1 4643 126 NEUROPATHIC PAIN AS A TRIGGER FOR HISTONE MODIFICATIONS IN LIMBIC CIRCUITRY. CHRONIC PAIN INVOLVES BOTH CENTRAL AND PERIPHERAL NEURONAL PLASTICITY THAT ENCOMPASSES CHANGES IN THE BRAIN, SPINAL CORD, AND PERIPHERAL NOCICEPTORS. WITHIN THE FOREBRAIN, MESOCORTICOLIMBIC REGIONS ASSOCIATED WITH EMOTIONAL REGULATION HAVE RECENTLY BEEN SHOWN TO EXHIBIT LASTING GENE EXPRESSION CHANGES IN MODELS OF CHRONIC PAIN. TO BETTER UNDERSTAND HOW SUCH ENDURING TRANSCRIPTIONAL CHANGES MIGHT BE REGULATED WITHIN BRAIN STRUCTURES ASSOCIATED WITH PROCESSING OF PAIN OR AFFECT, WE EXAMINED EPIGENETIC MODIFICATIONS INVOLVED WITH ACTIVE OR PERMISSIVE TRANSCRIPTIONAL STATES (HISTONE H3 LYSINE 4 MONO AND TRIMETHYLATION, AND HISTONE H3 LYSINE 27 ACETYLATION) IN PERIAQUEDUCTAL GRAY (PAG), LATERAL HYPOTHALAMUS (LH), NUCLEUS ACCUMBENS (NAC), AND VENTRAL TEGMENTAL AREA (VTA) 5 WEEKS AFTER SCIATIC NERVE INJURY IN MICE TO MODEL CHRONIC PAIN. FOR BOTH MALE AND FEMALE MICE IN CHRONIC PAIN, WE OBSERVED AN OVERALL TREND FOR A REDUCTION OF THESE EPIGENETIC MARKERS IN PERIAQUEDUCTAL GRAY, LH, AND NAC, BUT NOT VTA. MOREOVER, WE DISCOVERED THAT SOME EPIGENETIC MODIFICATIONS EXHIBITED CHANGES ASSOCIATED WITH PAIN HISTORY, WHILE OTHERS WERE ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY. WHEN TAKEN TOGETHER, THESE RESULTS SUGGEST THAT NERVE INJURY LEADS TO CHRONIC CHROMATIN-MEDIATED SUPPRESSION OF TRANSCRIPTION IN KEY LIMBIC BRAIN STRUCTURES AND CIRCUITS, WHICH MAY UNDERLIE ENDURING CHANGES IN PAIN PROCESSING AND SENSITIVITY WITHIN THESE SYSTEMS. 2023 2 5007 37 PERIPHERAL NERVE INJURY IS ASSOCIATED WITH CHRONIC, REVERSIBLE CHANGES IN GLOBAL DNA METHYLATION IN THE MOUSE PREFRONTAL CORTEX. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ARE ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS INCLUDING LOW BACK PAIN AND FIBROMYALGIA. THE MAGNITUDE OF THESE CHANGES CORRELATES WITH THE DURATION AND/OR THE INTENSITY OF CHRONIC PAIN. MOST STUDIES REPORT CHANGES IN COMMON AREAS INVOLVED IN PAIN MODULATION, INCLUDING THE PREFRONTAL CORTEX (PFC), AND PAIN-RELATED PATHOLOGICAL CHANGES IN THE PFC CAN BE REVERSED WITH EFFECTIVE TREATMENT. WHILE THE MECHANISMS UNDERLYING THESE CHANGES ARE UNKNOWN, THEY MUST BE DYNAMICALLY REGULATED. EPIGENETIC MODULATION OF GENE EXPRESSION IN RESPONSE TO EXPERIENCE AND ENVIRONMENT IS REVERSIBLE AND DYNAMIC. EPIGENETIC MODULATION BY DNA METHYLATION IS ASSOCIATED WITH ABNORMAL BEHAVIOR AND PATHOLOGICAL GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM. DNA METHYLATION MIGHT ALSO BE INVOLVED IN MEDIATING THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN IN THE BRAIN. WE THEREFORE TESTED A) WHETHER ALTERATIONS IN DNA METHYLATION ARE FOUND IN THE BRAIN LONG AFTER CHRONIC NEUROPATHIC PAIN IS INDUCED IN THE PERIPHERY USING THE SPARED NERVE INJURY MODAL AND B) WHETHER THESE INJURY-ASSOCIATED CHANGES ARE REVERSIBLE BY INTERVENTIONS THAT REVERSE THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN. SIX MONTHS FOLLOWING PERIPHERAL NERVE INJURY, ABNORMAL SENSORY THRESHOLDS AND INCREASED ANXIETY WERE ACCOMPANIED BY DECREASED GLOBAL METHYLATION IN THE PFC AND THE AMYGDALA BUT NOT IN THE VISUAL CORTEX OR THE THALAMUS. ENVIRONMENTAL ENRICHMENT ATTENUATED NERVE INJURY-INDUCED HYPERSENSITIVITY AND REVERSED THE CHANGES IN GLOBAL PFC METHYLATION. FURTHERMORE, GLOBAL PFC METHYLATION CORRELATED WITH MECHANICAL AND THERMAL SENSITIVITY IN NEUROPATHIC MICE. IN SUMMARY, INDUCTION OF CHRONIC PAIN BY PERIPHERAL NERVE INJURY IS ASSOCIATED WITH EPIGENETIC CHANGES IN THE BRAIN. THESE CHANGES ARE DETECTED LONG AFTER THE ORIGINAL INJURY, AT A LONG DISTANCE FROM THE SITE OF INJURY AND ARE REVERSIBLE WITH ENVIRONMENTAL MANIPULATION. