1 4857 156 OPTOGENETIC STIMULATION OF THE ANTERIOR CINGULATE CORTEX AMELIORATES AUTISTIC-LIKE BEHAVIORS IN RATS INDUCED BY NEONATAL ISOLATION, CAUDATE PUTAMEN AS A SITE FOR ALTERATION. EPIGENETIC AGENTS, SUCH AS NEONATAL ISOLATION DURING NEURODEVELOPMENTAL PERIOD OF LIFE, CAN CHANGE VARIOUS REGIONS OF THE BRAIN. IT MAY FURTHER INDUCE PSYCHOLOGICAL DISORDERS SUCH AS AUTISTIC-LIKE PHENOMENA. THIS STUDY INDICATED THE ROLE OF CHRONIC INCREASED ANTERIOR CINGULATE CORTEX (ACC) OUTPUT ON ALTERATION OF CAUDATE PUTAMEN (CPU) AS A MAIN BEHAVIOR REGULATOR REGION OF THE BRAIN IN ADULT MATERNAL DEPRIVED (MD) RATS. FOR MAKING AN ANIMAL MODEL, NEONATES WERE ISOLATED FROM THEIR MOTHERS IN POSTNATAL DAYS (PND 1-10, 3 H/DAY). SUBSEQUENTLY, THEY BILATERALLY RECEIVED PLENTI-CAMKIIA-HCHR2 (H134R)-MCHERRY-WPRE VIRUS IN ACC AREA VIA STEREOTAXIC SURGERY IN PND50. AFTER 22 DAYS, THESE REGIONS WERE EXPOSED TO BLUE LASER (473 NM) FOR SIX CONSECUTIVE DAYS (15 MIN/DAY). THEN, BEHAVIORAL DEFICITS WERE TESTED AND WERE COMPARED WITH CONTROL GROUP IN THE FOLLOWING DAY. ANIMALS WERE IMMEDIATELY KILLED AND THEIR BRAINS WERE PREPARED FOR TISSUE PROCESSING. RESULTS SHOWED THAT NEONATAL ISOLATION INDUCES AUTISTIC-LIKE BEHAVIORS AND LEADS TO OVEREXPRESSION OF NMDAR1 AND NOX2-GP91(PHOX) PROTEINS AND ELEVATION OF CATALASE ACTIVITY IN THE CPU REGIONS OF THE ADULT OFFSPRING COMPARED WITH CONTROL GROUP. CHRONIC OPTOGENETIC STIMULATION OF ACC NEURONS CONTAINING (CHR2+) LED TO SIGNIFICANT REDUCTION IN THE APPEARANCE OF STEREOTYPICAL BEHAVIOR AND ALIEN-PHOBIA IN MD RATS. THE AMOUNT OF NMDAR1 AND NOX2-GP91(PHOX) EXPRESSION AND THE CATALASE ACTIVITY IN CPU WERE REDUCED AFTER THIS TREATMENT. THEREFORE, AUTISTIC-LIKE BEHAVIOR SEEMS TO BE RELATED WITH ELEVATION OF NMDAR1 AND NOX2-GP91(PHOX) PROTEIN LEVELS THAT ENHANCE THE EFFECT OF GLUTAMATERGIC PROJECTION ON CPU REGIONS. OPTOGENETIC TREATMENT ALSO COULD AMELIORATE BEHAVIORAL DEFICITS BY MODULATING THESE PROTEIN DENSITIES. 2019 2 2423 29 EPIGENETIC SIGNATURES OF SMOKING IN FIVE BRAIN REGIONS. (1) BACKGROUND: EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) IN PERIPHERAL BLOOD HAVE REPEATEDLY FOUND ASSOCIATIONS BETWEEN TOBACCO SMOKING AND ABERRANT DNA METHYLATION (DNAM), BUT LITTLE IS KNOWN ABOUT DNAM SIGNATURES OF SMOKING IN THE HUMAN BRAIN, WHICH MAY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF ADDICTIVE BEHAVIOR OBSERVED IN CHRONIC SMOKERS. (2) METHODS: WE INVESTIGATED THE SIMILARITY OF DNAM SIGNATURES IN MATCHED BLOOD AND POSTMORTEM BRAIN SAMPLES (N = 10). IN ADDITION, WE PERFORMED EWASS IN FIVE BRAIN REGIONS BELONGING TO THE NEUROCIRCUITRY OF ADDICTION: ANTERIOR CINGULATE CORTEX (ACC), BRODMANN AREA 9, CAUDATE NUCLEUS, PUTAMEN, AND VENTRAL STRIATUM (N = 38-72). (3) RESULTS: CG15925993 WITHIN THE LOC339975 GENE WAS EPIGENOME-WIDE SIGNIFICANT IN THE ACC. OF 16 IDENTIFIED DIFFERENTIALLY METHYLATED REGIONS, TWO (PRSS50 AND LINC00612/A2M-AS1) OVERLAPPED BETWEEN MULTIPLE BRAIN REGIONS. FUNCTIONAL ENRICHMENT WAS DETECTED FOR BIOLOGICAL PROCESSES RELATED TO NEURONAL DEVELOPMENT, INFLAMMATORY SIGNALING AND IMMUNE CELL MIGRATION. ADDITIONALLY, OUR RESULTS INDICATE THE ASSOCIATION OF THE WELL-KNOWN AHRR CPG SITE CG05575921 WITH SMOKING IN THE BRAIN. (4) CONCLUSION: THE PRESENT STUDY PROVIDES FURTHER EVIDENCE OF THE STRONG RELATIONSHIP BETWEEN ABERRANT DNAM AND SMOKING. 2022 3 1706 38 DYNORPHIN/KOP AND NOCICEPTIN/NOP GENE EXPRESSION AND EPIGENETIC CHANGES BY COCAINE IN RAT STRIATUM AND NUCLEUS ACCUMBENS. COCAINE INDUCES NEUROCHEMICAL CHANGES OF ENDOGENOUS PRODYNORPHIN-KAPPA OPIOID RECEPTOR (PDYN-KOP) AND PRONOCICEPTIN/ORPHANINFQ-NOCICEPTIN RECEPTOR (PN/OFQ-NOP) SYSTEMS. BOTH SYSTEMS PLAY AN IMPORTANT ROLE IN REWARDING MECHANISMS AND ADDICTIVE STIMULUS PROCESSING BY MODULATING DRUG-INDUCED DOPAMINERGIC ACTIVATION IN THE MESOCORTICO-LIMBIC BRAIN AREAS. THEY ARE ALSO INVOLVED IN REGULATING STRESS MECHANISMS RELATED TO ADDICTION. THE AIM OF THIS STUDY WAS TO INVESTIGATE POSSIBLE CHANGES OF GENE