1 2044 120 EPIGENETIC CLOCK ANALYSIS OF BLOOD SAMPLES IN DRUG-NAIVE FIRST-EPISODE SCHIZOPHRENIA PATIENTS. BACKGROUND: SCHIZOPHRENIA (SCZ) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH PREMATURE AGE-RELATED PHYSIOLOGICAL CHANGES. HOWEVER, NUMEROUS PREVIOUS STUDIES EXAMINED THE EPIGENETIC AGE ACCELERATION IN SCZ PATIENTS AND YIELDED INCONCLUSIVE RESULTS. IN THIS STUDY, WE PROPOSE TO EXPLORE THE EPIGENETIC AGE ACCELERATION IN DRUG-NAIVE FIRST-EPISODE SCZ (FSCZ) PATIENTS AND INVESTIGATE WHETHER EPIGENETIC AGE ACCELERATION IS ASSOCIATED WITH ANTIPSYCHOTIC TREATMENT, PSYCHOTIC SYMPTOMS, COGNITION, AND SUBCORTICAL VOLUMES. METHODS: WE ASSESSED THE EPIGENETIC AGE IN 38 DRUG-NAIVE FSCZ PATIENTS AND 38 HEALTHY CONTROLS BY USING THREE INDEPENDENT CLOCKS, INCLUDING HORVATH, HANNUM AND LEVINE ALGORITHMS. THE EPIGENETIC AGE MEASUREMENTS IN SCZ PATIENTS WERE REPEATED AFTER RECEIVING 8 WEEKS RISPERIDONE MONOTHERAPY. RESULTS: OUR FINDINGS SHOWED SIGNIFICANTLY POSITIVE CORRELATIONS BETWEEN EPIGENETIC AGES ASSESSED BY THREE CLOCKS AND CHRONOLOGICAL AGE IN BOTH FSCZ PATIENTS AND HEALTHY CONTROLS. COMPARED WITH HEALTHY CONTROLS, DRUG-NAIVE FSCZ PATIENTS HAVE A SIGNIFICANT EPIGENETIC AGE DECELERATION IN HORVATH CLOCK (P = 0.01), BUT NOT IN HANNUM CLOCK (P = 0.07) AND LEVINE CLOCK (P = 0.43). THE EPIGENETIC AGES OF HANNUM CLOCK (P = 0.002) AND LEVINE CLOCK (P = 0.01) WERE SIGNIFICANTLY ACCELERATED IN SCZ PATIENTS AFTER 8-WEEK RISPERIDONE TREATMENT. HOWEVER, NO SIGNIFICANT ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION AND PSYCHOTIC SYMPTOMS, COGNITIVE FUNCTION, AS WELL AS SUBCORTICAL VOLUMES WERE OBSERVED IN FSCZ PATIENTS. CONCLUSION: THESE RESULTS DEMONSTRATE THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS. 2023 2 893 36 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 3 5735 28 SMALL VESSEL DISEASE-RELATED DEMENTIA: AN INVALID NEUROVASCULAR COUPLING? THE ARTERIOSCLEROSIS-DEPENDENT ALTERATION OF BRAIN PERFUSION IS ONE OF THE MAJOR DETERMINANTS IN SMALL VESSEL DISEASE, SINCE SMALL VESSELS HAVE A PIVOTAL ROLE IN THE BRAIN'S AUTOREGULATION. NEVERTHELESS, AS FAR AS WE KNOW, ENDOTHELIUM DISTRESS CAN POTENTIATE THE FLOW DYSREGULATION AND LEAD TO SUBCORTICAL VASCULAR DEMENTIA THAT IS RELATED TO SMALL VESSEL DISEASE (SVD), ALSO BEING DEFINED AS SUBCORTICAL VASCULAR DEMENTIA (SVAD), AS WELL AS MICROGLIA ACTIVATION, CHRONIC HYPOXIA AND HYPOPERFUSION, VESSEL-TONE DYSREGULATION, ALTERED ASTROCYTES, AND PERICYTES FUNCTIONING BLOOD-BRAIN BARRIER DISRUPTION. THE MOLECULAR BASIS OF THIS PATHOLOGY REMAINS CONTROVERSIAL. THE APPARENT CONSEQUENCE (OR A FIRST EVENT, TOO) IS THE MACROSCOPIC ALTERATION OF THE NEUROVASCULAR COUPLING. HERE, WE EXAMINED THE POSSIBLE MECHANISMS THAT LEAD A HEALTHY AGING PROCESS TOWARDS SUBCORTICAL DEMENTIA. WE REMARKED THAT SVD AND WHITE MATTER ABNORMALITIES RELATED TO AGE COULD BE ACCELERATED AND POTENTIATED BY DIFFERENT VASCULAR RISK FACTORS. VASCULAR FUNCTION CHANGES CAN BE HEAVILY INFLUENCED BY GENETIC AND EPIGENETIC FACTORS, WHICH ARE, TO THE BEST OF OUR KNOWLEDGE, MOSTLY UNKNOWN. METABOLIC DEMANDS, ACTIVE NEUROVASCULAR COUPLING, CORRECT GLYMPHATIC PROCESS, AND ADEQUATE OXIDATIVE AND INFLAMMATORY RESPONSES COULD BE BULWARKS IN DEFENSE OF THE CORRECT AGING PROCESS; THEIR IMPAIRMENTS LEAD TO A POTENTIALLY CATASTROPHIC AND NON-REVERSIBLE CONDITION. 