPTIC MODULATION IS ENHANCED VIA TRANSCRIPTIONAL REPRESSION OF TWO ENZYMES INVOLVED IN 2-AG DEGRADATION: ALPHA/BETA-HYDROLASE DOMAIN CONTAINING 6 (ABHD6) AND MONOACYLGLYCEROL LIPASE (MAGL). SUCH A PROCESS IS ORCHESTRATED BY THE EPIGENETIC COREPRESSOR LSD1 WHO DIRECTLY INTERACTS WITH PROMOTER REGULATORY REGIONS OF ABHD6 AND MAGL. REMARKABLY, NEGATIVE TRANSCRIPTIONAL CONTROL OF ABHD6 AND MAGL IS LOST IN THE HIPPOCAMPUS UPON CHRONIC PSYCHOSOCIAL STRESS, POSSIBLY CONTRIBUTING TO TRAUMA-INDUCED DRIFT OF SYNAPSE PHYSIOLOGY TOWARD UNCONTROLLED GLUTAMATE TRANSMISSION. WE PREVIOUSLY SHOWED THAT IN MICE LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INCREASES ITS HIPPOCAMPAL EXPRESSION IN RESPONSE TO PSYCHOSOCIAL STRESS PREVENTING EXCESSIVE CONSOLIDATION OF ANXIETY-RELATED PLASTICITY. IN THIS WORK, WE UNRAVEL A NODAL EPIGENETIC MODULATION OF ECB TURN OVER, SHEDDING NEW LIGHT ON THE MOLECULAR SUBSTRATE OF CONVERGING STRESS-TERMINATING EFFECTS DISPLAYED BY ECS AND LSD1. 2020 5 6561 34 TRANSGLUTAMINASE IS A THERAPEUTIC TARGET FOR OXIDATIVE STRESS, EXCITOTOXICITY AND STROKE: A NEW EPIGENETIC KID ON THE CNS BLOCK. TRANSGLUTAMINASES (TGS) ARE MULTIFUNCTIONAL, CALCIUM-DEPENDENT ENZYMES THAT HAVE BEEN RECENTLY IMPLICATED IN STROKE PATHOPHYSIOLOGY. CLASSICALLY, THESE ENZYMES ARE THOUGHT TO PARTICIPATE IN CELL INJURY AND DEATH IN CHRONIC NEURODEGENERATIVE CONDITIONS VIA THEIR ABILITY TO CATALYZE COVALENT, NONDEGRADABLE CROSSLINKS BETWEEN PROTEINS OR TO INCORPORATE POLYAMINES INTO PROTEIN SUBSTRATES. ACCUMULATING LINES OF INQUIRY INDICATE THAT SPECIFIC TG ISOFORMS CAN SHUTTLE INTO THE NUCLEUS WHEN THEY SENSE PATHOLOGIC CHANGES IN CALCIUM OR OXIDATIVE STRESS, BIND TO CHROMATIN AND THEREBY TRANSDUCE THESE CHANGES INTO TRANSCRIPTIONAL REPRESSION OF GENES INVOLVED IN METABOLIC OR OXIDANT ADAPTATION. HERE, WE REVIEW THE EVIDENCE THAT SUPPORTS PRINCIPALLY A ROLE FOR ONE ISOFORM OF THIS FAMILY, TG2, IN CELL INJURY AND DEATH ASSOCIATED WITH HEMORRHAGIC OR ISCHEMIC STROKE. WE ALSO OUTLINE AN EVOLVING MODEL IN WHICH TG2 IS A CRITICAL MEDIATOR BETWEEN PATHOLOGIC SIGNALING AND EPIGENETIC MODIFICATIONS THAT LEAD TO GENE REPRESSION. ACCORDINGLY, THE SALUTARY EFFECTS OF TG INHIBITORS IN STROKE MAY DERIVE FROM THEIR ABILITY TO RESTORE HOMEOSTASIS BY REMOVING INAPPROPRIATE DEACTIVATION OF ADAPTIVE GENETIC PROGRAMS BY OXIDATIVE STRESS OR EXTRASYNAPTIC GLUTAMATE RECEPTOR SIGNALING. 