EXPRESSION OF THE DYNORPHINERGIC AND NOCICEPTINERGIC SYSTEM COMPONENTS IN THE NUCLEUS ACCUMBENS (NA) AND IN MEDIAL AND LATERAL CAUDATE PUTAMEN (MCPU AND LCPU, RESPECTIVELY) OF RATS, FOLLOWING CHRONIC SUBCUTANEOUS INFUSION OF COCAINE. IN ADDITION, THE EPIGENETIC HISTONE MODIFICATIONS H3K4ME3 AND H3K27ME3 (AN ACTIVATING AND A REPRESSIVE MARKER, RESPECTIVELY) AT THE PROMOTER LEVEL OF THE PDYN, KOP, PN/OFQ AND NOP GENES WERE INVESTIGATED. RESULTS SHOWED THAT COCAINE INDUCED PDYN GENE EXPRESSION UP-REGULATION IN THE NA AND LCPU, AND ITS DOWN-REGULATION IN THE MCPU, WHEREAS KOP MRNA LEVELS WERE UNCHANGED. MOREOVER, COCAINE EXPOSURE DECREASED PN/OFQ GENE EXPRESSION IN THE NA AND LCPU, WHILE NOP MRNA LEVELS APPEARED SIGNIFICANTLY INCREASED IN THE NA AND DECREASED IN THE LCPU. SPECIFIC CHANGES OF THE H3K4ME3 AND H3K27ME3 LEVELS WERE FOUND AT PDYN, PN/OFQ, AND NOP GENE PROMOTER, CONSISTENT WITH THE OBSERVED GENE EXPRESSION ALTERATIONS. THE PRESENT FINDINGS CONTRIBUTE TO BETTER DEFINE THE ROLE OF ENDOGENOUS PDYN-KOP AND PN/OFQ-NOP SYSTEMS IN NEUROPLASTICITY MECHANISMS FOLLOWING CHRONIC COCAINE TREATMENT. THE EPIGENETIC HISTONE MODIFICATIONS UNDERLYING THE GENE EXPRESSION CHANGES LIKELY MEDIATE THE EFFECTS OF COCAINE ON TRANSCRIPTIONAL REGULATION OF SPECIFIC GENE PROMOTERS THAT RESULT IN LONG-LASTING DRUG-INDUCED PLASTICITY. 2014 4 1089 25 COCAINE-RELATED DNA METHYLATION IN CAUDATE NEURONS ALTERS 3D CHROMATIN STRUCTURE OF THE IRXA GENE CLUSTER. EPIGENETIC MECHANISMS, LIKE THOSE INVOLVING DNA METHYLATION, ARE THOUGHT TO MEDIATE THE RELATIONSHIP BETWEEN CHRONIC COCAINE DEPENDENCE AND MOLECULAR CHANGES IN ADDICTION-RELATED NEUROCIRCUITRY, BUT HAVE BEEN UNDERSTUDIED IN HUMAN BRAIN. WE INITIALLY USED REDUCED REPRESENTATION BISULFITE SEQUENCING (RRBS) TO GENERATE A METHYLOME-WIDE PROFILE OF COCAINE DEPENDENCE IN HUMAN POST-MORTEM CAUDATE TISSUE. WE FOCUSED ON THE IROQUOIS HOMEOBOX A (IRXA) GENE CLUSTER, WHERE HYPOMETHYLATION IN EXON 3 OF IRX2 IN NEURONAL NUCLEI WAS ASSOCIATED WITH COCAINE DEPENDENCE. WE REPLICATED THIS FINDING IN AN INDEPENDENT COHORT AND FOUND SIMILAR RESULTS IN THE DORSAL STRIATUM FROM COCAINE SELF-ADMINISTERING MICE. USING EPIGENOME EDITING AND 3C ASSAYS, WE DEMONSTRATED A CAUSAL RELATIONSHIP BETWEEN METHYLATION WITHIN THE IRX2 GENE BODY, CTCF PROTEIN BINDING, THREE-DIMENSIONAL (3D) CHROMATIN INTERACTION, AND GENE EXPRESSION. TOGETHER, THESE FINDINGS SUGGEST THAT COCAINE-RELATED HYPOMETHYLATION OF IRX2 CONTRIBUTES TO THE DEVELOPMENT AND MAINTENANCE OF COCAINE DEPENDENCE THROUGH ALTERATIONS IN 3D CHROMATIN STRUCTURE IN THE CAUDATE NUCLEUS. 2021 5 3331 40 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM. 2018 6 4218 34 METHYL SUPPLEMENTATION ATTENUATES COCAINE-SEEKING BEHAVIORS AND COCAINE-INDUCED C-FOS ACTIVATION IN A DNA METHYLATION-DEPENDENT MANNER. EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, REGULATE RESPONSIVENESS TO DRUGS OF ABUSE, SUCH AS COCAINE, BUT RELATIVELY LITTLE IS KNOWN ABOUT THE REGULATION OF ADDICTIVE-LIKE BEHAVIORS BY DNA METHYLATION. TO INVESTIGATE THE INFLUENCE OF DNA METHYLATION ON THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ON DRUG-SEEKING BEHAVIOR, RATS RECEIVING METHYL SUPPLEMENTATION VIA CHRONIC L-METHIONINE (MET) UNDERWENT EITHER A SENSITIZATION REGIMEN OF INTERMITTENT COCAINE INJECTIONS OR INTRAVENOUS SELF-ADMINISTRATION OF COCAINE, FOLLOWED BY CUE-INDUCED AND DRUG-PRIMED REINSTATEMENT. MET BLOCKED SENSITIZATION TO THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ATTENUATED DRUG-PRIMED REINSTATEMENT, WITH NO EFFECT ON CUE-INDUCED REINSTATEMENT OR SUCROSE SELF-ADMINISTRATION AND REINSTATEMENT. FURTHERMORE, UPREGULATION OF DNA METHYLTRANSFERASE 3A AND 3B AND GLOBAL DNA HYPOMETHYLATION WERE OBSERVED IN THE NUCLEUS ACCUMBENS CORE (NAC), BUT NOT IN THE MEDIAL PREFRONTAL CORTEX (MPFC), OF COCAINE-PRETREATED RATS. GLUTAMATERGIC PROJECTIONS FROM THE MPFC TO THE NAC ARE CRITICALLY INVOLVED IN THE REGULATION OF COCAINE-PRIMED REINSTATEMENT, AND ACTIVATION