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION THAT ARE ASSOCIATED WITH CHRONIC PAIN CONDITIONS MAY THEREFORE BE MEDIATED BY EPIGENETIC MECHANISMS. 2013 3 5019 36 PERSISTENT INFLAMMATORY PAIN IS LINKED WITH ANXIETY-LIKE BEHAVIORS, INCREASED BLOOD CORTICOSTERONE, AND REDUCED GLOBAL DNA METHYLATION IN THE RAT AMYGDALA. CHRONIC PAIN INCREASES THE RISK OF DEVELOPING ANXIETY, WITH LIMBIC AREAS BEING LIKELY NEUROLOGICAL SUBSTRATES. DESPITE HIGH CLINICAL RELEVANCE, LITTLE IS KNOWN ABOUT THE PRECISE BEHAVIORAL, HORMONAL, AND BRAIN NEUROPLASTIC CORRELATES OF ANXIETY IN THE CONTEXT OF PERSISTENT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT DECREASED NOCICEPTIVE THRESHOLDS IN CHRONIC PAIN MODELS ARE PARALLELED BY ANXIETY-LIKE BEHAVIOR IN RATS, BUT THERE ARE CONFLICTING IDEAS REGARDING ITS EFFECTS ON THE STRESS RESPONSE AND CIRCULATING CORTICOSTERONE LEVELS. EVEN LESS IS KNOWN ABOUT THE MOLECULAR MECHANISMS THROUGH WHICH THE BRAIN ENCODES PAIN-RELATED ANXIETY. THIS STUDY EXAMINES HOW PERSISTENT INFLAMMATORY PAIN IN A RAT MODEL WOULD IMPACT ANXIETY-LIKE BEHAVIORS AND CORTICOSTERONE RELEASE, AND WHETHER THESE CHANGES WOULD BE REFLECTED IN LEVELS OF GLOBAL DNA METHYLATION IN BRAIN AREAS INVOLVED IN STRESS REGULATION. COMPLETE FREUND'S ADJUVANT (CFA) OR SALINE WAS ADMINISTERED IN THE RIGHT HINDPAW OF ADULT MALE WISTAR RATS. BEHAVIORAL TESTING INCLUDED THE MEASUREMENT OF NOCICEPTIVE THRESHOLDS (DIGITAL ANESTHESIOMETER), MOTOR FUNCTION (OPEN FIELD TEST), AND ANXIETY-LIKE BEHAVIORS (ELEVATED PLUS MAZE AND THE DARK-LIGHT BOX TEST). CORTICOSTERONE WAS MEASURED VIA RADIOIMMUNOASSAY. GLOBAL DNA METHYLATION (ENZYME IMMUNOASSAY) AS WELL AS DNMT3A LEVELS (WESTERN BLOTTING) WERE QUANTIFIED IN THE AMYGDALA, PREFRONTAL CORTEX, AND VENTRAL HIPPOCAMPUS. CFA ADMINISTRATION RESULTED IN PERSISTENT REDUCTION IN NOCICEPTIVE THRESHOLD IN THE ABSENCE OF LOCOMOTOR ABNORMALITIES. INCREASED ANXIETY-LIKE BEHAVIORS WERE OBSERVED IN THE ELEVATED PLUS MAZE AND WERE ACCOMPANIED BY INCREASED BLOOD CORTICOSTERONE LEVELS 10 DAYS AFTER PAIN INDUCTION. GLOBAL DNA METHYLATION WAS DECREASED IN THE AMYGDALA, WITH NO CHANGES IN DNMT3A ABUNDANCE IN ANY OF THE REGIONS EXAMINED. PERSISTENT INFLAMMATORY PAIN PROMOTES ANXIETY -LIKE BEHAVIORS, HPA AXIS ACTIVATION, AND EPIGENETIC REGULATION THROUGH DNA METHYLATION IN THE AMYGDALA. THESE FINDINGS DESCRIBE A MOLECULAR MECHANISM THAT LINKS PAIN AND STRESS IN A WELL-CHARACTERIZED RODENT MODEL. 2022 4 5624 32 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 5 5199 40 PRENATAL MATERNAL STRESS IS ASSOCIATED WITH INCREASED SENSITIVITY TO NEUROPATHIC PAIN AND SEX-SPECIFIC CHANGES IN SUPRASPINAL MRNA EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES IN ADULTHOOD. EXPOSURE TO PRENATAL MATERNAL STRESS IMPACTS ADULT BEHAVIORAL OUTCOMES AND HAS BEEN SUGGESTED AS A RISK FACTOR FOR CHRONIC PAIN. HOWEVER, THE NEUROBIOLOGICAL MECHANISMS IMPLICATED ARE NOT WELL-CHARACTERIZED. IN THIS STUDY, WE ANALYZED THE EFFECT OF A PRENATAL MATERNAL STRESS ON THE DEVELOPMENT OF NEUROPATHIC PAIN-RELATED BEHAVIOURS AND GENE EXPRESSION IN THE FRONTAL CORTEX AND HIPPOCAMPUS IN ADULT OFFSPRING FOLLOWING CHRONIC CONSTRICTION INJURY OF THE SCIATIC NERVE IN MALE AND FEMALE CD1 MICE. NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY WAS AMPLIFIED IN BOTH MALE AND FEMALE PRENATALLY-STRESSED OFFSPRING, SUGGESTING THAT PRENATAL STRESS EXACERBATES PAIN AFTER INJURY. ANALYSIS OF MRNA EXPRESSION OF GENES