2020 4 3331 33 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 5 6312 33 THE RELATIONSHIP BETWEEN CEREBRAL SMALL VESSEL DISEASE, HIPPOCAMPAL VOLUME AND COGNITIVE FUNCTIONING IN PATIENTS WITH COPD: AN MRI STUDY. THE NEURAL CORRELATES OF COGNITIVE IMPAIRMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE NOT YET UNDERSTOOD. STRUCTURAL BRAIN ABNORMALITIES COULD POSSIBLY BE ASSOCIATED WITH THE PRESENCE OF COGNITIVE IMPAIRMENT THROUGH CIGARETTE SMOKE, INFLAMMATION, VASCULAR DISEASE, OR HYPOXEMIA IN THESE PATIENTS. THIS STUDY AIMED TO INVESTIGATE WHETHER MACROSTRUCTURAL BRAIN MAGNETIC RESONANCE IMAGING (MRI) FEATURES OF CEREBRAL SMALL VESSEL DISEASE (SVD) AND HIPPOCAMPAL VOLUME (HCV) ARE RELATED TO COGNITIVE PERFORMANCE IN PATIENTS WITH COPD. A SUBGROUP OF COGNITIVELY HIGH AND LOW-PERFORMING COPD PATIENTS OF THE COGNITIVE-PD STUDY, UNDERWENT A BRAIN 3T MRI. SVD AS A MARKER OF VASCULAR DAMAGE WAS ASSESSED USING QUALITATIVE VISUAL RATING SCALES. HCV AS A MARKER OF NEURODEGENERATION WAS ASSESSED USING THE LEARNING EMBEDDING FOR ATLAS PROPAGATION (LEAP) METHOD. FEATURES OF SVD AND HCV WERE COMPARED BETWEEN COGNITIVELY HIGH AND LOW-PERFORMING INDIVIDUALS USING MANN WHITNEY U TESTS AND INDEPENDENT SAMPLES T-TESTS, RESPECTIVELY. NO GROUP DIFFERENCES WERE REPORTED BETWEEN 25 HIGH-PERFORMING (MEAN AGE 60.3 (STANDARD DEVIATION [SD] 9.7) YEARS; 40.0% MEN; FORCED EXPIRATORY VOLUME IN FIRST SECOND [FEV(1)] 50.1% PREDICTED) AND 30 LOW-PERFORMING PATIENTS WITH COPD (MEAN AGE 60.6 (SD 6.8) YEARS; 53.3% MEN; FEV(1) 55.6% PREDICTED) REGARDING DEMOGRAPHICS, CLINICAL CHARACTERISTICS, COMORBIDITIES AND THE PRESENCE OF THE SVD FEATURES AND HCV. TO CONCLUDE, THE CURRENT STUDY DOES NOT PROVIDE EVIDENCE FOR A RELATIONSHIP BETWEEN CEREBRAL SVD AND HCV AND COGNITIVE FUNCTIONING IN PATIENTS WITH COPD. ADDITIONAL STUDIES WILL BE NEEDED TO DETERMINE OTHER POSSIBLE MECHANISMS OF COGNITIVE IMPAIRMENT IN PATIENTS WITH COPD, INCLUDING MICROSTRUCTURAL BRAIN CHANGES AND INFLAMMATORY-, HORMONAL-, METABOLIC- AND (EPI)GENETIC FACTORS. 2017 6 6108 33 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 7 4945 27 PATERNAL PRECONCEPTION EVERY-OTHER-DAY ETHANOL DRINKING ALTERS BEHAVIOR AND ETHANOL CONSUMPTION IN OFFSPRING. ALCOHOL USE DISORDER IS A DEVASTATING DISEASE WITH A COMPLEX ETIOLOGY. RECENT PRECLINICAL STUDIES HAVE REVEALED THAT PATERNAL PRECONCEPTION CHRONIC INTERMITTENT ETHANOL (ETOH) EXPOSURE VIA VAPORIZED ETOH ALTERED DRINKING BEHAVIORS AND SENSITIVITY TO ETOH SELECTIVELY IN MALE OFFSPRING. IN THE CURRENT STUDY, WE USED A VOLUNTARY ORAL ROUTE OF PATERNAL PRECONCEPTION ETOH EXPOSURE, I.E., INTERMITTENT EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING, AND TESTED OFFSPRING FOR BEHAVIORAL ALTERATIONS. FIFTEEN