OF BOTH BRAIN REGIONS IS SEEN IN HUMAN ADDICTS WHEN REEXPOSED TO THE DRUG. WHEN COMPARED WITH VEHICLE-PRETREATED RATS, THE IMMEDIATE EARLY GENE C-FOS (A MARKER OF NEURONAL ACTIVATION) WAS UPREGULATED IN THE NAC AND MPFC OF COCAINE-PRETREATED RATS AFTER COCAINE-PRIMED REINSTATEMENT, AND CHRONIC MET TREATMENT BLOCKED ITS INDUCTION IN BOTH REGIONS. COCAINE-INDUCED C-FOS EXPRESSION IN THE NAC WAS ASSOCIATED WITH REDUCED METHYLATION AT CPG DINUCLEOTIDES IN THE C-FOS GENE PROMOTER, EFFECTS REVERSED BY MET TREATMENT. OVERALL, THESE DATA SUGGEST THAT DRUG-SEEKING BEHAVIORS ARE, IN PART, ATTRIBUTABLE TO A DNA METHYLATION-DEPENDENT PROCESS, LIKELY OCCURRING AT SPECIFIC GENE LOCI (E.G., C-FOS) IN THE REWARD PATHWAY. 2015 7 2750 38 EXPRESSION LEVELS OF THE TYROSINE HYDROXYLASE GENE AND HISTONE MODIFICATIONS AROUND ITS PROMOTER IN THE LOCUS COERULEUS AND VENTRAL TEGMENTAL AREA OF RATS DURING FORCED ABSTINENCE FROM MORPHINE. BACKGROUND: EPIGENETIC MECHANISMS SUCH AS HISTONE MODIFICATIONS MAY BE INVOLVED IN THE STRUCTURAL AND BEHAVIORAL CHANGES ASSOCIATED WITH ADDICTION. WE STUDIED WHETHER MORPHINE-INDUCED CHANGES IN MRNA LEVELS OF THE CATECHOLAMINE BIOSYNTHESIS ENZYME, TYROSINE HYDROXYLASE (TH), ARE ASSOCIATED WITH HISTONE MODIFICATIONS AROUND THE PROMOTER OF THIS GENE IN THE LOCUS COERULEUS (LC) AND VENTRAL TEGMENTAL AREA (VTA) OF RATS. METHODS: DEPENDENCE WAS INDUCED IN RATS BY INTRAPERITONEAL INJECTIONS OF MORPHINE FOR 11 DAYS. THE ANIMALS WERE KILLED 2 H (CHRONIC MORPHINE), 24 H AND 7 DAYS (SPONTANEOUS WITHDRAWAL) AFTER THE LAST INJECTION OF MORPHINE. RESULTS: ANALYSIS OF OUR REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION PCR RESULTS BY 1-WAY ANOVA SHOWED SIGNIFICANT UPREGULATION (5.13 +/- 0.39 FOLDS) OF LC LEVELS OF THE TH TRANSCRIPT 24 H AFTER THE LAST INJECTION OF MORPHINE TO RATS, WHEN COMPARED WITH 2 H AND 7 DAYS TIME POINTS. CHRONIC MORPHINE AND MORPHINE ABSTINENCE FAILED TO CAUSE ANY SIGNIFICANT CHANGES IN THE LEVELS OF TH MRNA IN THE VTA AFTER CESSATION OF MORPHINE. CONSISTENTLY, CHROMATIN IMMUNOPRECIPITATION REAL-TIME QUANTITATIVE PCR ASSAYS REVEALED THAT 24 H AFTER THE LAST INJECTION OF MORPHINE, LEVELS OF H3 ACETYLATION WERE SIGNIFICANTLY INCREASED (4.12 +/- 0.38 FOLDS) AT THE PROMOTER OF THE TH GENE IN THE LC BUT NOT IN THE VTA. OUR DATA ALSO SHOWED THAT HISTONE H3 TRIMETHYLATION FAILED TO CHANGE AROUND THE TH GENE PROMOTER EITHER IN THE VTA OR IN THE LC AFTER MORPHINE ABSTINENCE. CONCLUSIONS: RESULTS OF THE PRESENT STUDY, FOR THE FIRST TIME, DEMONSTRATE THE INVOLVEMENT OF HISTONE H3 ACETYLATION IN THE REGULATION OF TH GENE EXPRESSION IN THE LC OF RATS DURING FORCED ABSTINENCE FROM MORPHINE. 2018 8 4498 38 MORPHINE REGULATES ARGONAUTE 2 AND TH EXPRESSION AND ACTIVITY BUT NOT MIR-133B IN MIDBRAIN DOPAMINERGIC NEURONS. EPIGENETIC CHANGES SUCH AS MICRORNAS (MIRS)/AGO2-INDUCED GENE SILENCING REPRESENT COMPLEX MOLECULAR SIGNATURE THAT REGULATE CELLULAR PLASTICITY. RECENT STUDIES SHOWED INVOLVEMENT OF MIRS AND AGO2 IN DRUG ADDICTION. IN THIS STUDY, WE SHOW THAT CHANGES IN GENE EXPRESSION INDUCED BY MORPHINE AND MORPHINE WITHDRAWAL OCCUR WITH CONCOMITANT EPIGENETIC MODIFICATIONS IN THE MESOLIMBIC DOPAMINERGIC (DA) PATHWAY [VENTRAL TEGMENTAL AREA (VTA)/NUCLEUS ACCUMBENS (NAC) SHELL], WHICH IS CRITICALLY INVOLVED IN DRUG-INDUCED DEPENDENCE. WE FOUND THAT ACUTE OR CHRONIC MORPHINE ADMINISTRATION AS WELL AS MORPHINE WITHDRAWAL DID NOT MODIFY MIR-133B MESSENGER RNA (MRNA) EXPRESSION IN THE VTA, WHEREAS AGO2 PROTEIN LEVELS WERE DECREASED AND INCREASED IN MORPHINE-DEPENDENT RATS AND AFTER MORPHINE WITHDRAWAL, RESPECTIVELY. THESE CHANGES WERE PARALLELED WITH ENHANCED AND DECREASED NAC TYROSINE HYDROXYLASE (TH) PROTEIN (AN EARLY DA MARKER) IN MORPHINE-DEPENDENT RATS AND AFTER WITHDRAWAL, RESPECTIVELY. WE ALSO OBSERVED CHANGES IN TH MRNA EXPRESSION IN THE VTA THAT COULD BE RELATED TO AGO2-INDUCED TRANSLATIONAL REPRESSION OF TH MRNA DURING MORPHINE WITHDRAWAL. HOWEVER, THE VTA NUMBER OF TH-POSITIVE NEURONS SUFFERED NO ALTERATIONS AFTER THE DIFFERENT TREATMENT. ACUTE MORPHINE ADMINISTRATION PRODUCED A MARKED INCREASE IN TH ACTIVITY AND DA TURNOVER IN THE NAC (SHELL). IN CONTRAST, PRECIPITATED MORPHINE WITHDRAWAL DECREASED TH ACTIVATION AND DID NOT CHANGE DA TURNOVER. THESE FINDINGS PROVIDE NEW INFORMATION INTO THE POSSIBLE CORRELATION BETWEEN AGO2/MIRS COMPLEX REGULATION AND DA NEURONS PLASTICITY DURING OPIATE ADDICTION. 