RELATED TO EPIGENETIC REGULATION AND STRESS RESPONSES IN THE FRONTAL CORTEX AND HIPPOCAMPUS, BRAIN STRUCTURES IMPLICATED IN CHRONIC PAIN, SHOWED DISTINCT SEX AND REGION-SPECIFIC PATTERNS OF DYSREGULATION. IN GENERAL, MRNA EXPRESSION WAS MOST FREQUENTLY ALTERED IN THE MALE HIPPOCAMPUS AND EFFECTS OF PRENATAL STRESS WERE MORE PREVALENT THAN EFFECTS OF NERVE INJURY IN BOTH SUPRASPINAL AREAS. THESE FINDINGS DEMONSTRATE THE IMPACT OF PRENATAL STRESS ON BEHAVIORAL SENSITIVITY TO A PAINFUL INJURY. CHANGES IN THE EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES SUGGEST A POSSIBLE MECHANISM BY WHICH THE EARLY LIFE STRESS BECOMES EMBEDDED IN THE CENTRAL NERVOUS SYSTEM. INCREASED UNDERSTANDING OF THE INTERACTIONS AMONG EARLY-LIFE STRESS, SEX, AND PAIN MAY LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND EPIGENETIC DRUGS FOR THE TREATMENT OF CHRONIC PAIN DISORDERS. 2020 6 6427 35 THE TRANSITION FROM ACUTE TO CHRONIC PAIN: DYNAMIC EPIGENETIC REPROGRAMMING OF THE MOUSE PREFRONTAL CORTEX UP TO 1 YEAR AFTER NERVE INJURY. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT STRUCTURAL AND FUNCTIONAL CHANGES THROUGHOUT THE NEUROAXIS, INCLUDING IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPORTANT IN THE INTEGRATION OF SENSORY, COGNITIVE, AND EMOTIONAL INFORMATION AND IN CONDITIONED PAIN MODULATION. WE PREVIOUSLY REPORTED WIDESPREAD EPIGENETIC REPROGRAMMING IN THE PFC MANY MONTHS AFTER NERVE INJURY IN RODENTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, CAN DRIVE CHANGES IN GENE EXPRESSION WITHOUT MODIFYING DNA SEQUENCES. TO DATE, LITTLE IS KNOWN ABOUT EPIGENETIC DYSREGULATION AT THE ONSET OF ACUTE PAIN OR HOW IT PROGRESSES AS PAIN TRANSITIONS FROM ACUTE TO CHRONIC. WE HYPOTHESIZE THAT ACUTE PAIN AFTER INJURY RESULTS IN RAPID AND PERSISTENT EPIGENETIC REMODELLING IN THE PFC THAT EVOLVES AS PAIN BECOMES CHRONIC. WE FURTHER PROPOSE THAT UNDERSTANDING EPIGENETIC REMODELLING WILL PROVIDE INSIGHTS INTO THE MECHANISMS DRIVING PAIN-RELATED CHANGES IN THE BRAIN. EPIGENOME-WIDE ANALYSIS WAS PERFORMED IN THE MOUSE PFC 1 DAY, 2 WEEKS, 6 MONTHS, AND 1 YEAR AFTER PERIPHERAL INJURY USING THE SPARED NERVE INJURY IN MICE. SPARED NERVE INJURY RESULTED IN RAPID AND PERSISTENT CHANGES IN DNA METHYLATION, WITH ROBUST DIFFERENTIAL METHYLATION OBSERVED BETWEEN SPARED NERVE INJURY AND SHAM-OPERATED CONTROL MICE AT ALL TIME POINTS. HUNDREDS OF DIFFERENTIALLY METHYLATED GENES WERE IDENTIFIED, INCLUDING MANY WITH KNOWN FUNCTION IN PAIN. PATHWAY ANALYSIS REVEALED ENRICHMENT IN GENES RELATED TO STIMULUS RESPONSE AT EARLY TIME POINTS, IMMUNE FUNCTION AT LATER TIME POINTS, AND ACTIN AND CYTOSKELETAL REGULATION THROUGHOUT THE TIME COURSE. THESE RESULTS EMPHASIZE THE IMPORTANCE OF CONSIDERING PAIN CHRONICITY IN BOTH PAIN RESEARCH AND IN TREATMENT OPTIMIZATION. 2020 7 1803 14 EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS ON THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NUCLEI OF HIPPOCAMPAL NEURONS IN RATS WITH DIFFERENT EXCITABILITY OF THE NERVOUS SYSTEM. IN RATS WITH LOW EXCITABILITY THRESHOLD OF THE NERVOUS SYSTEM DEMONSTRATING SIGNIFICANT AND PERSISTENT BEHAVIORAL DISORDERS UNDER STRESS CONDITIONS, THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NEURONAL NUCLEI OF HIPPOCAMPAL FIELD CA3 DECREASED OVER 2 WEEKS AFTER LONG-TERM EMOTIONAL AND PAIN STRESS. IT WAS HYPOTHESIZED THAT PROTEIN MECP2 TRIGGERS EPIGENETIC CHANGES IN DNA THAT UNDERLIE "STRESS MEMORY". 