2013 6 4420 29 MOLECULAR AND EPIGENETIC MECHANISMS FOR THE COMPLEX EFFECTS OF STRESS ON SYNAPTIC PHYSIOLOGY AND COGNITIVE FUNCTIONS. EVIDENCE OVER THE PAST DECADES HAS FOUND THAT STRESS, PARTICULARLY THROUGH THE CORTICOSTERONE STRESS HORMONES, PRODUCES COMPLEX CHANGES IN GLUTAMATERGIC SIGNALING IN PREFRONTAL CORTEX, WHICH LEADS TO THE ALTERATION OF COGNITIVE PROCESSES MEDICATED BY THIS BRAIN REGION. INTERESTINGLY, THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION APPEAR TO BE "U-SHAPED," DEPENDING UPON THE DURATION AND SEVERITY OF THE STRESSOR. THESE BIPHASIC EFFECTS OF ACUTE VS CHRONIC STRESS REPRESENT THE ADAPTIVE VS MALADAPTIVE RESPONSES TO STRESSFUL STIMULI. ANIMAL STUDIES SUGGEST THAT THE STRESS-INDUCED MODULATION OF EXCITATORY SYNAPTIC TRANSMISSION INVOLVES CHANGES IN PRESYNAPTIC GLUTAMATE RELEASE, POSTSYNAPTIC GLUTAMATE RECEPTOR MEMBRANE TRAFFICKING AND DEGRADATION, SPINE STRUCTURE AND CYTOSKELETON NETWORK, AND EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW WILL DISCUSS CURRENT FINDINGS ON THE KEY MOLECULES INVOLVED IN THE STRESS-INDUCED REGULATION OF PREFRONTAL CORTEX SYNAPTIC PHYSIOLOGY AND PREFRONTAL CORTEX-MEDIATED FUNCTIONS. UNDERSTANDING THE MOLECULAR AND EPIGENETIC MECHANISMS THAT UNDERLIE THE COMPLEX EFFECTS OF STRESS WILL HELP TO DEVELOP NOVEL STRATEGIES TO COPE WITH STRESS-RELATED MENTAL DISORDERS. 2017 7 4117 41 MECHANISMS OF AUTOPHAGIC RESPONSES TO ALTERED NUTRITIONAL STATUS. AUTOPHAGY IS A DYNAMIC PROCESS AND CRITICAL FOR CELLULAR REMODELING AND ORGANELLE QUALITY CONTROL. IN RESPONSE TO ALTERED NUTRITIONAL STATUS (E.G., FASTING AND FEEDING), AUTOPHAGIC ACTIVITY IS FINELY TUNED BY TRANSCRIPTIONAL, POSTTRANSLATIONAL, AND EPIGENETIC REGULATIONS VIA VARIOUS SIGNALING PATHWAYS, INCLUDING ENERGY SENSORS (E.G., MECHANISTIC TARGET OF RAPAMYCIN (MTOR)/ AMP-ACTIVATED PROTEIN KINASE - UNC-51 LIKE AUTOPHAGY ACTIVATING KINASE 1, MTORC1- WD REPEAT DOMAIN, PHOSPHOINOSITIDE INTERACTING 2, MTORC1- TRANSCRIPTION FACTOR EB, PERILIPIN 5- SIRTUIN 1, AND SIRTUIN 1-MEDIATED DEACETYLATION OF AUTOPHAGY PROTEINS), FASTING OR FEEDING INDUCED HORMONES (E.G., FIBROBLAST GROWTH FACTOR [FGF21]- PROTEIN KINASE A - JUMONJI DOMAIN-CONTAINING PROTEIN D3, FGF21- DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR - E3 LIGASE MIDLINE-1- TRANSCRIPTION FACTOR EB, FGF19-SHP- LYSINE-SPECIFIC DEMETHYLASE, INSULIN- INSULIN RECEPTOR SUBSTRATE - PROTEIN KINASE B - FORKHEAD BOX O, GLUCAGON- PROTEIN KINASE A - CAMP RESPONSE BINDING PROTEIN), AND LYSOSOMAL ENZYMES (E.G., CATHEPSIN B AND CATHEPSIN L). IN CONTRAST TO FASTING THAT INDUCES AUTOPHAGY AND HEALTH BENEFITS, NUTRIENT OVERSUPPLY (OVERFEEDING OR FEEDING ON HIGH ENERGY DIETS) DYSREGULATES AUTOPHAGY, WHICH HAS BEEN INCREASINGLY OBSERVED IN ANIMAL MODELS OF HUMAN CHRONIC DISEASES SUCH AS OBESITY, DIABETES, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CARDIOVASCULAR DISEASE. STUDIES HAVE REVEALED MULTIFACETED EFFECTS OF HIGH ENERGY DIETS ON