2015 9 1299 27 DECREASED REELIN EXPRESSION IN THE LEFT PREFRONTAL CORTEX (BA9) IN CHRONIC SCHIZOPHRENIA PATIENTS. BACKGROUND: REELIN IS UNDER EPIGENETIC CONTROL AND HAS BEEN REPORTED TO BE DECREASED IN CORTICAL REGIONS IN SCHIZOPHRENIA. METHODS: TO ESTABLISH IF EXPRESSION OF REELIN IS ALTERED IN SPECIFIC CORTICAL, HIPPOCAMPAL OR THALAMIC REGIONS OF SCHIZOPHRENIA PATIENTS, WE MEASURED GENE EXPRESSION OF REELIN IN A POSTMORTEM STUDY OF ELDERLY PATIENTS WITH SCHIZOPHRENIA AND NON-AFFECTED CONTROLS IN BOTH HEMISPHERES DIFFERENTIATING BETWEEN GRAY AND WHITE MATTER. WE COMPARED CEREBRAL POSTMORTEM SAMPLES (DORSOLATERAL PREFRONTAL CORTEX BA9 AND BA46, SUPERIOR TEMPORAL CORTEX BA22, ENTORHINAL CORTEX BA28, SENSORIC CORTEX BA1-3, HIPPOCAMPUS, CA4, MEDIODORSAL NUCLEUS OF THE THALAMUS) FROM 12 SCHIZOPHRENIA PATIENTS WITH 13 NORMAL SUBJECTS INVESTIGATING GENE EXPRESSION OF REELIN IN THE GRAY AND WHITE MATTER OF BOTH HEMISPHERES BY IN SITU-HYBRIDIZATION. RESULTS: THE LEFT PREFRONTAL AREA (BA9) OF SCHIZOPHRENIA PATIENTS REVEALED A DECREASED EXPRESSION OF REELIN-MRNA OF 29.1% IN THE WHITE (P = 0.022) AND 13.6% IN THE GRAY MATTER (P = 0.007) COMPARED TO THE CONTROL GROUP. NONE OF THE OTHER REGIONS EXAMINED SHOWED ANY STATISTICALLY SIGNIFICANT DIFFERENCES. CONCLUSION: SINCE REELIN IS RESPONSIBLE FOR MIGRATION AND SYNAPSE FORMATION, THE DECREASED GENE EXPRESSION OF REELIN IN THE LEFT PREFRONTAL AREA OF SCHIZOPHRENIA PATIENTS POINTS TO NEURODEVELOPMENTAL DEFICITS IN NEURONAL MIGRATION AND SYNAPTIC PLASTICITY. HOWEVER, OUR STUDY GROUP WAS SMALL, AND RESULTS SHOULD BE VERIFIED USING LARGER SAMPLES. 2012 10 3315 32 HIPPOCAMPAL MU OPIOID RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN RAT. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCED BY LONG-TERM BRAIN CHANGES. UNDERSTANDING THE NEUROCHEMICAL CHANGES UNDERLYING THE REINFORCING EFFECTS OF THIS DRUG OF ABUSE IS CRITICAL FOR REDUCING THE SOCIETAL BURDEN OF DRUG ADDICTION. THE MU OPIOID RECEPTOR PLAYS A MAJOR ROLE IN DRUG REWARD. THIS RECEPTOR IS MODULATED BY CHRONIC COCAINE TREATMENT IN SPECIFIC BRAIN STRUCTURES, BUT FEW STUDIES INVESTIGATED NEUROCHEMICAL ADAPTATIONS INDUCED BY VOLUNTARY COCAINE INTAKE. IN THIS STUDY, WE INVESTIGATED WHETHER INTRAVENOUS COCAINE-SELF ADMINISTRATION (0.33 MG/KG/INJECTION, FIXED-RATIO 1 [FR1], 10 DAYS) IN RATS INDUCES TRANSCRIPTIONAL AND FUNCTIONAL CHANGES OF THE MU OPIOID RECEPTOR IN REWARD-RELATED BRAIN REGIONS. EPIGENETIC PROCESSES WITH HISTONE MODIFICATIONS WERE EXAMINED FOR TWO ACTIVATING MARKS, H3K4ME3, AND H3K27AC. WE FOUND AN INCREASE OF MU OPIOID RECEPTOR GENE EXPRESSION ALONG WITH A POTENTIATION OF ITS FUNCTIONALITY IN HIPPOCAMPUS OF COCAINE SELF-ADMINISTERING ANIMALS COMPARED TO SALINE CONTROLS. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR REVEALED NO MODIFICATIONS OF THE HISTONE MARK H3K4ME3 AND H3K27AC LEVELS AT MU OPIOID RECEPTOR PROMOTER. OUR STUDY HIGHLIGHTS THE HIPPOCAMPUS AS AN IMPORTANT TARGET TO FURTHER INVESTIGATE NEUROADAPTIVE PROCESSES LEADING TO COCAINE ADDICTION. 