ETOH DRINKING SIRES AND 10 CONTROL SIRES WERE MATED TO ETOH NAIVE FEMALES TO PRODUCE ETOH-SIRED AND CONTROL-SIRED OFFSPRING. THESE OFFSPRING WERE TESTED USING THE ELEVATED PLUS MAZE, OPEN FIELD, DRINKING IN THE DARK, AND UNLIMITED ACCESS TWO-BOTTLE CHOICE ASSAYS. WE FOUND THAT PATERNAL PRECONCEPTION EVERY-OTHER-DAY TWO-BOTTLE CHOICE DRINKING RESULTED IN REDUCED ETOH CONSUMPTION SELECTIVELY IN MALE OFFSPRING IN THE DRINKING IN THE DARK ASSAY COMPARED TO CONTROL-SIRED OFFSPRING. NO DIFFERENCES WERE DETECTED IN EITHER SEX IN THE UNLIMITED ACCESS TWO-BOTTLE CHOICE AND ELEVATED PLUS MAZE ASSAYS. OPEN FIELD ANALYSIS REVEALED COMPLEX CHANGES IN BASAL BEHAVIOR AND ETOH-INDUCED BEHAVIORS THAT WERE SEX SPECIFIC. WE CONCLUDED THAT PATERNAL PRECONCEPTION VOLUNTARY ETOH CONSUMPTION HAS PERSISTENT EFFECTS THAT IMPACT THE NEXT GENERATION. THIS STUDY ADDS TO A GROWING APPRECIATION THAT ONE'S BEHAVIORAL RESPONSE TO ETOH AND ETOH DRINKING BEHAVIOR ARE IMPACTED BY ETOH EXPOSURE OF THE PRIOR GENERATION. 2019 8 5445 39 REPEATED VAPOR ETHANOL EXPOSURE INDUCES TRANSIENT HISTONE MODIFICATIONS IN THE BRAIN THAT ARE MODIFIED BY GENOTYPE AND BRAIN REGION. BACKGROUND: EMERGING RESEARCH IMPLICATES ETHANOL (ETOH)-INDUCED EPIGENETIC MODIFICATIONS IN REGULATING GENE EXPRESSION AND ETOH CONSUMPTION. HOWEVER, CONSENSUS ON SPECIFIC EPIGENETIC MODIFICATIONS INDUCED BY ETOH HAS NOT YET EMERGED, MAKING IT CHALLENGING TO IDENTIFY MECHANISMS AND DEVELOP TARGETED TREATMENTS. WE HYPOTHESIZED THAT CHRONIC INTERMITTENT ETOH (CIE) INDUCES PERSISTENT CHANGES IN HISTONE MODIFICATIONS ACROSS THE CEREBRAL CORTEX (CCX), NUCLEUS ACCUMBENS (NAC), AND PREFRONTAL CORTEX (PFC), AND THAT THESE HISTONE MODIFICATIONS ARE ALTERED IN A KNOCK-IN MOUSE STRAIN WITH ALTERED SENSITIVITY TO ETOH. METHODS: C57BL/6J (B6) MICE AND ALPHA1SHLA KNOCKIN MICE ON A B6 BACKGROUND WERE EXPOSED TO 16 H OF VAPOR ETOH OR ROOM AIR FOLLOWED BY 8 H OF ROOM AIR FOR 4 CONSECUTIVE DAYS AND SACRIFICED AT MULTIPLE TIME POINTS UP TO 72 H FOLLOWING EXPOSURE. HISTONE MODIFICATIONS WERE ASSESSED USING WESTERN BLOT AND DOT BLOT. RT-QPCR WAS USED TO STUDY EXPRESSION OF CHROMATIN MODIFYING ENZYMES IN NAC AND PFC. RESULTS: IN NAC, CIE SIGNIFICANTLY INCREASED ACETYLATION OF HISTONE SUBUNIT H3 AT LYSINE 9 (H3K9AC) BUT NOT LYSINE 14 (H3K14AC) OR LYSINE 27 (H3K27AC). IN PFC, CIE SIGNIFICANTLY INCREASED H3K9AC BUT NOT H3K14 OR H3K27AC. THERE WERE NO SIGNIFICANT CHANGES AT 8 OR 72 H AFTER ETOH EXPOSURE IN EITHER NAC OR PFC. CIE WAS ALSO ASSOCIATED WITH INCREASED EXPRESSION OF KAT2B, KAT5, AND TET1 IN NAC BUT NOT PFC. IN CCX, CIE HAD A SIGNIFICANT EFFECT ON LEVELS OF H3K18AC; THERE WAS ALSO A SIGNIFICANT EFFECT OF THE ALPHA1SHLA MUTATION ON LEVELS OF H3K27ME3, H3K14AC, AND H3K18AC AS WELL AS A TREND FOR H3S10PK14AC. CONCLUSIONS: THE ETOH-INDUCED HISTONE MODIFICATIONS OBSERVED WERE TRANSIENT AND VARIED SIGNIFICANTLY BETWEEN BRAIN REGIONS. A GENETIC MUTATION THAT ALTERED SENSITIVITY TO ETOH WAS ASSOCIATED WITH ALTERED INDUCTION OF HISTONE MODIFICATIONS DURING CIE. THESE RESULTS HAVE IMPLICATIONS FOR STUDYING ETOH-INDUCED HISTONE MODIFICATIONS AND ETOH SENSITIVITY. 