AUTOPHAGY, BEING EITHER AN INHIBITOR OR ENHANCER OF AUTOPHAGY. THE CONUNDRUM MAY ARISE FROM THE VARIATIONS IN METHODS FOR AUTOPHAGY ANALYSIS, COMPONENTS OF HIGH ENERGY DIETS AND CONTROL DIETS FOR TREATMENTS, TREATMENT DURATIONS, AND THE AGES OF GENETIC BACKGROUNDS OF LABORATORY ANIMALS. IN THIS ARTICLE, WE REVIEWED THE EVIDENCE FROM BOTH HUMAN AND ANIMAL STUDIES, PRESENTING THE MOLECULAR MECHANISM OF AUTOPHAGIC RESPONSE TO ALTERED NUTRITIONAL STATUS AND DISCUSSING THE CONTRIBUTING FACTORS OF AND POSSIBLE SOLUTION TO THE CURRENT CONUNDRUM CONCERNING THE EXACT ROLE OF HIGH ENERGY DIETS IN AUTOPHAGIC REGULATION. 2022 8 1315 34 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 9 3952 26 LOCUS-SPECIFIC EPIGENETIC REMODELING CONTROLS ADDICTION- AND DEPRESSION-RELATED BEHAVIORS. CHRONIC EXPOSURE TO DRUGS OF ABUSE OR STRESS REGULATES TRANSCRIPTION FACTORS, CHROMATIN-MODIFYING ENZYMES AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN DISCRETE BRAIN REGIONS. GIVEN THE PROMISCUITY OF THE ENZYMES INVOLVED, IT HAS NOT YET BEEN POSSIBLE TO OBTAIN DIRECT CAUSAL EVIDENCE TO IMPLICATE THE REGULATION OF TRANSCRIPTION AND CONSEQUENT BEHAVIORAL PLASTICITY BY CHROMATIN REMODELING THAT OCCURS AT A SINGLE GENE. WE INVESTIGATED THE MECHANISM LINKING CHROMATIN DYNAMICS TO NEUROBIOLOGICAL PHENOMENA BY APPLYING ENGINEERED TRANSCRIPTION FACTORS TO SELECTIVELY MODIFY CHROMATIN AT A SPECIFIC MOUSE GENE IN VIVO. WE FOUND THAT HISTONE METHYLATION OR ACETYLATION AT THE FOSB LOCUS IN NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, WAS SUFFICIENT TO CONTROL DRUG- AND STRESS-EVOKED TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES VIA INTERACTIONS WITH THE ENDOGENOUS TRANSCRIPTIONAL MACHINERY. THIS APPROACH ALLOWED US TO RELATE THE EPIGENETIC LANDSCAPE AT A GIVEN GENE DIRECTLY TO REGULATION OF ITS EXPRESSION AND TO ITS SUBSEQUENT EFFECTS ON REWARD BEHAVIOR. 2014 10 3328 35 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 11 6806 34 [EPIGENETICS AND DRUG ADDICTION: A FOCUS ON MECP2 AND ON HISTONE ACETYLATION]. CHRONIC DRUG EXPOSURE ALTERS GENE EXPRESSION IN THE BRAIN, WHICH IS BELIEVED TO UNDERLIE COMPULSIVE DRUG SEEKING AND DRUG TAKING BEHAVIOR. RECENT EVIDENCE SHOWS THAT DRUG-INDUCED LONG-TERM NEUROADAPTATIONS IN THE BRAIN ARE MEDIATED IN PART BY EPIGENETIC MECHANISMS. BY REMODELING CHROMATIN, THIS TYPE OF REGULATION CONTRIBUTES TO DRUG-INDUCED SYNAPTIC PLASTICITY THAT TRANSLATES INTO BEHAVIORAL MODIFICATIONS. HOW DRUG-INDUCED ALTERATIONS IN DNA METHYLATION REGULATE GENE EXPRESSION IS REVIEWED HERE, WITH A FOCUS ON MECP2, A PROTEIN BINDING METHYLATED DNA. THE IMPORTANCE OF HISTONE MODIFICATIONS, ESPECIALLY ACETYLATION IS ALSO DISCUSSED, WITH AN EMPHASIS ON THE EFFECTS OF INHIBITORS OF HISTONE DEACETYLASES ON DRUG-INDUCED BEHAVIORAL CHANGES. THE PRECISE IDENTIFICATION OF THE EPIGENETIC MECHANISMS THAT ARE UNDER THE CONTROL OF DRUGS OF ABUSE MAY HELP TO UNCOVER NOVEL TARGETS FOR THE TREATMENT OF DRUG SEEKING AND RELAPSE. 