1 807 138 CHANGE IN MICRORNAS ASSOCIATED WITH NEURONAL ADAPTIVE RESPONSES IN THE NUCLEUS ACCUMBENS UNDER NEUROPATHIC PAIN. NEUROPATHIC PAIN IS THE MOST DIFFICULT TYPE OF PAIN TO CONTROL, AND PATIENTS LOSE THEIR MOTIVATION FOR THE PURPOSIVE PURSUIT WITH A DECREASE IN THEIR QUALITY OF LIFE. USING A FUNCTIONAL MAGNETIC RESONANCE IMAGING ANALYSIS, WE DEMONSTRATED THAT BLOOD OXYGENATION LEVEL-DEPENDENT SIGNAL INTENSITY WAS INCREASED IN THE IPSILATERAL NUCLEUS ACCUMBENS (N.ACC.) FOLLOWING PERIPHERAL NERVE INJURY. MICRORNAS ARE SMALL, NONCODING RNA MOLECULES THAT DIRECT THE POST-TRANSCRIPTIONAL SUPPRESSION OF GENE EXPRESSION, AND PLAY AN IMPORTANT ROLE IN REGULATING SYNAPTIC PLASTICITY. IN THIS STUDY, WE FOUND THAT SCIATIC NERVE LIGATION INDUCED A DRASTIC DECREASE IN THE EXPRESSION OF MIR200B AND MIR429 IN N.ACC. NEURONS. THE EXPRESSION OF DNA METHYLTRANSFERASE 3A (DNMT3A), WHICH IS THE ONE OF THE PREDICTED TARGETS OF MIR200B/429, WAS SIGNIFICANTLY INCREASED IN THE LIMBIC FOREBRAIN INCLUDING N.ACC. AT 7 D AFTER SCIATIC NERVE LIGATION. DOUBLE-IMMUNOLABELING WITH ANTIBODIES SPECIFIC TO DNMT3A AND NR1 SHOWED THAT DNMT3A-IMMUNOREACTIVITY IN THE N.ACC. WAS LOCATED IN NR1-LABELED NEURONS, INDICATING THAT INCREASED DNMT3A PROTEINS WERE DOMINANTLY EXPRESSED IN POSTSYNAPTIC NEURONS IN THE N.ACC. AREA UNDER A NEUROPATHIC PAIN-LIKE STATE. THE RESULTS OF THESE ANALYSES PROVIDE NEW INSIGHT INTO AN EPIGENETIC MODIFICATION THAT IS ACCOMPANIED BY A DRAMATIC DECREASE IN MIR200B AND MIR429 ALONG WITH THE DYSFUNCTION OF "MESOLIMBIC MOTIVATION/VALUATION CIRCUITRY" UNDER A NEUROPATHIC PAIN-LIKE STATE. THESE PHENOMENA MAY RESULT IN AN INCREASE IN DNMT3A IN NEURONS OF THE N.ACC. UNDER NEUROPATHIC PAIN, WHICH LEADS TO THE LONG-TERM TRANSCRIPTION-SILENCING OF SEVERAL GENES. 2011 2 1337 24 DESIGN AND MEASUREMENT IN A STUDY OF WAR EXPOSURE, HEALTH, AND AGING: PROTOCOL FOR THE VIETNAM HEALTH AND AGING STUDY. BACKGROUND: SURVIVORS OF WAR THROUGHOUT THE WORLD EXPERIENCE ILLNESSES AND INJURIES THAT ARE CRUCIAL TO UNDERSTAND, GIVEN THE ONGOING TREATMENT AND ADAPTATION THEY DEMAND. IN DEVELOPING COUNTRIES LIKE VIETNAM, WHERE POPULATION AGING AND CHRONIC DISEASE BURDENS ARE RAPIDLY RISING, AGING POPULATIONS HAVE SEEN A DISPROPORTIONATE SHARE OF ARMED CONFLICT AND RELATED CASUALTIES. THIS PAPER DESCRIBES THE VIETNAM HEALTH AND AGING STUDY (VHAS), A UNIQUE RESOURCE FOR INVESTIGATING MECHANISMS OF ASSOCIATION BETWEEN DIVERSE EXPOSURES TO ARMED CONFLICT DURING THE VIETNAM WAR AND MULTIPLE DIMENSIONS OF OLDER ADULT HEALTH