2006 8 5444 48 REPEATED TOLUENE EXPOSURE MODIFIES THE ACETYLATION PATTERN OF HISTONES H3 AND H4 IN THE RAT BRAIN. TOLUENE IS A VOLATILE ORGANIC SOLVENT WITH ADDICTIVE POTENTIAL THAT EXHIBITS SIMILARITIES IN ITS PHYSIOLOGICAL EFFECTS AND MODES OF ACTION TO OTHER ADDICTIVE DRUGS. DESPITE ITS WIDESPREAD ABUSE, THE MOLECULAR MECHANISMS DRIVING THE RESPONSE AND ADAPTATION OF THE ORGANISM TO THIS DRUG ARE NOT FULLY UNDERSTOOD. IN RECENT YEARS, DIFFERENT EPIGENETIC MECHANISMS THAT MODULATE GENE EXPRESSION HAVE BEEN SHOWN TO BE ASSOCIATED TO COCAINE, AMPHETAMINE AND ALCOHOL MISUSE-INDUCED ALTERATIONS IN NEURONAL FUNCTION. FOR EXAMPLE, IT HAS BEEN DEMONSTRATED THAT DRUG CONSUMPTION INDUCES VARIATIONS IN HISTONE ACETYLATION LEVELS IN BRAIN REWARD REGIONS AND THESE PLAY A RELEVANT ROLE ON THE ABUSE-ASSOCIATED BEHAVIORAL PLASTICITY. IN ORDER TO DECIPHER WHETHER REPEATED TOLUENE EXPOSURE COULD MEDIATE EPIGENETIC CHANGES IN THE RAT BRAIN, WE HERE ANALYZED THE ACETYLATION PATTERN OF HISTONES H3 AND H4 IN THREE BRAIN AREAS THAT HAVE BEEN PREVIOUSLY ASSOCIATED TO SUBSTANCE ABUSE REWARD PATHWAYS: THE NUCLEUS ACCUMBENS (NAC), THE VENTRAL TEGMENTAL AREA (VTA) AND THE CENTRAL AMYGDALA (CEA). USING IMMUNOFLUORESCENCE ANALYSIS OF BRAIN SECTIONS WITH SPECIFIC ANTIBODIES THAT RECOGNIZE THE ACETYLATED FORMS OF HISTONES H3 AND H4, WE DEMONSTRATE THAT CHRONIC TOLUENE INHALATION DIFFERENTIALLY MODIFIES HISTONE H3 AND H4 ACETYLATION IN THE NAC AND THE VTA WHILE NO EFFECT IS OBSERVED IN THE CEA. OUR RESULTS SUGGEST THAT THE ACTIVITY OF CHROMATIN-MODIFYING ENZYMES SUCH AS HISTONE DE-ACETYLASES (HDACS) IN CERTAIN BRAIN AREAS ARE RESPONSIVE TO TOLUENE INHALATION AND MIGHT BE CRUCIAL MEDIATORS IN THE ADDICTIVE RESPONSE TO TOLUENE. 2011 9 5709 38 SIRT1 DECREASES EMOTIONAL PAIN VULNERABILITY WITH ASSOCIATED CAMKIIALPHA DEACETYLATION IN CENTRAL AMYGDALA. EMOTIONAL DISORDERS ARE COMMON COMORBID CONDITIONS THAT FURTHER EXACERBATE THE SEVERITY AND CHRONICITY OF CHRONIC PAIN. HOWEVER, INDIVIDUALS SHOW CONSIDERABLE VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN UNDER SIMILAR PAIN CONDITIONS. IN THIS STUDY ON MALE RAT AND MOUSE MODELS OF CHRONIC NEUROPATHIC PAIN, WE IDENTIFY THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) IN CENTRAL AMYGDALA AS A KEY EPIGENETIC REGULATOR THAT CONTROLS THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDERLYING THE INDIVIDUAL VULNERABILITY TO CHRONIC PAIN. WE FOUND THAT ANIMALS THAT WERE VULNERABLE TO DEVELOPING BEHAVIORS OF ANXIETY AND DEPRESSION UNDER THE PAIN CONDITION DISPLAYED REDUCED SIRT1 PROTEIN LEVELS IN CENTRAL AMYGDALA, BUT NOT THOSE ANIMALS RESISTANT TO THE EMOTIONAL DISORDERS. VIRAL OVEREXPRESSION OF LOCAL SIRT1 REVERSED THIS VULNERABILITY, BUT VIRAL KNOCKDOWN OF LOCAL SIRT1 MIMICKED THE PAIN EFFECT, ELICITING THE PAIN VULNERABILITY IN PAIN-FREE ANIMALS. THE SIRT1 ACTION WAS ASSOCIATED WITH CAMKIIALPHA DOWNREGULATION AND DEACETYLATION OF HISTONE H3 LYSINE 9 AT THE CAMKIIALPHA PROMOTER. THESE RESULTS SUGGEST THAT, BY TRANSCRIPTIONAL REPRESSION OF CAMKIIALPHA IN CENTRAL AMYGDALA, SIRT1 FUNCTIONS TO GUARD AGAINST THE EMOTIONAL PAIN VULNERABILITY UNDER CHRONIC PAIN CONDITIONS. THIS STUDY INDICATES THAT SIRT1 MAY SERVE AS A POTENTIAL THERAPEUTIC MOLECULE FOR INDIVIDUALIZED TREATMENT OF CHRONIC PAIN WITH VULNERABLE EMOTIONAL DISORDERS.SIGNIFICANCE STATEMENT CHRONIC PAIN IS A PREVALENT NEUROLOGICAL DISEASE WITH NO EFFECTIVE TREATMENT AT PRESENT. PAIN PATIENTS DISPLAY CONSIDERABLY VARIABLE VULNERABILITY TO DEVELOPING CHRONIC PAIN, INDICATING INDIVIDUAL-BASED MOLECULAR MECHANISMS UNDERLYING THE PAIN VULNERABILITY, WHICH IS HARDLY ADDRESSED IN CURRENT PRECLINICAL RESEARCH. IN THIS STUDY, WE HAVE IDENTIFIED THE HISTONE