2015 12 5624 29 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 13 3203 37 HDAC3 ACTIVITY WITHIN THE NUCLEUS ACCUMBENS REGULATES COCAINE-INDUCED PLASTICITY AND BEHAVIOR IN A CELL-TYPE-SPECIFIC MANNER. EPIGENETIC MECHANISMS REGULATE PROCESSES OF NEUROPLASTICITY CRITICAL TO COCAINE-INDUCED BEHAVIORS. THIS INCLUDES THE CLASS I HISTONE DEACETYLASE (HDAC) HDAC3, KNOWN TO ACT AS A NEGATIVE REGULATOR OF COCAINE-ASSOCIATED MEMORY FORMATION WITHIN THE NUCLEUS ACCUMBENS (NAC). DESPITE THIS, IT REMAINS UNKNOWN HOW COCAINE ALTERS HDAC3-DEPENDENT MECHANISMS. HERE, WE PROFILED HDAC3 EXPRESSION AND ACTIVITY IN TOTAL NAC MOUSE TISSUE FOLLOWING COCAINE EXPOSURE. ALTHOUGH CHRONIC COCAINE DID NOT AFFECT EXPRESSION OF HDAC3 WITHIN THE NAC, CHRONIC COCAINE DID AFFECT PROMOTER-SPECIFIC CHANGES IN HDAC3 AND H4K8AC OCCUPANCY. THESE CHANGES IN PROMOTER OCCUPANCY CORRELATED WITH COCAINE-INDUCED CHANGES IN EXPRESSION OF PLASTICITY-RELATED GENES. TO CAUSALLY DETERMINE WHETHER COCAINE-INDUCED PLASTICITY IS MEDIATED BY HDAC3'S DEACETYLASE ACTIVITY, WE OVEREXPRESSED A DEACETYLASE-DEAD HDAC3 POINT MUTANT (HDAC3-Y298H-V5) WITHIN THE NAC OF ADULT MALE MICE. WE FOUND THAT DISRUPTING HDAC3'S ENZYMATIC ACTIVITY ALTERED SELECTIVE CHANGES IN GENE EXPRESSION AND SYNAPTIC PLASTICITY FOLLOWING COCAINE EXPOSURE, DESPITE HAVING NO EFFECTS ON COCAINE-INDUCED BEHAVIORS. IN FURTHER ASSESSING HDAC3'S ROLE WITHIN THE NAC, WE OBSERVED THAT CHRONIC COCAINE INCREASES HDAC3 EXPRESSION IN DRD1 BUT NOT DRD2-CELLS OF THE NAC. MOREOVER, WE DISCOVERED THAT HDAC3 ACTS SELECTIVELY WITHIN D1R CELL-TYPES TO REGULATE COCAINE-ASSOCIATED MEMORY FORMATION AND COCAINE-SEEKING. OVERALL, THESE RESULTS SUGGEST THAT COCAINE INDUCES CELL-TYPE-SPECIFIC CHANGES IN EPIGENETIC MECHANISMS TO PROMOTE PLASTICITY IMPORTANT FOR DRIVING COCAINE-RELATED BEHAVIORS.SIGNIFICANCE STATEMENT DRUGS OF ABUSE ALTER MOLECULAR MECHANISMS THROUGHOUT THE REWARD CIRCUITRY THAT CAN LEAD TO PERSISTENT DRUG-ASSOCIATED BEHAVIORS. EPIGENETIC REGULATORS ARE CRITICAL DRIVERS OF DRUG-INDUCED CHANGES IN GENE EXPRESSION. HERE, WE DEMONSTRATE THAT THE ACTIVITY OF AN EPIGENETIC ENZYME PROMOTES NEUROPLASTICITY WITHIN THE NUCLEUS ACCUMBENS (NAC) CRITICAL TO COCAINE ACTION. IN ADDITION, WE DEMONSTRATE THAT THESE CHANGES IN EPIGENETIC ACTIVITY DRIVE COCAINE-SEEKING BEHAVIORS IN A CELL-TYPE-SPECIFIC MANNER. THESE FINDINGS ARE KEY IN UNDERSTANDING AND TARGETING COCAINE'S IMPACT OF NEURAL CIRCUITRY AND BEHAVIOR. 