AMONG SURVIVORS OF THAT WAR. METHODS: THE VHAS UTILIZES A LONGITUDINAL DESIGN, THE FIRST WAVE OF DATA COLLECTION CONDUCTED IN 2018 AMONG 2447 OLDER ADULTS. A SECOND WAVE OF FOLLOW-UP DATA COLLECTION, SCHEDULED TO TAKE PLACE IN 2021, WILL EXAMINE LIFE COURSE, SOCIAL RELATIONAL AND HEALTH AND MORTALITY TRANSITIONS. THE VHAS WAS CONDUCTED IN FOUR NORTHERN VIETNAMESE DISTRICTS PURPOSIVELY SELECTED TO REPRESENT A SPECTRUM OF WAR EXPOSURE AS INDICATED BY INTENSITY OF BOMBINGS. ADDITIONALLY, VHAS USES RANDOM SAMPLING WITHIN GENDER AND MILITARY SERVICE SUBDOMAINS TO PERMIT UNIQUE GENDER-SPECIFIC ANALYSES OF MILITARY SERVICE, TRAUMA EXPOSURE AND HEALTH. THE VHAS' FACE-TO-FACE INTERVIEWS INCLUDE MODULES DETAILING WAR AND MILITARY SERVICE EXPERIENCES; WARZONE STRESSORS; AND MULTIPLE DIMENSIONS OF HEALTH SUCH AS CHRONIC DISEASE, FUNCTIONAL LIMITATION, DISABILITY, HEALTH BEHAVIORS, COGNITION AND PSYCHOLOGICAL HEALTH. BIOMARKER DATA COLLECTED FOR THE FULL VHAS SAMPLE INCLUDES ANTHROPOMETRIC AND FUNCTIONAL TESTS SUCH AS GRIP STRENGTH AND BLOOD PRESSURE, HAIR SAMPLES FOR CORTISOL ASSAY, AND CAPILLARY BLOOD SAMPLES TO ASSAY C-REACTIVE PROTEIN, CHOLESTEROL, HBA1C, AND OTHER MARKERS OF INTEREST FOR CARDIOVASCULAR AND OTHER DISEASE RISKS AND FOR TESTING THE IMPACT OF EARLY LIFE STRESSORS ON LATER LIFE HEALTH. BLOOD SAMPLES WILL ALSO PERMIT EPIGENETIC ANALYSIS OF BIOLOGICAL AGING. DISCUSSION: FUTURE VHAS INVESTIGATIONS WILL EXAMINE DYNAMIC LINKAGES BETWEEN WAR EXPOSURE, MORTALITY AND MORBIDITY, WHILE TAKING INTO ACCOUNT THE SELECTIVE NATURE OF EACH OF THESE PROCESSES. LONGITUDINAL ANALYSES WILL EXAMINE LATE-LIFE HEALTH TRANSITIONS AND WAR-RELATED RESILIENCY. 2019 3 6912 50 [UNDERSTANDING OF THE PSYCHIATRY IN PALLIATIVE CARE: DYSFUNCTION OF THE REWARDING SYSTEM UNDER THE PAIN STATE ASSOCIATED WITH EXACERBATING PAIN]. RECENT HUMAN BRAIN IMAGING STUDIES HAVE EXAMINED DIFFERENCES IN ACTIVITY IN THE NUCLEUS ACCUMBENS (N.ACC.) IN RESPONSE TO HEAT STIMULI BETWEEN CONTROLS AND PATIENTS WITH CHRONIC PAIN, AND HAVE REVEALED THAT THE N.ACC. PLAYS A ROLE IN PREDICTING THE VALUE OF A NOXIOUS STIMULUS AND ITS OFFSET, AND IN THE CONSEQUENT CHANGES IN THE MOTIVATIONAL STATE. NEVERTHELESS, THE MOLECULAR MECHANISMS OF CHANGE IN THE CIRCUITRY INVOLVED IN EMOTION AND MOTIVATION IN RESPONSE TO CHRONIC PAIN STIMULI WERE NOT FULLY EXPLORED. ON THE OTHER HAND, IT HAS BEEN CONSIDERED THAT MICRO RNAS (MIRNAS) PLAY IMPORTANT ROLES AS KEY MODULATORS OF POST-TRANSCRIPTIONAL GENE EXPRESSION. WE HAVE REPORTED THAT CHANGES IN