2015 9 2815 29 FIBROMYALGIA: GENETICS AND EPIGENETICS INSIGHTS MAY PROVIDE THE BASIS FOR THE DEVELOPMENT OF DIAGNOSTIC BIOMARKERS. FIBROMYALGIA IS A DISEASE CHARACTERIZED BY CHRONIC WIDESPREAD PAIN WITH ADDITIONAL SYMPTOMS, SUCH AS JOINT STIFFNESS, FATIGUE, SLEEP DISTURBANCE, COGNITIVE DYSFUNCTION, AND DEPRESSION. CURRENTLY, FIBROMYALGIA DIAGNOSIS IS BASED EXCLUSIVELY ON A COMPREHENSIVE CLINICAL ASSESSMENT, ACCORDING TO 2016 ACR CRITERIA, BUT VALIDATED BIOLOGICAL BIOMARKERS ASSOCIATED WITH FIBROMYALGIA HAVE NOT YET BEEN IDENTIFIED. GENOME-WIDE ASSOCIATION STUDIES INVESTIGATED GENES POTENTIALLY INVOLVED IN FIBROMYALGIA PATHOGENESIS HIGHLIGHTING THAT GENETIC FACTORS ARE POSSIBLY RESPONSIBLE FOR UP TO 50% OF THE DISEASE SUSCEPTIBILITY. POTENTIAL CANDIDATE GENES FOUND ASSOCIATED TO FIBROMYALGIA ARE SLC64A4, TRPV2, MYT1L, AND NRXN3. FURTHERMORE, A GENE-ENVIRONMENTAL INTERACTION HAS BEEN PROPOSED AS TRIGGERING MECHANISM, THROUGH EPIGENETIC ALTERATIONS: IN PARTICULAR, FIBROMYALGIA APPEARS TO BE CHARACTERIZED BY A HYPOMETHYLATED DNA PATTERN, IN GENES IMPLICATED IN STRESS RESPONSE, DNA REPAIR, AUTONOMIC SYSTEM RESPONSE, AND SUBCORTICAL NEURONAL ABNORMALITIES. DIFFERENCES IN THE GENOME-WIDE EXPRESSION PROFILE OF MICRORNAS WERE FOUND AMONG MULTIPLE TISSUES, INDICATING THE INVOLVEMENT OF DISTINCT PROCESSES IN FIBROMYALGIA PATHOGENESIS. FURTHER STUDIES SHOULD BE DEDICATED TO STRENGTH THESE PRELIMINARY FINDINGS, IN LARGER MULTICENTER COHORTS, TO IDENTIFY RELIABLE DIRECTIONS FOR BIOMARKER RESEARCH AND CLINICAL PRACTICE. 2019 10 4943 32 PATERNAL PRECONCEPTION ALCOHOL EXPOSURE IMPARTS INTERGENERATIONAL ALCOHOL-RELATED BEHAVIORS TO MALE OFFSPRING ON A PURE C57BL/6J BACKGROUND. WHILE ALCOHOL USE DISORDER (AUD) IS A HIGHLY HERITABLE CONDITION, THE BASIS OF AUD IN FAMILIES WITH A HISTORY OF ALCOHOLISM IS DIFFICULT TO EXPLAIN BY GENETIC VARIATION ALONE. EMERGING EVIDENCE SUGGESTS THAT PARENTAL EXPERIENCE PRIOR TO CONCEPTION CAN AFFECT INHERITANCE OF COMPLEX BEHAVIORS IN OFFSPRING VIA NON-GENOMIC (EPIGENETIC) MECHANISMS. FOR INSTANCE, MALE C57BL/6J (B6) MICE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL (CIE) PRIOR TO MATING WITH STRAIN 129S1/SVIMJ ETHANOL-NAIVE FEMALES PRODUCE MALE OFFSPRING WITH REDUCED ETHANOL-DRINKING PREFERENCE, INCREASED ETHANOL SENSITIVITY, AND INCREASED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION IN THE VENTRAL TEGMENTAL AREA (VTA). IN THE PRESENT STUDY, WE TESTED THE HYPOTHESIS THAT THESE INTERGENERATIONAL EFFECTS OF PATERNAL CIE ARE REPRODUCIBLE IN MALE OFFSPRING ON AN INBRED B6 BACKGROUND. TO THIS END, B6 MALES WERE EXPOSED TO 6 WEEKS OF CIE (OR ROOM AIR AS A CONTROL) BEFORE MATING WITH ETHANOL-NAIVE B6 FEMALES TO PRODUCE ETHANOL (E)-SIRED AND CONTROL (C)-SIRED MALE AND FEMALE OFFSPRING. WE OBSERVED A SEX-SPECIFIC EFFECT, AS E-SIRED MALES EXHIBITED DECREASED TWO-BOTTLE FREE-CHOICE ETHANOL-DRINKING PREFERENCE, INCREASED SENSITIVITY TO THE ANXIOLYTIC EFFECTS OF ETHANOL, AND INCREASED VTA BDNF EXPRESSION; NO DIFFERENCES WERE OBSERVED IN FEMALE OFFSPRING. THESE FINDINGS CONFIRM AND EXTEND OUR PREVIOUS RESULTS BY DEMONSTRATING THAT THE EFFECTS OF PATERNAL PRECONCEPTION ETHANOL ARE REPRODUCIBLE USING GENETICALLY IDENTICAL, INBRED B6 ANIMALS. 