DEACETYLASE SIRTUIN 1 (SIRT1) AS A KEY REGULATOR THAT CONTROLS THIS PAIN VULNERABILITY. THIS STUDY REVEALS THAT THE SIRT1-CAMKIIAALPHA PATHWAY IN CENTRAL AMYGDALA ACTS AS AN EPIGENETIC MECHANISM THAT GUARDS AGAINST THE DEVELOPMENT OF COMORBID EMOTIONAL DISORDERS UNDER CHRONIC PAIN, AND THAT ITS DYSFUNCTION CAUSES INCREASED VULNERABILITY TO THE DEVELOPMENT OF CHRONIC PAIN. THESE FINDINGS SUGGEST THAT SIRT1 ACTIVATORS MAY BE USED IN A NOVEL THERAPEUTIC APPROACH FOR INDIVIDUAL-BASED TREATMENT OF CHRONIC PAIN. 2020 10 3314 44 HIPPOCAMPAL CANNABINOID 1 RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN MALE RATS. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCING LONG-TERM NEUROPLASTIC CHANGES THAT, IN TURN, CONTRIBUTE TO MALADAPTIVE BEHAVIORS. THIS BEHAVIORAL DYSREGULATION IS ASSOCIATED WITH TRANSCRIPTIONAL REPROGRAMMING IN BRAIN REWARD CIRCUITRY, ALTHOUGH THE MECHANISMS UNDERLYING THIS MODULATION REMAIN POORLY UNDERSTOOD. THE ENDOGENOUS CANNABINOID SYSTEM MAY PLAY A ROLE IN THIS PROCESS IN THAT CANNABINOID MECHANISMS MODULATE DRUG REWARD AND CONTRIBUTE TO COCAINE-INDUCED NEURAL ADAPTATIONS. IN THIS STUDY, WE INVESTIGATED WHETHER COCAINE SELF-ADMINISTRATION INDUCES LONG-TERM ADAPTATIONS, INCLUDING TRANSCRIPTIONAL MODIFICATIONS AND ASSOCIATED EPIGENETIC PROCESSES. WE FIRST EXAMINED ENDOCANNABINOID GENE EXPRESSION IN REWARD-RELATED BRAIN REGIONS OF THE RAT FOLLOWING SELF-ADMINISTERED (0.33 MG/KG INTRAVENOUS, FR1, 10 DAYS) COCAINE INJECTIONS. INTERESTINGLY, WE FOUND INCREASED CNR1 EXPRESSION IN SEVERAL STRUCTURES, INCLUDING PREFRONTAL CORTEX, NUCLEUS ACCUMBENS, DORSAL STRIATUM, HIPPOCAMPUS, HABENULA, AMYGDALA, LATERAL HYPOTHALAMUS, VENTRAL TEGMENTAL AREA, AND ROSTROMEDIAL TEGMENTAL NUCLEUS, WITH MOST PRONOUNCED EFFECTS IN THE HIPPOCAMPUS. ENDOCANNABINOID LEVELS, MEASURED BY MASS SPECTROMETRY, WERE ALSO ALTERED IN THIS STRUCTURE. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR IN THE HIPPOCAMPUS REVEALED THAT TWO ACTIVATING HISTONE MARKS, H3K4ME3 AND H3K27AC, WERE ENRICHED AT SPECIFIC ENDOCANNABINOID GENES FOLLOWING COCAINE INTAKE. TARGETING CB1 RECEPTORS USING CHROMOSOME CONFORMATION CAPTURE, WE HIGHLIGHTED SPATIAL CHROMATIN RE-ORGANIZATION IN THE HIPPOCAMPUS, AS WELL AS IN THE NUCLEUS ACCUMBENS, SUGGESTING THAT DESTABILIZATION OF THE CHROMATIN MAY CONTRIBUTE TO NEURONAL RESPONSES TO COCAINE. OVERALL, OUR RESULTS HIGHLIGHT A KEY ROLE FOR THE HIPPOCAMPUS IN COCAINE-INDUCED PLASTICITY AND BROADEN THE UNDERSTANDING OF NEURONAL ALTERATIONS ASSOCIATED WITH ENDOCANNABINOID SIGNALING. THE LATTER SUGGESTS THAT EPIGENETIC MODIFICATIONS CONTRIBUTE TO MALADAPTIVE BEHAVIORS ASSOCIATED WITH CHRONIC DRUG USE. 2022 11 1614 33 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES. 2021 12 3952 28 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 13 5974 31 TET1 IN NUCLEUS ACCUMBENS OPPOSES DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. DEPRESSION IS A LEADING CAUSE OF DISEASE BURDEN, YET CURRENT THERAPIES FULLY TREAT <50% OF AFFECTED INDIVIDUALS. INCREASING EVIDENCE IMPLICATES EPIGENETIC MECHANISMS IN DEPRESSION AND ANTIDEPRESSANT ACTION. HERE WE EXAMINED A POSSIBLE ROLE FOR THE DNA DIOXYGENASE, TEN-ELEVEN TRANSLOCATION PROTEIN 1 (TET1), IN DEPRESSION-RELATED BEHAVIORAL ABNORMALITIES. WE APPLIED CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MOUSE MODEL OF DEPRESSION-LIKE BEHAVIORS, AND EXAMINED TET1 EXPRESSION CHANGES IN NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW DECREASED TET1 EXPRESSION IN NAC IN STRESS-SUSCEPTIBLE MICE ONLY. SURPRISINGLY, SELECTIVE KNOCKOUT OF TET1 