MIRNAS ARE ASSOCIATED WITH PREDICTED CHANGES IN GENE EXPRESSION OF CANDIDATE TARGETS IN THE N.ACC. UNDER NEUROPATHIC PAIN. THEREFORE, WE HAVE INTRODUCED A NEW INSIGHT INTO AN EPIGENETIC DYSFUNCTION OF "MESOLIMBIC MOTIVATION/VALUATION CIRCUITRY" UNDER A NEUROPATHIC PAIN-LIKE STATE. THESE FINDINGS RAISE INTRIGUING POSSIBILITIES THAT MIRNA-MODULATING CELLULAR EVENTS ALONG WITH EPIGENETIC MODIFICATIONS MAY BE ASSOCIATED WITH NEURAL PLASTICITY AND NEURONAL ADAPTIVE RESPONSES IN MESOLIMBIC MOTIVATION/VALUATION CIRCUITRY UNDER WHICH THE NEUROPATHIC PAIN MAY INDUCE NEGATIVE EMOTIONS, EXACERBATING PAIN. 2013 4 3179 32 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED. 2016 5 5200 29 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES. 2016 6 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 7 6108 36 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 8 2300 40 EPIGENETIC REGULATION OF BDNF EXPRESSION IN THE PRIMARY SENSORY NEURONS AFTER PERIPHERAL NERVE INJURY: IMPLICATIONS IN THE DEVELOPMENT OF NEUROPATHIC PAIN. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IS KNOWN TO BE UP-REGULATED IN THE DORSAL ROOT GANGLION (DRG) AFTER PERIPHERAL NERVE INJURY, AND TO CONTRIBUTE TO NEUROPATHIC PAIN. HERE, WE FOUND THAT THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA AT DAY 7 POST-INJURY WERE INHIBITED ONLY WHEN ANTI-BDNF ANTIBODY WAS INTRATHECALLY ADMINISTRATED AT DAY 2 POST-INJURY. CONSISTENT WITH BEHAVIORAL RESULTS, WESTERN BLOT ANALYSIS SHOWED THAT THE EXPRESSION LEVELS OF BDNF PROTEIN IN THE SPINAL DORSAL HORN WERE MARKEDLY INDUCED DURING EARLY STAGE POST-INJURY. MOREOVER, THE MAXIMAL INCREASE IN BDNF MRNA EXPRESSION IN THE DRG WAS OBSERVED AT DAY 1 POST-INJURY, AND SIGNIFICANTLY ELEVATED LEVELS WERE SUSTAINED FOR AT LEAST 14 DAYS. FOUR OF FIVE BDNF MRNA TRANSCRIPTS WERE UP-REGULATED AFTER NERVE INJURY, AND THE MOST INDUCIBLE TRANSCRIPT WAS EXON I. USING A CHROMATIN IMMUNOPRECIPITATION (CHIP) ASSAY, WE FOUND THAT NERVE INJURY PROMOTES HISTONE H3 AND H4 ACETYLATION, TRANSCRIPTIONALLY ACTIVE MODIFICATIONS, AT BDNF PROMOTER I AT DAY 1 POST-INJURY, AND THE LEVELS OF HISTONE ACETYLATION REMAIN ELEVATED FOR AT LEAST 7 DAYS. TAKEN TOGETHER, OUR FINDINGS SUGGEST THAT AN INITIAL INCREASE IN BDNF EXON I EXPRESSION CONTROLLED BY EPIGENETIC MECHANISMS MIGHT HAVE A CRUCIAL ROLE IN THE DEVELOPMENT OF NEUROPATHIC PAIN. 2013 9 1009 39 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 10 2272 37 EPIGENETIC REDUCTION OF MIR-214-3P UPREGULATES ASTROCYTIC COLONY-STIMULATING