2017 11 173 51 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD. 2023 12 5657 25 SEX-DEPENDENT PRONOCICEPTIVE ROLE OF SPINAL ALPHA(5) -GABA(A) RECEPTOR AND ITS EPIGENETIC REGULATION IN NEUROPATHIC RODENTS. EXTRASYNAPTIC ALPHA(5) -SUBUNIT CONTAINING GABA(A) (ALPHA(5) -GABA(A) ) RECEPTORS PARTICIPATE IN CHRONIC PAIN. PREVIOUSLY, WE REPORTED A SEX DIFFERENCE IN THE ACTION OF ALPHA(5) -GABA(A) RECEPTORS IN DYSFUNCTIONAL PAIN. HOWEVER, THE UNDERLYING MECHANISMS REMAIN UNKNOWN. THE AIM OF THIS STUDY WAS TO EXAMINE THIS SEXUAL DIMORPHISM IN NEUROPATHIC RODENTS AND THE MECHANISMS INVOLVED. FEMALE AND MALE WISTAR RATS OR ICR MICE WERE SUBJECTED TO NERVE INJURY FOLLOWED BY ALPHA(5) -GABA(A) RECEPTOR INVERSE AGONIST INTRATHECAL ADMINISTRATION, L-655,708. THE DRUG PRODUCED AN ANTIALLODYNIC EFFECT IN NERVE-INJURED FEMALE RATS AND MICE, AND A LOWER EFFECT IN MALES. WE HYPOTHESIZED THAT CHANGES IN ALPHA(5) -GABA(A) RECEPTOR, PROBABLY INFLUENCED BY HORMONAL AND EPIGENETIC STATUS, MIGHT UNDERLIE THIS SEX DIFFERENCE. THUS, WE PERFORMED QPCR AND WESTERN BLOT. NERVE INJURY INCREASED ALPHA(5) -GABA(A) MRNA AND PROTEIN IN FEMALE DORSAL ROOT GANGLIA (DRG) AND DECREASED THEM IN DRG AND SPINAL CORD OF MALES. TO INVESTIGATE THE HORMONAL INFLUENCE OVER ALPHA(5) -GABA(A) RECEPTOR ACTIONS, WE PERFORMED NERVE INJURY TO OVARIECTOMIZED RATS AND RECONSTITUTED THEM WITH 17BETA-ESTRADIOL (E2). OVARIECTOMY ABROGATED L-655,708 ANTIALLODYNIC EFFECT AND E2 RESTORED IT. OVARIECTOMY DECREASED ALPHA(5) -GABA(A) RECEPTOR AND ESTROGEN RECEPTOR ALPHA PROTEIN IN DRG OF NEUROPATHIC FEMALE RATS, WHILE E2 ENHANCED THEM. SINCE DNA METHYLATION MIGHT CONTRIBUTE TO ALPHA(5) -GABA(A) RECEPTOR DOWN-REGULATION IN MALES, WE EXAMINED CPG ISLAND DNA METHYLATION OF ALPHA(5) -GABA(A) RECEPTOR CODING GENE THROUGH PYROSEQUENCING. NERVE INJURY INCREASED METHYLATION IN MALE, BUT NOT FEMALE RATS. PHARMACOLOGICAL INHIBITION OF DNA METHYLTRANSFERASES INCREASED ALPHA(5) -GABA(A) RECEPTOR AND ENABLED L-655,708 ANTINOCICEPTIVE EFFECT IN MALE RATS. THESE RESULTS SUGGEST THAT ALPHA(5) -GABA(A) RECEPTOR IS A SUITABLE TARGET TO TREAT CHRONIC PAIN IN FEMALES. 2021 13 1009 32 CHRONIC VOLUNTARY ETHANOL DRINKING IN CYNOMOLGUS MACAQUES ELICITS GENE EXPRESSION CHANGES IN PREFRONTAL CORTICAL AREA 46. BACKGROUND: GENOME-WIDE PROFILING TO EXAMINE BRAIN TRANSCRIPTIONAL FEATURES ASSOCIATED WITH EXCESSIVE ETHANOL (ETOH) CONSUMPTION HAS BEEN APPLIED TO A VARIETY OF SPECIES INCLUDING RODENTS, NONHUMAN PRIMATES (NHPS), AND HUMANS. HOWEVER, THESE DATA WERE OBTAINED FROM CROSS-SECTIONAL SAMPLES WHICH ARE PARTICULARLY VULNERABLE TO INDIVIDUAL VARIATION WHEN OBTAINED FROM SMALL OUTBRED POPULATIONS TYPICAL OF HUMAN AND NHP STUDIES. IN THE CURRENT STUDY, A NOVEL WITHIN-SUBJECT DESIGN