2021 11 2363 30 EPIGENETIC REGULATION OF SPINAL CORD GENE EXPRESSION CONTRIBUTES TO ENHANCED POSTOPERATIVE PAIN AND ANALGESIC TOLERANCE SUBSEQUENT TO CONTINUOUS OPIOID EXPOSURE. BACKGROUND: OPIOIDS HAVE BECOME THE MAINSTAY FOR TREATMENT OF MODERATE TO SEVERE PAIN AND ARE COMMONLY USED TO TREAT SURGICAL PAIN. WHILE OPIOID ADMINISTRATION HAS BEEN SHOWN TO CAUSE OPIOID-INDUCED HYPERALGESIA AND TOLERANCE, INTERACTIONS BETWEEN OPIOID ADMINISTRATION AND SURGERY WITH RESPECT TO THESE PROBLEMATIC ADAPTATIONS HAVE SCARCELY BEEN ADDRESSED. ACCUMULATING EVIDENCE SUGGESTS OPIOIDS AND NOCICEPTIVE SIGNALING MAY CONVERGE ON EPIGENETIC MECHANISMS IN SPINAL CORD TO ENHANCE OR PROLONG NEUROPLASTIC CHANGES. EPIGENETIC REGULATION OF BDNF (BRAIN-DERIVED NEUROTROPHIC FACTOR) AND PDYN (PRODYNORPHIN) GENES MAY BE INVOLVED. RESULTS: FOUR DAYS OF ASCENDING DOSES OF MORPHINE TREATMENT CAUSED OPIOID-INDUCED HYPERALGESIA AND REDUCED OPIOID ANALGESIC EFFICACY IN MICE. BOTH OPIOID-INDUCED HYPERALGESIA AND THE REDUCED OPIOID ANALGESIC EFFICACY WERE ENHANCED IN MICE THAT RECEIVED HINDPAW INCISIONS. THE EXPRESSION OF BDNF AND PDYN (QPCR) WAS INCREASED AFTER MORPHINE TREATMENT AND INCISION. CHROMATIN IMMUNOPRECIPITATION ASSAYS DEMONSTRATED THAT THE PDYN AND BDNF PROMOTERS WERE MORE STRONGLY ASSOCIATED WITH ACETYLATED H3K9 AFTER MORPHINE PLUS INCISION THAN IN THE MORPHINE OR INCISION ALONE GROUPS. SELECTIVE TROPOMYOSIN-RELATED KINASE B (ANA-12) AND KAPPA-OPIOID RECEPTOR (NOR-BINALTORPHIMINE) ANTAGONISTS WERE ADMINISTERED INTRATHECALLY, BOTH REDUCED HYPERALGESIA ONE OR THREE DAYS AFTER SURGERY. ADMINISTRATION OF ANA-12 OR NOR-BINALTORPHIMINE ATTENUATED THE DECREASED MORPHINE ANALGESIC EFFICACY ON DAY 1, BUT ONLY NOR-BINALTORPHIMINE WAS EFFECTIVE ON DAY 3 AFTER INCISION IN OPIOID-EXPOSED GROUP. COADMINISTRATION OF HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID DAILY WITH MORPHINE BLOCKED THE DEVELOPMENT OF OPIOID-INDUCED HYPERALGESIA AND ATTENUATED INCISION-ENHANCED HYPERALGESIA IN MORPHINE-TREATED MICE. ANACARDIC ACID HAD SIMILAR EFFECTS ON ANALGESIC TOLERANCE, SHOWING THE INVOLVEMENT OF HISTONE ACETYLATION IN THE INTERACTIONS DETECTED. CONCLUSIONS: SPINAL EPIGENETIC CHANGES INVOLVING BDNF AND PDYN MAY CONTRIBUTE TO THE ENHANCED POSTOPERATIVE NOCICEPTIVE SENSITIZATION AND ANALGESIC TOLERANCE OBSERVED AFTER CONTINUOUS OPIOID EXPOSURE. TREATMENTS BLOCKING THE EPIGENETICALLY MEDIATED UP-REGULATION OF THESE GENES OR ADMINISTRATION OF TRKB OR KAPPA-OPIOID RECEPTOR ANTAGONISTS MAY IMPROVE THE CLINICAL UTILITY OF OPIOIDS, PARTICULARLY AFTER SURGERY. 2016 12 5819 33 STRESS CHANGES AMPHETAMINE RESPONSE, D2 RECEPTOR EXPRESSION AND EPIGENETIC REGULATION IN LOW-ANXIETY RATS. THE AIM OF THIS STUDY WAS TO ASSESS THE INFLUENCE OF CHRONIC RESTRAINT STRESS ON AMPHETAMINE (AMPH)-RELATED APPETITIVE 50-KHZ ULTRASONIC VOCALISATIONS (USVS) IN RATS DIFFERING IN FREEZING DURATION IN A CONTEXTUAL FEAR TEST (CFT), I.E. HR (HIGH-ANXIETY RESPONSIVE) AND LR (LOW-ANXIETY RESPONSIVE) RATS. THE LR AND THE HR RATS, PREVIOUSLY EXPOSED TO AN AMPH BINGE EXPERIENCE, DIFFERED IN SENSITIVITY TO AMPH'S REWARDING EFFECTS, MEASURED AS APPETITIVE VOCALISATIONS. MOREOVER, CHRONIC RESTRAINT STRESS ATTENUATED AMPH-RELATED APPETITIVE VOCALISATIONS IN THE LR RATS BUT HAD NO INFLUENCE ON THE HR RATS' BEHAVIOUR. TO SPECIFY, THE RESTRAINT LR RATS VOCALISED APPETITIVELY LESS IN THE AMPH-ASSOCIATED CONTEXT AND AFTER AN AMPH CHALLENGE THAN THE CONTROL LR RATS. THIS PHENOMENON WAS ASSOCIATED WITH A DECREASE IN THE MRNA LEVEL FOR D2 DOPAMINE RECEPTOR IN THE AMYGDALA AND ITS PROTEIN EXPRESSION IN THE BASAL AMYGDALA (BA) AND OPPOSITE CHANGES IN THE NUCLEUS ACCUMBENS (NAC) - AN INCREASE IN THE MRNA LEVEL FOR D2 DOPAMINE RECEPTOR AND ITS PROTEIN EXPRESSION IN THE NAC SHELL, COMPARED TO CONTROL CONDITIONS. MOREOVER, WE OBSERVED THAT CHRONIC RESTRAINT STRESS INFLUENCED EPIGENETIC REGULATION IN THE LR AND THE HR RATS DIFFERENTLY. THE CONTRASTING CHANGES WERE OBSERVED IN THE DENTATE GYRUS (DG) OF THE HIPPOCAMPUS - THE LR RATS PRESENTED A DECREASE, BUT THE HR RATS SHOWED AN INCREASE IN H3K9 TRIMETHYLATION. THE RESTRAINT LR RATS ALSO SHOWED HIGHER MIR-494 AND MIR-34C LEVELS IN THE NAC THAN THE CONTROL LR GROUP. OUR STUDY PROVIDES BEHAVIOURAL AND BIOCHEMICAL DATA CONCERNING THE ROLE OF DIFFERENCES IN FEAR-CONDITIONED RESPONSE IN STRESS VULNERABILITY AND AMPH-ASSOCIATED APPETITIVE BEHAVIOUR. THE LR RATS WERE LESS SENSITIVE TO THE REWARDING EFFECTS OF AMPH WHEN PREVIOUSLY EXPOSED TO CHRONIC STRESS THAT WAS ACCOMPANIED BY CHANGES IN D2 DOPAMINE RECEPTOR EXPRESSION AND EPIGENETIC REGULATION IN MESOLIMBIC AREAS. 