2021 14 2280 44 EPIGENETIC REGULATION IN DRUG ADDICTION. THE INTERACTION BETWEEN ENVIRONMENTAL SIGNALS AND GENES HAS NOW TAKEN ON A CLEAR MOLECULAR FORM AS DEMONSTRATED BY STABLE CHANGES IN CHROMATIN STRUCTURE. THESE CHANGES OCCUR THROUGH ACTIVATION OR REPRESSION OF SPECIFIC GENE PROGRAMMES BY A COMBINATION OF CHROMATIN REMODELLING, ACTIVATION AND ENZYMATIC MODIFICATION OF DNA AND HISTONES AS WELL AS NUCLEOSOMAL SUBUNIT EXCHANGE. RECENT RESEARCH INVESTIGATING THE MOLECULAR MECHANISMS CONTROLLING DRUG-INDUCED TRANSCRIPTIONAL, BEHAVIOURAL AND SYNAPTIC ACTIVITY HAS SHOWN A DIRECT ROLE FOR CHROMATIN REMODELLING--TERMED AS EPIGENETIC REGULATION--OF NEURONAL GENE PROGRAMMES AND SUBSEQUENT ADDICTIVE BEHAVIOUR ARISING FROM IT. RECENT DATA SUGGEST THAT REPEATED EXPOSURE TO CERTAIN DRUGS PROMOTES CHANGES IN LEVELS OF HISTONE ACETYLATION, PHOSPHORYLATION AND METHYLATION, TOGETHER WITH ALTERATIONS IN DNA METHYLATION LEVELS IN THE NEURONS OF THE BRAIN REWARD CENTRE, LOCALISED IN THE NUCLEUS ACCUMBENS (NAC) REGION OF THE LIMBIC SYSTEM. THE COMBINATION OF ACETYLATING, PHOSPHORYLATING AND METHYLATING H3 AND H4 HISTONE TAILS ALTER CHROMATIN COMPACTION THEREBY PROMOTING ALTERED LEVELS OF CELLULAR GENE EXPRESSION. HISTONE MODIFICATIONS, WHICH WEAKEN HISTONE INTERACTION WITH DNA OR THAT PROMOTE RECRUITMENT OF TRANSCRIPTIONAL ACTIVATING COMPLEXES, CORRELATE WITH PERMISSIVE GENE EXPRESSION. HISTONE DEACETYLATION, (WHICH STRENGTHEN HISTONE: DNA CONTACTS), OR HISTONE METHYLATION, (WHICH RECRUITS REPRESSIVE COMPLEXES TO CHROMATIN), PROMOTE A STATE OF TRANSCRIPTIONAL REPRESSION. USING ANIMAL MODELS, ACUTE COCAINE TREATMENT INCREASES H4 ACETYLATION AT ACUTELY REGULATED GENE PROMOTERS, WHEREAS H3 ACETYLATION APPEARS TO PREDOMINATE AT CHRONICALLY INDUCED PROMOTERS. CHRONIC COCAINE AND ALCOHOL TREATMENT ACTIVATE AND REPRESS MANY GENES SUCH AS FOSB, CDK5, AND BDNF, WHERE THEIR DYSREGULATION, AT THE CHROMATIN LEVEL, CONTRIBUTE TO THE DEVELOPMENT AND MAINTENANCE OF ADDICTION. FOLLOWING DRUG EXPOSURE, IT IS STILL UNKNOWN, HOWVER, HOW LONG THESE CHANGES IN CHROMATIN STRUCTURE PERSIST IN AFFECTING NEURONAL FUNCTION, BUT SOME DO SO FOR LIFE. 2012 15 5078 29 PHYSIOLOGY AND PATHOPHYSIOLOGY OF MATRIX METALLOPROTEASES. MATRIX METALLOPROTEASES (MMPS) COMPRISE A FAMILY OF ENZYMES THAT CLEAVE PROTEIN SUBSTRATES BASED ON A CONSERVED MECHANISM INVOLVING ACTIVATION OF AN ACTIVE SITE-BOUND WATER MOLECULE BY A ZN(2+) ION. ALTHOUGH THE CATALYTIC DOMAIN OF MMPS IS STRUCTURALLY HIGHLY SIMILAR, THERE ARE MANY DIFFERENCES WITH RESPECT TO SUBSTRATE SPECIFICITY, CELLULAR AND TISSUE LOCALIZATION, MEMBRANE