WAS USED TO EXAMINE THE EFFECTS OF VOLUNTARY ETOH CONSUMPTION ON PREFRONTAL CORTEX (PFC) GENE EXPRESSION IN A NHP MODEL. METHODS: TWO COHORTS OF CYNOMOLGUS MACAQUES (N = 23) UNDERWENT A SCHEDULE-INDUCED POLYDIPSIA PROCEDURE TO ESTABLISH ETOH SELF-ADMINISTRATION FOLLOWED BY 6 MONTHS OF DAILY OPEN ACCESS TO ETOH (4% W/V) AND WATER. INDIVIDUAL DAILY ETOH INTAKES RANGED FROM AN AVERAGE OF 0.7 TO 3.7 G/KG/D. DORSAL LATERAL PFC AREA 46 (A46) BRAIN BIOPSIES WERE COLLECTED IN ETOH-NAIVE AND CONTROL MONKEYS; CONTRALATERAL A46 BIOPSIES WERE COLLECTED FROM THE SAME MONKEYS FOLLOWING THE 6 MONTHS OF FLUID CONSUMPTION. GENE EXPRESSION CHANGES WERE ASSESSED USING RNA-SEQ PAIRED ANALYSIS, WHICH ALLOWED FOR CORRECTION OF INDIVIDUAL BASELINE DIFFERENCES IN GENE EXPRESSION. RESULTS: A TOTAL OF 675 GENES WERE SIGNIFICANTLY DOWN-REGULATED FOLLOWING ETOH CONSUMPTION; THESE WERE FUNCTIONALLY ENRICHED FOR IMMUNE RESPONSE, CELL ADHESION, PLASMA MEMBRANE, AND EXTRACELLULAR MATRIX. A TOTAL OF 567 GENES THAT WERE UP-REGULATED FOLLOWING ETOH CONSUMPTION WERE ENRICHED IN MICRORNA TARGET SITES AND INCLUDED TARGET SITES ASSOCIATED WITH TOLL-LIKE RECEPTOR PATHWAYS. THE DIFFERENTIALLY EXPRESSED GENES WERE ALSO SIGNIFICANTLY ENRICHED IN TRANSCRIPTION FACTOR BINDING SITES. CONCLUSIONS: THE DATA PRESENTED HERE ARE THE FIRST TO USE A LONGITUDINAL BIOPSY STRATEGY TO EXAMINE HOW CHRONIC ETOH CONSUMPTION AFFECTS GENE EXPRESSION IN THE PRIMATE PFC. PROMINENT EFFECTS WERE SEEN IN BOTH CELL ADHESION AND NEUROIMMUNE PATHWAYS; THE LATTER CONTAINED BOTH PRO- AND ANTIINFLAMMATORY GENES. THE DATA ALSO INDICATE THAT CHANGES IN MIRNAS AND TRANSCRIPTION FACTORS MAY BE IMPORTANT EPIGENETIC REGULATORS OF ETOH CONSUMPTION. 2020 14 1761 34 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS. 2013 15 5784 29 SPONTANEOUS FIRING AS AN EPIGENETIC FACTOR IN BRAIN DEVELOPMENT--PHYSIOLOGICAL CONSEQUENCES OF CHRONIC TETRODOTOXIN AND PICROTOXIN EXPOSURE ON CULTURED RAT NEOCORTEX NEURONS. FUNCTIONAL CONSEQUENCES OF EITHER SUPPRESSING OR INTENSIFYING SPONTANEOUS NEURONAL FIRING HAVE BEEN STUDIED IN DEVELOPING RAT CEREBRAL CORTEX CULTURES USING, RESPECTIVELY, TETRODOTOXIN (TTX) AND PICROTOXIN (PTX) ADDED CHRONICALLY TO THE GROWTH MEDIUM. SIMPLE MEASURES DERIVED FROM THE INTERSPIKE INTERVAL HISTOGRAM WERE ABLE TO POWERFULLY DISCRIMINATE BETWEEN AGE AND TREATMENT GROUPS. AFTER RETURN TO CONTROL MEDIUM, MOST TTX-TREATED NEURONS SPONTANEOUSLY DISPLAYED STEREOTYPED CLUSTERING OF ACTION POTENTIALS ('PHASIC' FIRING) WHICH CLOSELY RESEMBLED THE CHARACTERISTIC FIRING PATTERNS SEEN ACUTELY IN THE PRESENCE OF PTX. THE 'TTX-SYNDROME' THUS SUGGESTS THAT GABAERGIC SYNAPTIC INHIBITION IS INEFFECTIVE IN CORTICAL NETWORKS GROWN UNDER CONDITIONS WHICH PREVENT THE EXPRESSION OF BIOELECTRIC ACTIVITY. IN CONTRAST, AFTER RETURN TO CONTROL MEDIUM, NEURONS WHICH HAD BEEN PARTIALLY DISINHIBITED THROUGHOUT DEVELOPMENT (BY CONTINUOUS EXPOSURE TO PTX) HAD EVEN LESS PHASIC FIRING THAN WAS MEASURED IN AGE-MATCHED CONTROLS. BASED UPON THESE AND PREVIOUS FINDINGS, A TWO (MAIN) FACTOR MODEL IS PUT FORTH WHICH CAN ECONOMICALLY ACCOUNT FOR THE MAJOR EFFECTS. THE WORKING HYPOTHESIS EMBODIED IN THIS MODEL IS THAT PHASIC NEURONAL DISCHARGES NOT ONLY ACCELERATE THE MATURATION OF EXCITATORY CONNECTIONS WITHIN THE NEOCORTEX BUT, EVEN MORE IMPORTANT, ARE CRUCIAL FOR THE DEVELOPMENT OF ADEQUATE INHIBITORY SYNAPTIC TRANSMISSION. 