IN NAC NEURONS OF ADULT MICE PRODUCED ANTIDEPRESSANT-LIKE EFFECTS IN SEVERAL BEHAVIORAL ASSAYS. TO IDENTIFY TET1 TARGETS THAT MEDIATE THESE ACTIONS, WE PERFORMED RNASEQ ON NAC AFTER CONDITIONAL DELETION OF TET1 AND FOUND THAT IMMUNE-RELATED GENES ARE THE MOST HIGHLY DYSREGULATED. MOREOVER, MANY OF THESE GENES ARE ALSO UPREGULATED IN THE NAC OF RESILIENT MICE AFTER CHRONIC SOCIAL DEFEAT STRESS. THESE FINDINGS REVEAL A NOVEL ROLE FOR TET1, AN ENZYME IMPORTANT FOR DNA HYDROXYMETHYLATION, IN THE BRAIN'S REWARD CIRCUITRY IN MODULATING STRESS RESPONSES IN MICE. WE ALSO IDENTIFY A SUBSET OF GENES THAT ARE REGULATED BY TET1 IN THIS CIRCUITRY. THESE FINDINGS PROVIDE NEW INSIGHT INTO THE PATHOPHYSIOLOGY OF DEPRESSION, WHICH CAN AID IN FUTURE ANTIDEPRESSANT DRUG DISCOVERY EFFORTS. 2017 14 6801 45 [EPIGENETIC MECHANISMS AND ALCOHOL USE DISORDERS: A POTENTIAL THERAPEUTIC TARGET]. ALCOHOL USE DISORDER IS A DEVASTATING ILLNESS WITH A PROFOUND HEALTH IMPACT, AND ITS DEVELOPMENT IS DEPENDENT ON BOTH GENETIC AND ENVIRONMENTAL FACTORS. THIS DISEASE OCCURS OVER TIME AND REQUIRES CHANGES IN BRAIN GENE EXPRESSION. THERE IS CONVERGING EVIDENCE SUGGESTING THAT THE EPIGENETIC PROCESSES MAY PLAY A ROLE IN THE ALCOHOL-INDUCED GENE REGULATIONS AND BEHAVIOR SUCH AS THE INTERVENTION OF DNA METHYLATION AND HISTONE ACETYLATION. HISTONE ACETYLATION, LIKE HISTONE METHYLATION, IS A HIGHLY DYNAMIC PROCESS REGULATED BY TWO CLASSES OF ENZYMES: HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES (HDACS). TO DATE, 18 HUMAN HDAC ISOFORMS HAVE BEEN CHARACTERIZED, AND BASED ON THEIR SEQUENCE HOMOLOGIES AND COFACTOR DEPENDENCIES, THEY HAVE BEEN PHYLOGENETICALLY CATEGORIZED INTO 4 MAIN CLASSES: CLASSES I, II (A AND B), III, AND IV. IN THE BRAIN, EXPRESSION OF THE DIFFERENT CLASSES OF HDACS VARIES BETWEEN CELL TYPES AND ALSO IN THEIR SUBCELLULAR LOCALIZATION (NUCLEUS AND/OR CYTOSOL). FURTHERMORE, WE RECENTLY SHOWED THAT A SINGLE ETHANOL EXPOSURE INHIBITS HDAC ACTIVITY AND INCREASES BOTH H3 AND H4 HISTONE ACETYLATION WITHIN THE AMYGDALA OF RATS. IN THE BRAIN OF ALCOHOLIC PATIENTS, ETHANOL HAS BEEN SHOWN TO INDUCE HISTONE-RELATED AND DNA METHYLATION EPIGENETIC CHANGES IN SEVERAL REWARD REGIONS INVOLVED IN REWARD PROCESSES SUCH AS HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA. WE RECENTLY DEMONSTRATED ALTERATION OF HISTONE H3 ACETYLATION LEVELS IN SEVERAL BRAIN REGIONS FROM THE REWARD CIRCUIT OF RATS MADE DEPENDENT TO ALCOHOL AFTER CHRONIC AND INTERMITTENT EXPOSURE TO ETHANOL VAPOR. IN NEURONAL CELL LINE CULTURE, ETHANOL WAS SHOWN TO INDUCE HDAC EXPRESSION. IN MOUSE AND RAT BRAIN, NUMEROUS STUDIES REPORTED EPIGENETIC ALTERATIONS FOLLOWING ETHANOL EXPOSURE. WE ALSO DEMONSTRATED THAT BOTH THE EXPRESSION OF GENES AND THE ACTIVITY OF ENZYMES INVOLVED IN EPIGENETIC MECHANISMS ARE CHANGED AFTER REPEATED ADMINISTRATIONS OF ETHANOL IN MICE SENSITIZED TO THE MOTOR STIMULANT EFFECT OF ETHANOL (A MODEL OF DRUG-INDUCED NEUROPLASTICITY). NUMEROUS STUDIES HAVE SHOWN THAT HDAC INHIBITORS ARE ABLE TO COUNTER ETHANOL-INDUCED BEHAVIORS AND THE ETHANOL-INDUCED CHANGES IN THE LEVELS OF HDAC AND/OR LEVELS OF ACETYLATED HDAC. FOR EXAMPLE, TRICHOSTATIN A (TSA) TREATMENT CAUSED THE REVERSAL OF ETHANOL-INDUCED TOLERANCE, ANXIETY, AND ETHANOL DRINKING BY INHIBITING HDAC ACTIVITY, THEREBY INCREASING HISTONE ACETYLATION IN THE AMYGDALA OF RATS. ANOTHER STUDY DEMONSTRATED THAT TSA PREVENTED THE DEVELOPMENT OF ETHANOL WITHDRAWAL INDUCED ANXIETY IN RATS BY RESCUING DEFICITS IN HISTONE ACETYLATION INDUCED BY INCREASED HDAC ACTIVITY IN THE AMYGDALA. WE HAVE DEMONSTRATED