FACTOR-1 AND CONTRIBUTES TO NEUROPATHIC PAIN INDUCED BY NERVE INJURY. EMERGING EVIDENCE HAS INDICATED THAT COLONY-STIMULATING FACTOR-1 (CSF1) MODULATES NEUROINFLAMMATION IN THE CENTRAL NERVOUS SYSTEM AND THE DEVELOPMENT OF NEUROPATHIC PAIN, WHILE THE UNDERLYING MECHANISM REMAINS UNKNOWN. HERE, WE IDENTIFIED THE INCREASED EXPRESSION OF CSF1 DERIVED FROM ACTIVATED ASTROCYTES IN THE IPSILATERAL DORSAL HORN IN RATS WITH SPINAL NERVE LIGATION (SNL). SUPPRESSION OF CSF1 EXPRESSION ALLEVIATED NEUROINFLAMMATION, NEURONAL HYPEREXCITABILITY, AND GLUTAMATERGIC RECEPTOR SUBUNIT UPREGULATION IN THE DORSAL HORN AND IMPROVED SNL-INDUCED PAIN BEHAVIOR. WE ALSO FOUND REDUCED MIR-214-3P EXPRESSION IN THE IPSILATERAL DORSAL HORN FOLLOWING AN SNL PROCEDURE; MIR-214-3P DIRECTLY BOUND TO THE 3'-UTR OF CSF1 MRNA AND NEGATIVELY REGULATED CSF1 EXPRESSION. INTRATHECAL DELIVERY OF MIR-214-3P MIMIC REVERSED THE ENHANCED EXPRESSION OF CSF1 AND ASTROCYTE OVERACTIVITY AND ALLEVIATED THE IL-6 UPREGULATION AND PAIN BEHAVIOR INDUCED BY SNL. MOREOVER, SUPPRESSION OF SPINAL MIR-214-3P INCREASED ASTROCYTE REACTIVITY, PROMOTED CSF1 AND IL-6 PRODUCTION, AND INDUCED PAIN HYPERSENSITIVITY IN NAIVE ANIMALS. FURTHERMORE, SNL INDUCED THE EXPRESSION OF DNA METHYLTRANSFERASE 3A (DNMT3A) THAT WAS ASSOCIATED WITH THE HYPERMETHYLATION OF THE MIR-214-3P PROMOTER, LEADING TO REDUCED MIR-214-3P EXPRESSION IN THE MODEL RODENTS. TREATMENT WITH THE DNMT INHIBITOR ZEBULARINE SIGNIFICANTLY REDUCED CYTOSINE METHYLATION IN THE MIR-214-3P PROMOTER; THIS REDUCED METHYLATION CONSEQUENTLY INCREASED THE EXPRESSION OF MIR-214-3P AND DECREASED THE CONTENT OF CSF1 IN THE IPSILATERAL DORSAL HORN AND, FURTHER, ATTENUATED IL-6 PRODUCTION AND PAIN BEHAVIOR IN RATS WITH SNL. TOGETHER, OUR DATA INDICATE THAT THE DNMT3A-MEDIATED EPIGENETIC SUPPRESSION OF MIR-214-3P ENHANCED CSF1 PRODUCTION IN ASTROCYTES, WHICH SUBSEQUENTLY INDUCED NEUROINFLAMMATION AND PAIN BEHAVIOR IN SNL MODEL RATS. 2020 11 5021 35 PERSISTENT PAIN MAINTAINS MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL THROUGH REDUCED MECP2 REPRESSION OF GLUA1 IN RAT CENTRAL AMYGDALA. AS LONG-TERM OPIOIDS ARE INCREASINGLY USED FOR CONTROL OF CHRONIC PAIN, HOW PAIN AFFECTS THE REWARDING EFFECT OF OPIOIDS AND HENCE RISK OF PRESCRIPTION OPIOID MISUSE AND ABUSE REMAINS A HEALTHCARE CONCERN AND A CHALLENGING ISSUE IN CURRENT PAIN MANAGEMENT. IN THIS STUDY, USING A RAT MODEL OF MORPHINE SELF-ADMINISTRATION, WE INVESTIGATED THE MOLECULAR MECHANISMS UNDERLYING THE IMPACT OF PAIN ON OPERANT BEHAVIOR