1992 16 910 26 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS. 2014 17 314 29 ALCOHOL USE DISORDER IS ASSOCIATED WITH UPREGULATION OF MICRORNA-34A AND MICRORNA-34C IN HIPPOCAMPAL POSTMORTEM TISSUE. BACKGROUND: TO INVESTIGATE EPIGENETIC MECHANISMS POTENTIALLY INVOLVED IN THE COGNITIVE DECLINE ASSOCIATED WITH CHRONIC ALCOHOL INTAKE, WE EVALUATED THE EXPRESSIONS OF THREE MICRO-RNAS (MIR-34A, -34B, AND -34C) HIGHLY EXPRESSED IN THE HIPPOCAMPUS AND INVOLVED IN NEURONAL PHYSIOLOGY AND PATHOLOGY. MIR-34A PARTICIPATES IN FUNCTIONING AND SURVIVAL OF MATURE NEURONS; MIR-34B IS ASSOCIATED WITH ALZHEIMER-LIKE DISORDERS; AND MIR-34C IS IMPLICATED IN THE MEMORY IMPAIRMENT OF ALZHEIMER DISEASE IN RODENTS AND HUMANS. METHODS: A TOTAL OF 69 CASES WERE SELECTED FROM THE BIOBANK FOR AGING STUDIES AND CATEGORIZED ACCORDING TO THE ABSENCE (N = 50) OR PRESENCE (N = 19) OF ALCOHOL USE DISORDER (AUD). CASES PRESENTING WITH NEUROPATHOLOGICAL DIAGNOSES OF DEMENTIAS WERE EXCLUDED. TOTAL RNA WAS EXTRACTED FROM HIPPOCAMPAL PARAFFINIZED SLICES, COMPLEMENTARY DNA WAS SYNTHESIZED FROM MIRS, AND RT-QPCR WAS PERFORMED WITH TAQMAN((R)) ASSAYS. RESULTS: HIGHER EXPRESSIONS OF MIR-34A AND MIR-34C, BUT NOT OF MIR-34B, WERE FOUND IN THE GROUP WITH AUD IN COMPARISON WITH THE GROUP WITHOUT AUD AFTER ADJUSTMENT FOR POTENTIAL CONFOUNDERS (AGE, SEX, BODY MASS INDEX, PRESENCE OF HYPERTENSION, DIABETES MELLITUS, SMOKING, AND PHYSICAL INACTIVITY). CONCLUSIONS: HIPPOCAMPAL UPREGULATION OF MIR-34A AND MIR-34C MAY BE INVOLVED IN THE COGNITIVE DECLINE ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION. 2021 18 774 26 CELL TYPE-SPECIFIC MECHANISM OF SETD1A HETEROZYGOSITY IN SCHIZOPHRENIA PATHOGENESIS. SCHIZOPHRENIA (SCZ) IS A CHRONIC, SERIOUS MENTAL DISORDER. ALTHOUGH MORE THAN 200 SCZ-ASSOCIATED GENES HAVE BEEN IDENTIFIED, THE UNDERLYING MOLECULAR AND CELLULAR MECHANISMS REMAIN LARGELY UNKNOWN. HERE, WE GENERATED A SETD1A (SET DOMAIN CONTAINING 1A) HAPLOINSUFFICIENCY MOUSE MODEL TO UNDERSTAND HOW THIS SCZ-ASSOCIATED EPIGENETIC FACTOR AFFECTS GENE EXPRESSION IN BRAIN REGIONS HIGHLY RELEVANT TO SCZ. SINGLE-CELL RNA SEQUENCING REVEALED THAT SETD1A HETEROZYGOSITY CAUSES HIGHLY VARIABLE TRANSCRIPTIONAL ADAPTATIONS ACROSS DIFFERENT CELL TYPES IN PREFRONTAL CORTEX (PFC) AND STRIATUM. THE FOXP2(+) NEURONS EXHIBIT THE MOST PROMINENT GENE EXPRESSION CHANGES AMONG THE DIFFERENT NEURON SUBTYPES IN PFC, WHICH CORRELATE WITH CHANGES IN HISTONE H3 LYSINE 4 TRIMETHYLATION. MANY OF THE GENES DYSREGULATED IN SETD1A(+/-) MICE ARE INVOLVED IN NEURON MORPHOGENESIS AND SYNAPTIC FUNCTION. CONSISTENTLY, SETD1A(+/-) MICE EXHIBIT CERTAIN BEHAVIORAL FEATURES OF PATIENTS WITH SCZ. COLLECTIVELY, OUR STUDY ESTABLISHES SETD1A(+/-) MICE AS A MODEL FOR UNDERSTANDING SCZ AND UNCOVERS A COMPLEX BRAIN REGION- AND CELL TYPE-SPECIFIC DYSREGULATION THAT POTENTIALLY UNDERLIES SCZ PATHOGENESIS. 