THAT TREATMENT WITH THE HDAC INHIBITOR SODIUM BUTYRATE BLOCKS BOTH THE DEVELOPMENT AND THE EXPRESSION OF ETHANOL-INDUCED BEHAVIORAL SENSITIZATION IN MICE. IN THIS CONTEXT, CONVERGING EVIDENCE INDICATES THAT HDAC INHIBITORS COULD BE USEFUL IN COUNTERACTING ETHANOL-INDUCED GENE REGULATIONS VIA EPIGENETIC MECHANISMS, THAT IS, HDAC INHIBITORS COULD AFFECT DIFFERENT ACETYLATION SITES AND MAY ALSO ALTER THE EXPRESSION OF DIFFERENT GENES THAT COULD IN TURN COUNTERACT THE EFFECT OF ETHANOL. RECENT WORK IN RODENTS HAS SHOWN THAT SYSTEMIC ADMINISTRATION OF PAN HDAC CLASS I AND II INHIBITORS, TSA AND N-HYDROXY-N-PHENYL-OCTANEDIAMIDE [SUBEROYLANILIDE HYDROXAMIC ACID] (SAHA), AND OF THE MORE SELECTIVE INHIBITOR (MAINLY HDAC1 AND HDAC9) MS-275, DECREASE BINGE-LIKE ALCOHOL DRINKING IN MICE. SAHA SELECTIVELY REDUCED ETHANOL OPERANT SELF-ADMINISTRATION AND SEEKING IN RATS. OUR PREVIOUS STUDY REVEALED THAT MS-275 STRONGLY DECREASED OPERANT ETHANOL SELF-ADMINISTRATION IN ALCOHOL-DEPENDENT RATS WHEN ADMINISTERED 30 MINUTES BEFORE THE SESSION AT THE SECOND DAY OF INJECTION. WE ALSO DEMONSTRATED THAT INTRA-CEREBRO-VENTRICULAR INFUSION OF MS-275 INCREASES ACETYLATION OF HISTONE 4 WITHIN THE NUCLEUS ACCUMBENS AND THE DORSOLATERAL STRIATUM, ASSOCIATED TO A DECREASE IN ETHANOL SELF-ADMINISTRATION BY ABOUT 75%. MS-275 ALSO DIMINISHED BOTH THE MOTIVATION TO CONSUME ETHANOL (25% DECREASE), RELAPSE (BY ABOUT 50%) AND POSTPONED REACQUISITION AFTER ABSTINENCE. BOTH LITERATURE AND SEVERAL OF OUR STUDIES STRONGLY SUPPORT THE POTENTIAL THERAPEUTIC INTEREST OF TARGETING EPIGENETIC MECHANISMS IN EXCESSIVE ALCOHOL DRINKING AND STRENGTHEN THEINTEREST OF FOCUSING ON SPECIFIC ISOFORMS OF HISTONE DEACETYLASES. 2017 15 2280 42 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 16 2013 33 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 17 377 33 AN EPIGENETIC HYPOTHESIS FOR THE GENOMIC MEMORY OF PAIN. CHRONIC PAIN IS ACCOMPANIED WITH LONG-TERM SENSORY, AFFECTIVE AND COGNITIVE DISTURBANCES. WHAT ARE THE MECHANISMS THAT MEDIATE THE LONG-TERM CONSEQUENCES OF PAINFUL EXPERIENCES AND EMBED THEM IN THE GENOME? WE HYPOTHESIZE THAT ALTERATIONS IN DNA METHYLATION, AN ENZYMATIC COVALENT MODIFICATION OF CYTOSINE BASES IN DNA, SERVE AS A "GENOMIC" MEMORY OF PAIN IN THE ADULT CORTEX. DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR LONG-TERM REGULATION OF GENE EXPRESSION. NEURONAL PLASTICITY AT THE NEUROANATOMICAL, FUNCTIONAL, MORPHOLOGICAL, PHYSIOLOGICAL AND MOLECULAR LEVELS HAS BEEN DEMONSTRATED THROUGHOUT THE NEUROAXIS IN RESPONSE TO PERSISTENT PAIN, INCLUDING IN THE ADULT PREFRONTAL CORTEX (PFC). WE HAVE PREVIOUSLY REPORTED WIDESPREAD CHANGES IN GENE EXPRESSION AND DNA METHYLATION IN THE PFC MANY MONTHS FOLLOWING PERIPHERAL NERVE INJURY. IN SUPPORT OF THIS HYPOTHESIS, WE SHOW HERE THAT UP-REGULATION OF A GENE INVOLVED WITH SYNAPTIC FUNCTION, SYNAPTOTAGMIN II (SYT2), IN THE PFC IN A CHRONIC PAIN MODEL IS ASSOCIATED WITH LONG-TERM CHANGES IN DNA METHYLATION. THE CHALLENGES OF UNDERSTANDING THE CONTRIBUTIONS OF EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION WITHIN THE PFC TO PAIN CHRONICITY AND THEIR THERAPEUTIC IMPLICATIONS ARE DISCUSSED. 