OF MORPHINE INTAKE AND MORPHINE SEEKING BEFORE AND AFTER MORPHINE WITHDRAWAL. WE FOUND THAT RATS WITH PERSISTENT PAIN CONSUMED A SIMILAR AMOUNT OF DAILY MORPHINE TO THAT IN CONTROL RATS WITHOUT PAIN, BUT MAINTAINED THEIR LEVEL-PRESSING BEHAVIOR OF MORPHINE SEEKING AFTER ABSTINENCE OF MORPHINE AT 0.2 MG/KG, WHEREAS THIS BEHAVIOR WAS GRADUALLY DIMINISHED IN CONTROL RATS. IN THE CENTRAL NUCLEUS OF AMYGDALA (CEA), A LIMBIC STRUCTURE CRITICALLY INVOLVED IN THE AFFECTIVE DIMENSION OF PAIN, PROTEINS OF GLUA1 SUBUNITS OF GLUTAMATE AMPA RECEPTORS WERE UPREGULATED DURING MORPHINE WITHDRAWAL, AND VIRAL KNOCKDOWN OF CEA GLUA1 ELIMINATED THE MORPHINE-SEEKING BEHAVIOR IN WITHDRAWN RATS OF THE PAIN GROUP. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT THE METHYL CPG-BINDING PROTEIN 2 (MECP2) WAS ENRICHED IN THE PROMOTER REGION OF GRIA1 ENCODING GLUA1 AND THIS ENRICHMENT WAS SIGNIFICANTLY ATTENUATED IN WITHDRAWN RATS OF THE PAIN GROUP. FURTHERMORE, VIRAL OVEREXPRESSION OF CEA MECP2 REPRESSED THE GLUA1 LEVEL AND ELIMINATED THE MAINTENANCE OF MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL. THESE RESULTS SUGGEST DIRECT MECP2 REPRESSION OF GLUA1 FUNCTION AS A LIKELY MECHANISM FOR MORPHINE-SEEKING BEHAVIOR MAINTAINED BY LONG-LASTING AFFECTIVE PAIN AFTER MORPHINE WITHDRAWAL. 2015 12 4699 34 NFATC2-DEPENDENT EPIGENETIC UPREGULATION OF CXCL14 IS INVOLVED IN THE DEVELOPMENT OF NEUROPATHIC PAIN INDUCED BY PACLITAXEL. BACKGROUND: THE MAJOR DOSE-LIMITING TOXICITY OF PACLITAXEL, ONE OF THE MOST COMMONLY USED DRUGS TO TREAT SOLID TUMOR, IS PAINFUL NEUROPATHY. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING PACLITAXEL-INDUCED PAINFUL NEUROPATHY ARE LARGELY UNCLARIFIED. METHODS: PAW WITHDRAWAL THRESHOLD WAS MEASURED IN THE RATS FOLLOWING INTRAPERITONEAL INJECTION OF PACLITAXEL. THE QPCR, WESTERN BLOTTING, PROTEIN OR CHROMATIN IMMUNOPRECIPITATION, CHIP-SEQ IDENTIFICATION OF NFATC2 BINDING SITES, AND MICROARRAY ANALYSIS WERE PERFORMED TO EXPLORE THE MOLECULAR MECHANISM. RESULTS: WE FOUND THAT PACLITAXEL TREATMENT INCREASED THE NUCLEAR EXPRESSION OF NFATC2 IN THE SPINAL DORSAL HORN, AND KNOCKDOWN OF NFATC2 WITH NFATC2 SIRNA SIGNIFICANTLY ATTENUATED THE MECHANICAL ALLODYNIA INDUCED BY PACLITAXEL. FURTHER BINDING SITE ANALYSIS UTILIZING CHIP-SEQ ASSAY COMBINING WITH GENE EXPRESSION PROFILE REVEALED A SHIFT OF NFATC2 BINDING SITE CLOSER TO TTS OF TARGET GENES IN DORSAL HORN AFTER PACLITAXEL TREATMENT. WE FURTHER FOUND THAT NFATC2 OCCUPANCY MAY DIRECTLY UPREGULATE THE CHEMOKINE CXCL14 