2022 19 1610 38 DNA METHYLATION/DEMETHYLATION NETWORK EXPRESSION IN PSYCHOTIC PATIENTS WITH A HISTORY OF ALCOHOL ABUSE. BACKGROUND: RECENT STUDIES SUGGEST THAT PROTRACTED AND EXCESSIVE ALCOHOL USE INDUCES AN EPIGENETIC DYSREGULATION IN HUMAN AND RODENT BRAINS. WE RECENTLY REPORTED THAT DNA METHYLATION DYNAMICS ARE ALTERED IN BRAINS OF PSYCHOTIC (PS) PATIENTS, INCLUDING SCHIZOPHRENIA AND BIPOLAR DISORDER PATIENTS. BECAUSE PS PATIENTS ARE OFTEN COMORBID WITH CHRONIC ALCOHOL ABUSE, WE EXAMINED WHETHER THE ALTERED EXPRESSION OF MULTIPLE MEMBERS OF THE DNA METHYLATION/DEMETHYLATION NETWORK OBSERVED IN POSTMORTEM BRAINS OF PS PATIENTS WAS MODIFIED IN PS PATIENTS WITH A HISTORY OF CHRONIC ALCOHOL ABUSE. METHODS: DNA-METHYLTRANSFERASE-1 (DNMT1) MRNA-POSITIVE NEURONS WERE COUNTED IN SITU IN PREFRONTAL CORTEX SAMPLES OBTAINED FROM THE HARVARD BRAIN TISSUE RESOURCE CENTER, BELMONT, MA. 10-11-TRANSLOCATION (TETS 1, 2, 3), APOLIPOPROTEIN B EDITING COMPLEX ENZYME (APOBEC-3C), GROWTH AND DNA-DAMAGE-INDUCIBLE PROTEIN 45BETA (GADD45BETA), AND METHYL-BINDING DOMAIN PROTEIN-4 (MBD4) MRNAS WERE MEASURED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION IN INFERIOR PARIETAL CORTICAL LOBULE SAMPLES OBTAINED FROM THE STANLEY FOUNDATION NEUROPATHOLOGY CONSORTIUM, BETHESDA, MD. RESULTS: WE OBSERVED AN INCREASE IN DNMT1 MRNA-POSITIVE NEURONS IN PS PATIENTS COMPARED WITH NON-PS SUBJECTS. IN ADDITION, THERE WAS A PRONOUNCED DECREASE IN APOBEC-3C AND A PRONOUNCED INCREASE IN GADD45BETA AND TET1 MRNAS IN PS PATIENTS WITH NO HISTORY OF ALCOHOL ABUSE. IN PS PATIENTS WITH A HISTORY OF CHRONIC ALCOHOL ABUSE, THE NUMBERS OF DNMT1-POSITIVE NEURONS WERE NOT INCREASED SIGNIFICANTLY. FURTHERMORE, THE DECREASE IN APOBEC-3C MRNA WAS LESS PRONOUNCED, WHILE THE INCREASE IN TET1 MRNA HAD A TENDENCY TO BE POTENTIATED IN THOSE PS PATIENTS THAT WERE CHRONIC ALCOHOL ABUSERS. GADD45BETA AND MBD4 MRNAS WERE NOT INFLUENCED BY ALCOHOL ABUSE. THE EFFECT OF CHRONIC ALCOHOL ABUSE ON DNA METHYLATION/DEMETHYLATION NETWORK ENZYMES CANNOT BE ATTRIBUTED TO CONFOUNDING DEMOGRAPHIC VARIABLES OR TO THE TYPE AND DOSE OF MEDICATION USED. CONCLUSIONS: BASED ON THESE RESULTS, WE HYPOTHESIZE THAT PS PATIENTS MAY ABUSE ALCOHOL AS A POTENTIAL ATTEMPT AT SELF-MEDICATION TO NORMALIZE ALTERED DNA METHYLATION/DEMETHYLATION NETWORK PATHWAYS. HOWEVER, BEFORE ACCEPTING THIS CONCLUSION, WE NEED TO STUDY ALTERATIONS IN THE DNA METHYLATION/DEMETHYLATION PATHWAYS AND THE DNA METHYLATION DYNAMICS IN A SUBSTANTIAL NUMBER OF ALCOHOLIC PS AND NON-PS PATIENTS. ADDITIONAL INVESTIGATION MAY ALSO BE NECESSARY TO DETERMINE WHETHER THE ALTERED DNA METHYLATION DYNAMICS ARE DIRECT OR THE CONSEQUENCE OF AN INDIRECT INTERACTION OF ALCOHOL WITH THE NEUROPATHOGENETIC MECHANISMS UNDERLYING PSYCHOSIS. 2013 20 1800 22 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA. 2019