BINDING AND REGULATION THAT MAKE THIS A VERY VERSATILE FAMILY OF ENZYMES WITH A MULTITUDE OF PHYSIOLOGICAL FUNCTIONS, MANY OF WHICH ARE STILL NOT FULLY UNDERSTOOD. ESSENTIALLY, ALL MEMBERS OF THE MMP FAMILY HAVE BEEN LINKED TO DISEASE DEVELOPMENT, NOTABLY TO CANCER METASTASIS, CHRONIC INFLAMMATION AND THE ENSUING TISSUE DAMAGE AS WELL AS TO NEUROLOGICAL DISORDERS. THIS HAS STIMULATED A FLURRY OF STUDIES INTO MMP INHIBITORS AS THERAPEUTIC AGENTS, AS WELL AS INTO MEASURING MMP LEVELS AS DIAGNOSTIC OR PROGNOSTIC MARKERS. AS WITH MOST PROTEIN FAMILIES, DECIPHERING THE FUNCTION(S) OF MMPS IS DIFFICULT, AS THEY CAN MODIFY MANY PROTEINS. WHICH OF THESE REACTIONS ARE PHYSIOLOGICALLY OR PATHOPHYSIOLOGICALLY RELEVANT IS OFTEN NOT CLEAR, ALTHOUGH STUDIES ON KNOCKOUT ANIMALS, HUMAN GENETIC AND EPIGENETIC, AS WELL AS BIOCHEMICAL STUDIES USING NATURAL OR SYNTHETIC INHIBITORS HAVE PROVIDED INSIGHT TO A GREAT EXTENT. IN THIS REVIEW, WE WILL GIVE AN OVERVIEW OF 23 MEMBERS OF THE HUMAN MMP FAMILY AND DESCRIBE FUNCTIONS, LINKAGES TO DISEASE AND STRUCTURAL AND MECHANISTIC FEATURES. MMPS CAN BE GROUPED INTO SOLUBLE (INCLUDING MATRILYSINS) AND MEMBRANE-ANCHORED SPECIES. WE ADHERE TO THE 'MMP NOMENCLATURE' AND PROVIDE THE READER WITH REFERENCE TO THE MANY, OFTEN DIVERSE, NAMES FOR THIS ENZYME FAMILY IN THE INTRODUCTION. 2011 16 584 40 BEHAVIORAL NEUROADAPTATION TO ALCOHOL: FROM GLUCOCORTICOIDS TO HISTONE ACETYLATION. A PRIME MECHANISM THAT CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF ALCOHOLISM IS THE DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS ACTIVITY AND THE RELEASE OF GLUCOCORTICOIDS (CORTISOL IN HUMANS AND PRIMATES, CORTICOSTERONE IN RODENTS) FROM THE ADRENAL GLANDS. IN THE BRAIN, SUSTAINED, LOCAL ELEVATION OF GLUCOCORTICOID CONCENTRATION EVEN LONG AFTER CESSATION OF CHRONIC ALCOHOL CONSUMPTION COMPROMISES FUNCTIONAL INTEGRITY OF A CIRCUIT, INCLUDING THE PREFRONTAL CORTEX (PFC), THE HIPPOCAMPUS (HPC), AND THE AMYGDALA (AMG). THESE STRUCTURES ARE IMPLICATED IN LEARNING AND MEMORY PROCESSES AS WELL AS IN ORCHESTRATING NEUROADAPTIVE RESPONSES TO STRESS AND ANXIETY RESPONSES. THUS, POTENTIATION OF ANXIETY-RELATED NEUROADAPTATION BY ALCOHOL IS CHARACTERIZED BY AN ABNORMALLY AMG HYPERACTIVITY COUPLED WITH A HYPOFUNCTION OF THE PFC AND THE HPC. THIS REVIEW DESCRIBES RESEARCH ON MOLECULAR AND EPIGENETIC MECHANISMS BY WHICH ALCOHOL CAUSES DISTINCT REGION-SPECIFIC ADAPTIVE CHANGES IN GENE EXPRESSION PATTERNS AND ULTIMATELY LEADS TO A VARIETY OF COGNITIVE AND BEHAVIORAL IMPAIRMENTS ON PREFRONTAL- AND HIPPOCAMPAL-BASED TASKS. ALCOHOL-INDUCED NEUROADAPTATIONS INVOLVE THE DYSREGULATION OF NUMEROUS SIGNALING CASCADES, LEADING TO LONG-TERM