2019 13 6612 34 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION. 2012 14 5535 28 ROLE OF BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS IN RELAPSE TO COCAINE-SEEKING BEHAVIOR IN MICE. COCAINE ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER CHARACTERIZED BY COMPULSIVE DRUG SEEKING. PRELIMINARY STUDY SUGGESTED THAT BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC READER PROTEIN, PARTICIPATES IN COCAINE-INDUCED REWARD AND NEUROPLASTICITY. HOWEVER, THE EXACT ROLE OF BRD4 IN COCAINE ADDICTION, PARTICULARLY COCAINE RELAPSE, REMAINS ELUSIVE. IN THIS STUDY, WE FOUND THAT BRD4 PHOSPHORYLATION IN THE NUCLEUS ACCUMBENS (NAC) WAS CLOSELY RELATED TO THE MAINTENANCE OF COCAINE REINFORCEMENT AND RELAPSE IN DIFFERENT COCAINE EXPOSURE PARADIGMS. COCAINE SIGNIFICANTLY INCREASED THE BINDING OF PHOSPHORYLATED BRD4 (PBRD4) AT THE PROMOTER OF GRIA2 AND BDNF GENES IN THE NAC. (+)JQ1, A SELECTIVE BRD4 INHIBITOR, MARKEDLY REDUCED THE REINFORCEMENT AND REINSTATEMENT OF COCAINE-SEEKING BEHAVIORS, WHICH WAS ACCOMPANIED BY THE DECREASED EXPRESSIONS OF GRIA2 AND BDNF. FURTHERMORE, CHROMATIN IMMUNOPRECIPITATION ASSAY SHOWED THAT (+)JQ1 CLEARLY ATTENUATED COCAINE-ENHANCED BINDING OF PBRD4 AT THE PROMOTOR OF GRIA2 AND BDNF GENES. BLOCKADE OF CASEIN KINASE II SIGNIFICANTLY ATTENUATED BRD4 PHOSPHORYLATION AND COCAINE RELAPSE-LIKE BEHAVIORS, SUGGESTING THE IMPORTANT ROLE OF PBRD4 IN MODULATING COCAINE EFFECT. TOGETHER, OUR FINDINGS SUGGEST THAT BRD4 PHOSPHORYLATION IN THE NAC MODULATES MULTIPLE ADDICTION-RELATED BEHAVIORS OF COCAINE AND PARTICULARLY RELAPSE TO COCAINE-SEEKING BEHAVIORS. INHIBITION OF BRD4 ACTIVITY MAY BE A NOVEL TARGET AGAINST COCAINE ADDICTION AND RELAPSE. 2020 15 6108 46 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS. 2019 16 4236 31 METHYLATION OF THE TYROSINE HYDROXYLASE GENE IS DYSREGULATED BY COCAINE DEPENDENCE IN THE HUMAN STRIATUM. COCAINE DEPENDENCE IS A CHRONIC, RELAPSING DISORDER CAUSED BY LASTING CHANGES IN THE BRAIN. ANIMAL STUDIES HAVE IDENTIFIED COCAINE-RELATED ALTERATIONS IN STRIATAL DNA METHYLATION; HOWEVER, IT IS UNCLEAR HOW METHYLATION IS RELATED TO COCAINE DEPENDENCE IN HUMANS. WE GENERATED METHYLOMIC PROFILES OF THE NUCLEUS ACCUMBENS USING HUMAN POSTMORTEM BRAINS FROM A COHORT OF INDIVIDUALS WITH COCAINE DEPENDENCE AND HEALTHY CONTROLS (N = 25 PER GROUP). WE FOUND HYPERMETHYLATION IN A CLUSTER OF CPGS WITHIN THE GENE BODY OF TYROSINE HYDROXYLASE (TH), CONTAINING A PUTATIVE BINDING SITE FOR THE EARLY GROWTH RESPONSE 1 (EGR1) TRANSCRIPTION FACTOR, WHICH IS HYPERMETHYLATED IN THE CAUDATE NUCLEUS OF COCAINE-DEPENDENT INDIVIDUALS. WE REPLICATED THIS FINDING AND FOUND IT TO BE SPECIFIC TO STRIATAL NEURONAL NUCLEI. FURTHERMORE, THIS LOCUS DEMONSTRATES ENHANCER ACTIVITY WHICH IS ATTENUATED BY METHYLATION AND ENHANCED BY EGR1 OVEREXPRESSION. THESE RESULTS SUGGEST THAT COCAINE DEPENDENCE ALTERS THE EPIGENETIC REGULATION OF DOPAMINERGIC SIGNALING GENES. 2021 17 1320 32 DEMETHYLATION REGULATION OF BDNF GENE EXPRESSION IN DORSAL ROOT GANGLION NEURONS IS IMPLICATED IN OPIOID-INDUCED PAIN HYPERSENSITIVITY IN RATS. REPEATED ADMINISTRATION OF MORPHINE MAY RESULT IN OPIOID-INDUCED HYPERSENSITIVITY (OIH), WHICH INVOLVES ALTERED EXPRESSION OF NUMEROUS GENES, INCLUDING BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN DORSAL ROOT GANGLION (DRG) NEURONS. YET, IT REMAINS UNCLEAR HOW BDNF EXPRESSION IS INCREASED IN DRG NEURONS AFTER REPEATED MORPHINE TREATMENT. DNA METHYLATION IS AN IMPORTANT MECHANISM OF EPIGENETIC CONTROL OF GENE EXPRESSION. IN THE CURRENT STUDY, WE HYPOTHESIZED THAT THE DEMETHYLATION REGULATION OF CERTAIN BDNF GENE PROMOTERS IN DRG NEURONS MAY CONTRIBUTE TO THE DEVELOPMENT OF OIH. REAL-TIME RT-PCR WAS USED TO ASSESS CHANGES IN THE MRNA TRANSCRIPTION LEVELS OF MAJOR BDNF EXONS INCLUDING EXON I, II, IV, VI, AS WELL AS TOTAL BDNF MRNA IN DRGS FROM RATS AFTER