2015 18 4150 44 MECHANISTIC INSIGHTS INTO EPIGENETIC MODULATION OF ETHANOL CONSUMPTION. THERE IS GROWING EVIDENCE THAT SMALL-MOLECULE INHIBITORS OF EPIGENETIC MODULATORS, SUCH AS HISTONE DEACETYLASES (HDAC) AND DNA METHYLTRANSFERASES (DNMT), CAN REDUCE VOLUNTARY ETHANOL CONSUMPTION IN ANIMAL MODELS, BUT MOLECULAR AND CELLULAR PROCESSES UNDERLYING THIS BEHAVIORAL EFFECT ARE POORLY UNDERSTOOD. WE USED C57BL/6J MALE MICE TO INVESTIGATE THE EFFECTS OF TWO FDA-APPROVED DRUGS, DECITABINE (A DNMT INHIBITOR) AND SAHA (AN HDAC INHIBITOR), ON ETHANOL CONSUMPTION USING TWO TESTS: BINGE-LIKE DRINKING IN THE DARK (DID) AND CHRONIC INTERMITTENT EVERY OTHER DAY (EOD) DRINKING. DECITABINE BUT NOT SAHA REDUCED ETHANOL CONSUMPTION IN BOTH TESTS. WE FURTHER INVESTIGATED DECITABINE'S EFFECTS ON THE BRAIN'S REWARD PATHWAY BY GENE EXPRESSION PROFILING IN THE VENTRAL TEGMENTAL AREA (VTA), USING RNA SEQUENCING AND ELECTROPHYSIOLOGICAL RECORDINGS FROM VTA DOPAMINERGIC NEURONS. DECITABINE-INDUCED DECREASES IN EOD DRINKING WERE ASSOCIATED WITH GLOBAL CHANGES IN GENE EXPRESSION, IMPLICATING REGULATION OF CEREBRAL BLOOD FLOW, EXTRACELLULAR MATRIX ORGANIZATION, AND NEUROIMMUNE FUNCTIONS IN DECITABINE ACTIONS. IN ADDITION, AN IN VIVO ADMINISTRATION OF DECITABINE SHORTENED ETHANOL-INDUCED EXCITATION OF VTA DOPAMINERGIC NEURONS IN VITRO, SUGGESTING THAT DECITABINE REDUCES ETHANOL DRINKING VIA CHANGES IN THE REWARD PATHWAY. TAKEN TOGETHER, OUR DATA SUGGEST A CONTRIBUTION OF BOTH NEURONAL AND NON-NEURONAL MECHANISMS IN THE VTA IN THE REGULATION OF ETHANOL CONSUMPTION. DECITABINE AND OTHER EPIGENETIC COMPOUNDS HAVE BEEN APPROVED FOR CANCER TREATMENT, AND UNDERSTANDING THEIR MECHANISMS OF ACTIONS IN THE BRAIN MAY ASSIST IN REPURPOSING THESE DRUGS AND DEVELOPING NOVEL THERAPIES FOR CENTRAL DISORDERS, INCLUDING DRUG ADDICTION. 2017 19 5818 37 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES. 2014 20 4401 37 MODULATION OF NEURONAL PLASTICITY FOLLOWING CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE WITH THE MOOD STABILIZER VALPROIC ACID. RATIONALE: COMBINATORY THERAPY IS WIDELY USED IN PSYCHIATRY OWING TO THE POSSIBILITY THAT DRUGS WITH DIFFERENT MECHANISMS OF ACTION MAY SYNERGIZE TO IMPROVE FUNCTIONS DETERIORATED IN SCHIZOPHRENIA, BIPOLAR DISORDERS, AND MAJOR DEPRESSION. WHILE COMBINATORY STRATEGIES RELY ON RECEPTOR AND SYNAPTIC MECHANISMS, IT SHOULD ALSO BE CONSIDERED THAT TWO DRUGS MAY ALSO "INTERACT" ON THE LONG-TERM TO DETERMINE MORE ROBUST CHANGES IN NEURONAL PLASTICITY, WHICH REPRESENTS A DOWNSTREAM TARGET IMPORTANT FOR FUNCTIONAL RECOVERY. OBJECTIVE: THE AIM OF THE STUDY IS TO INVESTIGATE NEUROADAPTIVE CHANGES SET IN MOTION BY CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE AND THE MOOD STABILIZER VALPROATE. METHODS: ANIMALS WERE CHRONICALLY TREATED WITH LURASIDONE, VALPROATE, OR THE COMBINATION OF THE TWO DRUGS AND KILLED 24 H AFTER THE LAST INJECTION TO EVALUATE ALTERATIONS OF DIFFERENT MEASURES OF NEURONAL PLASTICITY SUCH AS THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), THE IMMEDIATE EARLY GENE ACTIVITY-REGULATED CYTOSKELETAL ASSOCIATED PROTEIN, AND THE EPIGENETIC REGULATORS HDAC 1, 2, AND 5 IN DORSAL AND VENTRAL HIPPOCAMPUS. RESULTS: THE RESULTS SUGGEST THAT COADMINISTRATION OF LURASIDONE AND VALPROATE PRODUCES, WHEN COMPARED TO THE SINGLE DRUGS, A LARGER INCREASE IN THE EXPRESSION OF BDNF IN THE VENTRAL HIPPOCAMPUS, THROUGH THE REGULATION OF SPECIFIC NEUROTROPHIN TRANSCRIPTS. WE ALSO FOUND THAT THE HISTONE DEACETYLASES WERE REGULATED BY THE DRUG COMBINATION, SUGGESTING THAT SOME OF THE TRANSCRIPTIONAL CHANGES MAY BE SUSTAINED BY EPIGENETIC MECHANISMS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE BENEFICIAL EFFECTS ASSOCIATED WITH COMBINATORY TREATMENT BETWEEN A SECOND-GENERATION ANTIPSYCHOTIC AND A MOOD STABILIZER COULD RESULT FROM THE ABILITY TO MODULATE NEUROPLASTIC MOLECULES, WHOSE EXPRESSION AND FUNCTION IS DETERIORATED IN DIFFERENT PSYCHIATRIC CONDITIONS. 2013