CHANGES IN TRANSCRIPTIONAL PROFILES OF GENES, THROUGH THE ACTIONS OF TRANSCRIPTION FACTORS SUCH AS [CAMP RESPONSE ELEMENT-BINDING PROTEIN (CREB)] AND CHROMATIN REMODELING DUE TO POSTTRANSLATIONAL MODIFICATIONS OF HISTONE PROTEINS. WE DESCRIBE THE ROLE OF PREFRONTAL-HPC-AMG CIRCUIT IN MEDIATING THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL ON LEARNING AND MEMORY, AND REGION-SPECIFIC MOLECULAR AND EPIGENETIC MECHANISMS INVOLVED IN THIS PROCESS. THIS REVIEW FIRST DISCUSSES THE IMPORTANCE OF BRAIN REGION-SPECIFIC DYSREGULATION OF GLUCOCORTICOID CONCENTRATION IN THE DEVELOPMENT OF ALCOHOL DEPENDENCE AND DESCRIBES HOW PERSISTENTLY INCREASED GLUCOCORTICOID LEVELS IN PFC MAY BE INVOLVED IN MEDIATING WORKING MEMORY IMPAIRMENTS AND NEUROADAPTIVE CHANGES DURING WITHDRAWAL FROM CHRONIC ALCOHOL INTAKE. IT THEN HIGHLIGHTS THE ROLE OF CAMP-PKA-CREB SIGNALING CASCADE AND HISTONE ACETYLATION WITHIN THE PFC AND LIMBIC STRUCTURES IN ALCOHOL-INDUCED ANXIETY AND BEHAVIORAL IMPAIRMENTS, AND HOW AN UNDERSTANDING OF FUNCTIONAL ALTERATIONS OF THESE PATHWAYS MIGHT LEAD TO BETTER TREATMENTS FOR NEUROPSYCHIATRIC DISORDERS. 2016 17 1856 29 ELEVATION OF N-ACETYLTRANSFERASE 10 IN HIPPOCAMPAL NEURONS MEDIATES DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. MAJOR DEPRESSIVE DISORDER (MDD) IS ONE OF THE MOST DEBILITATING AND SEVERE MENTAL DISEASES GLOBALLY. INCREASING EVIDENCE HAS SHOWN THAT EPIGENETICS IS CRITICAL FOR UNDERSTANDING BRAIN FUNCTION AND BRAIN DISORDERS, INCLUDING MDD. N-ACETYLTRANSFERASE 10 (NAT10), ACTING ON HISTONES, MRNA AND OTHER SUBSTRATES, HAS BEEN REPORTED TO BE INVOLVED IN EPIGENETIC EVENTS, INCLUDING HISTONE ACETYLATION AND MRNA MODIFICATIONS. NAT10 IS HIGHLY EXPRESSED IN THE BRAIN. HOWEVER, THE POTENTIAL EFFECTS OF NAT10 ON MDD ARE STILL UNKNOWN. HERE, WE EXPLOITED CHRONIC MILD STRESS (CMS) TO INDUCE ANXIETY- AND DEPRESSION-LIKE BEHAVIORS IN MICE AND FOUND THAT THE EXPRESSION OF NAT10 IN THE MOUSE HIPPOCAMPUS WAS UPREGULATED AFTER CMS TREATMENT. INHIBITION OF NAT10 BY PHARMACOLOGICAL METHODS PRODUCED ANXIOLYTIC- AND ANTIDEPRESSANT-LIKE EFFECTS. NEURON-SPECIFIC OVEREXPRESSION OF NAT10 IN THE HIPPOCAMPUS RESULTED IN ANXIETY- AND DEPRESSION-LIKE BEHAVIORS, ACCOMPANIED BY HIGHER SIRT1 PROTEIN LEVELS, AND LOWER DENDRITIC SPINE DENSITIES. OVERALL, IT WAS FOUND THAT ELEVATION OF NAT10 IN HIPPOCAMPAL NEURONS IS INVOLVED IN THE OCCURRENCE OF ANXIETY- AND DEPRESSION-LIKE BEHAVIORS, SUGGESTING THAT NAT10 COULD BE A POTENTIAL NEW TARGET FOR DEVELOPING ANXIOLYTICS AND ANTIDEPRESSANTS. 