REPEATED MORPHINE ADMINISTRATION. THE LEVELS OF EXON IV AND TOTAL BDNF MRNA WERE SIGNIFICANTLY UPREGULATED BY REPEATED MORPHINE ADMINISTRATION, AS COMPARED TO THAT IN SALINE CONTROL GROUP. FURTHER, ELISA ARRAY AND IMMUNOCYTOCHEMISTRY STUDY REVEALED A ROBUST UPREGULATION OF BDNF PROTEIN EXPRESSION IN DRG NEURONS AFTER REPEATED MORPHINE EXPOSURE. CORRESPONDINGLY, THE METHYLATION LEVELS OF BDNF EXON IV PROMOTER SHOWED A SIGNIFICANT DOWNREGULATION BY MORPHINE TREATMENT. IMPORTANTLY, INTRATHECAL ADMINISTRATION OF A BDNF ANTIBODY, BUT NOT CONTROL IGG, SIGNIFICANTLY INHIBITED MECHANICAL HYPERSENSITIVITY THAT DEVELOPED IN RATS AFTER REPEATED MORPHINE TREATMENT. CONVERSELY, INTRATHECAL ADMINISTRATION OF AN INHIBITOR OF DNA METHYLATION, 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) MARKEDLY UPREGULATED THE BDNF PROTEIN EXPRESSION IN DRG NEURONS AND ENHANCED THE MECHANICAL ALLODYNIA AFTER REPEATED MORPHINE EXPOSURE. TOGETHER, OUR FINDINGS SUGGEST THAT DEMETHYLATION REGULATION OF BDNF GENE PROMOTER MAY BE IMPLICATED IN THE DEVELOPMENT OF OIH THROUGH EPIGENETIC CONTROL OF BDNF EXPRESSION IN DRG NEURONS. 2016 18 2364 40 EPIGENETIC REGULATION OF SPINAL CORD GENE EXPRESSION CONTROLS OPIOID-INDUCED HYPERALGESIA. BACKGROUND: THE LONG TERM USE OF OPIOIDS FOR THE TREATMENT OF PAIN LEADS TO A GROUP OF MALADAPTATIONS WHICH INCLUDES OPIOID-INDUCED HYPERALGESIA (OIH). OIH TYPICALLY RESOLVES WITHIN FEW DAYS AFTER CESSATION OF MORPHINE TREATMENT IN MICE BUT IS PROLONGED FOR WEEKS IF HISTONE DEACETYLASE (HDAC) ACTIVITY IS INHIBITED DURING OPIOID TREATMENT. THE PRESENT WORK SEEKS TO IDENTIFY GENE TARGETS SUPPORTING THE EPIGENETIC EFFECTS RESPONSIBLE FOR OIH PROLONGATION. RESULTS: MICE WERE TREATED WITH MORPHINE ACCORDING TO AN ASCENDING DOSE PROTOCOL. SOME MICE ALSO RECEIVED THE SELECTIVE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ADDITIONALLY. CHRONIC MORPHINE TREATMENT WITH SIMULTANEOUS HDAC INHIBITION ENHANCED OIH, AND SEVERAL SPINAL CORD GENES WERE UP-REGULATED. THE EXPRESSION OF BDNF (BRAIN-DERIVED NEUROTROPHIC FACTOR) AND PDYN (PRODYNORPHIN) WERE MOST CLOSELY RELATED TO THE OBSERVED BEHAVIORAL CHANGES. CHIP (CHROMATIN IMMUOPRECIPATION) ASSAYS DEMONSTRATED THAT PROMOTER REGIONS OF PDYN AND BDNF WERE STRONGLY ASSOCIATED WITH ACEH3K9 (ACETYLATED HISTONE H3 LYSINE9) AFTER MORPHINE AND SAHA TREATMENT. FURTHERMORE, MORPHINE TREATMENT CAUSED AN INCREASE IN SPINAL BDNF AND DYNORPHIN LEVELS, AND THESE LEVELS WERE FURTHER INCREASED IN SAHA TREATED MICE. THE SELECTIVE TRKB (TROPOMYOSIN-RECEPTOR-KINASE) ANTAGONIST ANA-12 REDUCED OIH WHEN GIVEN ONE OR SEVEN DAYS AFTER CESSATION OF MORPHINE. TREATMENT WITH THE SELECTIVE KAPPA OPIOID RECEPTOR ANTAGONIST NOR-BNI ALSO REDUCED ESTABLISHED OIH. THE CO-ADMINISTRATION OF EITHER RECEPTOR ANTAGONIST AGENT DAILY WITH MORPHINE RESULTED IN ATTENUATION OF HYPERALGESIA PRESENT ONE DAY AFTER CESSATION OF TREATMENT. ADDITIONALLY, REPEATED MORPHINE EXPOSURE INDUCED A RISE IN BDNF EXPRESSION THAT WAS ASSOCIATED WITH AN INCREASED NUMBER OF BDNF+ CELLS IN THE SPINAL CORD DORSAL HORN, SHOWING STRONG CO-LOCALIZATION WITH ACEH3K9 IN NEURONAL CELLS. LASTLY, SPINAL APPLICATION OF LOW DOSE BDNF OR DYNORPHIN A AFTER RESOLUTION OF OIH PRODUCED MECHANICAL HYPERSENSITIVITY, WITH NO EFFECT IN CONTROLS. CONCLUSIONS: THE PRESENT STUDY IDENTIFIED TWO GENES WHOSE EXPRESSION IS REGULATED BY EPIGENETIC MECHANISMS DURING MORPHINE EXPOSURE. TREATMENTS AIMED AT PREVENTING THE ACETYLATION OF HISTONES OR BLOCKING BDNF AND DYNORPHIN SIGNALING MAY REDUCE OIH AND IMPROVE LONG-TERM PAIN USING OPIOIDS. 2014 19 69 30 A MEDIAL PREFRONTAL CORTEX-NUCLEUS ACUMENS CORTICOTROPIN-RELEASING FACTOR CIRCUITRY FOR NEUROPATHIC PAIN-INCREASED SUSCEPTIBILITY TO OPIOID REWARD. RECENT STUDIES HAVE SHOWN THAT PERSISTENT PAIN FACILITATES THE RESPONSE TO MORPHINE REWARD. HOWEVER, THE CIRCUIT MECHANISM UNDERLYING THIS PROCESS REMAINS AMBIGUOUS. IN THIS STUDY, USING CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN MICE, WE FOUND THAT PERSISTENT NEUROPATHIC PAIN REDUCED THE MINIMUM NUMBER OF MORPHINE CONDITIONING SESSIONS REQUIRED TO INDUCE CONDITIONED PLACE PREFERENCE (CPP) BEHAVIOR. THIS DOSE OF MORPHINE HAD NO EFFECT ON THE PAIN THRESHOLD. IN THE MEDIAL PREFRONTAL CORTEX (MPFC), WHICH IS INVOLVED IN BOTH PAIN AND EMOTION PROCESSING, CORTICOTROPIN-RELEASING FACTOR (CRF) EXPRESSING NEURONAL ACTIVITY WAS INCREASED IN CCI MICE. CHEMOGENETIC INHIBITION OF MPFC CRF NEURONS REVERSED CCI-INDUCED MORPHINE CPP FACILITATION. FURTHERMORE, THE NUCLEUS ACUMENS (NAC) RECEIVED MPFC CRF FUNCTIONAL PROJECTIONS THAT EXERTED EXCITATORY EFFECTS ON NAC NEURONS. OPTOGENETIC INHIBITION OF MPCF NEURONAL TERMINALS OR LOCAL INFUSION OF THE CRF RECEPTOR 1 (CRFR1) ANTAGONIST IN THE NAC RESTORED THE EFFECTS OF NEUROPATHIC PAIN ON MORPHINE-INDUCED CPP BEHAVIOR, BUT NOT IN NORMAL MICE. ON A MOLECULAR LEVEL, IN CCI MICE, CRFR1 PROTEIN EXPRESSION WAS INCREASED IN THE NAC BY A HISTONE DIMETHYLTRANSFERASE G9A-MEDIATED EPIGENETIC MECHANISM. LOCAL G9A KNOCKDOWN INCREASED THE EXPRESSION OF CRFR1 AND MIMICKED CCI-INDUCED HYPERSENSITIVITY TO ACQUIRING MORPHINE CPP. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE A PREVIOUSLY UNKNOWN AND SPECIFIC MPFC CRF ENGAGEMENT OF NAC NEURONAL CIRCUITS, THE SENSITIZATION OF WHICH FACILITATES BEHAVIORAL RESPONSES TO MORPHINE REWARD IN NEUROPATHIC PAIN STATES VIA CRFR1S. 2018 20 893 45 CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL IMPAIR SYNAPTIC GABA(A) RECEPTOR-MEDIATED NEUROTRANSMISSION IN DEEP-LAYER PREFRONTAL CORTEX. BACKGROUND: THE PREFRONTAL CORTEX (PFC) ACTS AS AN INTEGRATIVE HUB FOR THE PROCESSING OF CORTICAL AND SUBCORTICAL INPUT INTO MEANINGFUL EFFERENT SIGNALING, PERMITTING COMPLEX ASSOCIATIVE BEHAVIORS. PFC DYSFUNCTION IS CONSISTENTLY OBSERVED WITH ETHANOL (ETOH) DEPENDENCE AND IS A CORE COMPONENT OF THE PATHOLOGY OF ALCOHOL USE DISORDERS IN CURRENT MODELS OF ADDICTION. WHILE INTRACORTICAL GAMMA-AMINOBUTRYRIC ACID (GABA)ERGIC NEUROTRANSMISSION IS UNDERSTOOD TO BE ESSENTIAL FOR MAINTAINING COORDINATED NETWORK ACTIVITY WITHIN THE CORTEX, RELATIVELY LITTLE IS KNOWN REGARDING FUNCTIONAL GABAERGIC ADAPTATIONS IN PFC DURING ETOH DEPENDENCE. METHODS: IN THE PRESENT STUDY, MALE AND FEMALE (> POSTNATAL DAY 60) SPRAGUE-DAWLEY RATS WERE ADMINISTERED ETOH (5.0 G/KG; INTRAGASTRIC GAVAGE) FOR 14 TO 15 CONSECUTIVE DAYS. TWENTY-FOUR HOURS AFTER THE FINAL ADMINISTRATION, ANIMALS WERE SACRIFICED AND BRAINS EXTRACTED FOR ELECTROPHYSIOLOGICAL RECORDINGS OF ISOLATED GABA(A) RECEPTOR-MEDIATED CURRENTS OR ANALYSIS OF GABA(A) RECEPTOR SUBUNIT PROTEIN EXPRESSION IN DEEP-LAYER PFC NEURONS. RESULTS: CHRONIC ETOH EXPOSURE SIGNIFICANTLY ATTENUATED ACTIVITY-DEPENDENT SPONTANEOUS GABA(A) RECEPTOR-MEDIATED INHIBITORY POSTSYNAPTIC CURRENT (IPSC) FREQUENCY WITH NO EFFECT ON AMPLITUDE. FURTHERMORE, ANALYSIS OF IPSC DECAY KINETICS REVEALED A SIGNIFICANT ENHANCEMENT OF IPSC DECAY TIME THAT WAS ASSOCIATED WITH DECREMENTS IN EXPRESSION OF THE ALPHA1 GABA(A) RECEPTOR SUBUNIT, INDICATIVE OF FURTHER IMPAIRED PHASIC INHIBITION. THESE PHENOMENA OCCURRED IRRESPECTIVE OF NEURON PROJECTION DESTINATION AND SEX. BASED ON PREVIOUS OBSERVATIONS BY OUR LABORATORY OF AN EPIGENETIC MECHANISM FOR ETOH-INDUCED CHANGES IN CORTICAL GABA(A) RECEPTOR SUBUNIT EXPRESSION, THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A WAS ADMINISTERED TO WATER- AND ETOH-EXPOSED ANIMALS, AND PREVENTED ETOH-INDUCED CHANGES IN SPONTANEOUS IPSC FREQUENCY, IPSC DECAY KINETICS, AND GABA(A) RECEPTOR SUBUNIT EXPRESSION. CONCLUSIONS: TAKEN TOGETHER, THESE RESULTS DEMONSTRATE THAT CHRONIC ETOH EXPOSURE IMPAIRS SYNAPTIC INHIBITORY NEUROTRANSMISSION IN DEEP-LAYER PYRAMIDAL NEURONS OF THE MEDIAL PFC IN BOTH MALE AND FEMALE RATS. THESE MALADAPTATIONS OCCUR IN NEURONS PROJECTING TO NUMEROUS REGIONS IMPLICATED IN THE SEQUELAE OF ETOH DEPENDENCE, OFFERING A MECHANISTIC LINK BETWEEN THE MANIFESTATION OF PFC DYSFUNCTION AND NEGATIVE AFFECTIVE STATES OBSERVED WITH EXTENDED CONSUMPTION. 2019