2022 18 2243 28 EPIGENETIC MODULATION OF CHRONIC ANXIETY AND PAIN BY HISTONE DEACETYLATION. PROLONGED EXPOSURE OF THE CENTRAL AMYGDALA (CEA) TO ELEVATED CORTICOSTEROIDS (CORT) FACILITATES LONG-TERM ANXIETY AND PAIN THROUGH ACTIVATION OF GLUCOCORTICOID RECEPTORS (GRS) AND CORTICOTROPIN-RELEASING FACTOR (CRF). HOWEVER, THE MECHANISMS MAINTAINING THESE RESPONSES ARE UNKNOWN. SINCE CHRONIC PHENOTYPES CAN BE SUSTAINED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS SUCH AS DEACETYLATION, WE TESTED THE HYPOTHESIS THAT HISTONE DEACETYLATION CONTRIBUTES TO THE MAINTENANCE OF CHRONIC ANXIETY AND PAIN INDUCED BY PROLONGED EXPOSURE OF THE CEA TO CORT. WE FOUND THAT BILATERAL INFUSIONS OF A HISTONE DEACETYLASE INHIBITOR INTO THE CEA ATTENUATED ANXIETY-LIKE BEHAVIOR AS WELL AS SOMATIC AND VISCERAL HYPERSENSITIVITY RESULTING FROM ELEVATED CORT EXPOSURE. MOREOVER, WE DELINEATED A NOVEL PATHWAY THROUGH WHICH HISTONE DEACETYLATION COULD CONTRIBUTE TO CORT REGULATION OF GR AND SUBSEQUENT CRF EXPRESSION IN THE CEA. SPECIFICALLY, DEACETYLATION OF HISTONE 3 AT LYSINE 9 (H3K9), THROUGH THE COORDINATED ACTION OF THE NAD+-DEPENDENT PROTEIN DEACETYLASE SIRTUIN-6 (SIRT6) AND NUCLEAR FACTOR KAPPA B (NFKAPPAB), SEQUESTERS GR EXPRESSION LEADING TO DISINHIBITION OF CRF. OUR RESULTS INDICATE THAT EPIGENETIC PROGRAMMING IN THE AMYGDALA, SPECIFICALLY HISTONE MODIFICATIONS, IS IMPORTANT IN THE MAINTENANCE OF CHRONIC ANXIETY AND PAIN. 2015 19 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 20 6400 30 THE ROLES OF CLASS I HISTONE DEACETYLASES (HDACS) IN MEMORY, LEARNING, AND EXECUTIVE COGNITIVE FUNCTIONS: A REVIEW. COORDINATED CHANGES IN GENE EXPRESSION ARE CRITICAL FOR SYNAPTIC PLASTICITY SUPPORTING LEARNING, MEMORY, AND OPTIMAL COGNITIVE TASK PERFORMANCE. THESE GENE EXPRESSION CHANGES ARE NOT ONLY MEDIATED BY SIGNALING PATHWAYS THAT ACTIVATE TRANSCRIPTION FACTORS, BUT ALSO BY CHROMATIN MODIFICATIONS THAT INFLUENCE THE ACCESSIBILITY OF THE TRANSCRIPTIONAL MACHINERY TO SPECIFIC GENOMIC REGIONS. DURING THE PAST DECADE, EVIDENCE ACCUMULATED THAT ALTERATIONS IN CHROMATIN-BASED EPIGENETIC REGULATION OF GENE EXPRESSION ARE LINKED TO COGNITIVE DYSFUNCTIONS IN THE AGEING OR NEURODEGENERATING BRAIN AS WELL AS TO COGNITIVE DYSFUNCTIONS RESULTING FROM CHRONIC STRESS EXPOSURE. THIS REVIEW SUMMARIZES THE RESULTS OF STUDIES THAT UNRAVELED A ROLE OF HISTONE MODIFYING ENZYMES AND HISTONE MODIFICATIONS IN NORMAL AND IMPAIRED LEARNING AND MEMORY, AND IN THE DISRUPTION OF EXECUTIVE COGNITIVE TASK PERFORMANCE. IT EMPHASIZES THE DIFFERENT ROLES OF SPECIFIC CLASS I HISTONE DEACETYLASES (HDACS) IN COGNITIVE PROCESSES GOVERNED BY THE HIPPOCAMPUS AND PREFRONTAL CORTEX AND DISCUSSES THE POTENTIAL THERAPEUTIC IMPLICATIONS OF TARGETING THEM TO HOLD THE PROGRESSION OF DISEASE-RELATED COGNITIVE DYSFUNCTIONS. 2017