EXPRESSION IN DORSAL HORN, WHICH WAS MEDIATED BY ENHANCED INTERACTION BETWEEN NFATC2 AND P300 AND CONSEQUENTLY INCREASED ACETYLATION OF HISTONE H4 IN CXCL14 PROMOTER REGION. ALSO, KNOCKDOWN OF CXCL14 IN DORSAL HORN SIGNIFICANTLY ATTENUATED MECHANICAL ALLODYNIA INDUCED BY PACLITAXEL. CONCLUSION: THESE RESULTS SUGGESTED THAT ENHANCED INTERACTION BETWEEN P300 AND NFATC2 MEDIATED THE EPIGENETIC UPREGULATION OF CXCL14 IN THE SPINAL DORSAL HORN, WHICH CONTRIBUTED TO THE CHEMOTHERAPEUTIC PACLITAXEL-INDUCED CHRONIC PAIN. 2020 13 3314 45 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 14 5402 39 REDUCTION OF SIRT1-MEDIATED EPIGENETIC UPREGULATION OF NAV1.7 CONTRIBUTES TO OXALIPLATIN-INDUCED NEUROPATHIC PAIN. BACKGROUND: CLINICALLY, NEUROPATHIC PAIN IS A SEVERE SIDE EFFECT OF OXALIPLATIN CHEMOTHERAPY, WHICH USUALLY LEADS TO DOSE REDUCTION OR CESSATION OF TREATMENT. DUE TO THE UNAWARENESS OF DETAILED MECHANISMS OF OXALIPLATIN-INDUCED NEUROPATHIC PAIN, IT IS DIFFICULT TO DEVELOP AN EFFECTIVE THERAPY AND LIMITS ITS CLINICAL USE. OBJECTIVES: THE AIM OF THE PRESENT STUDY WAS TO IDENTIFY THE ROLE OF SIRTUIN 1 (SIRT1) REDUCTION IN EPIGENETIC REGULATION OF THE EXPRESSION OF VOLTAGE-GATED SODIUM CHANNELS 1.7 (NAV1.7) IN THE DORSAL ROOT GANGLION (DRG) DURING OXALIPLATIN-INDUCED NEUROPATHIC PAIN. STUDY DESIGN: CONTROLLED ANIMAL STUDY. SETTING: UNIVERSITY LABORATORY. METHODS: THE VON FREY TEST WAS PERFORMED TO EVALUATE PAIN BEHAVIOR IN RATS. REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION, WESTERN BLOTTING, ELECTROPHYSIOLOGICAL RECORDING, CHROMATIN IMMUNOPRECIPITATION, AND SMALL INTERFERING RNA (SIRNA) WERE USED TO ILLUSTRATE THE MECHANISMS. RESULTS: IN THE PRESENT STUDY, WE FOUND THAT BOTH THE ACTIVITY AND EXPRESSION OF SIRT1 WERE SIGNIFICANTLY DECREASED IN RAT DRG FOLLOWING OXALIPLATIN TREATMENT. THE ACTIVATOR OF SIRT1, RESVERATROL, NOT ONLY INCREASED THE ACTIVITY AND EXPRESSION OF SIRT1, BUT ALSO ATTENUATED THE MECHANICAL ALLODYNIA FOLLOWING OXALIPLATIN TREATMENT. IN ADDITION, LOCAL KNOCKDOWN OF SIRT1 BY INTRATHECAL INJECTION OF SIRT1 SIRNA CAUSED MECHANICAL ALLODYNIA IN NAIVE RATS. BESIDES, OXALIPLATIN TREATMENT ENHANCED THE ACTION POTENTIAL FIRING FREQUENCY OF DRG NEURONS AND THE EXPRESSION OF NAV1.7 IN DRG AND ACTIVATION OF SIRT1 BY RESVERATROL REVERSED THIS EFFECT. FURTHERMORE, BLOCKING NAV1.7 BY PROTX II (A SELECTIVE NAV1.7 CHANNEL BLOCKER) REVERSED OXALIPLATIN-INDUCED MECHANICAL ALLODYNIA. IN ADDITION, HISTONE H3 HYPERACETYLATION AT THE NAV1.7 PROMOTER IN DRG OF RATS FOLLOWING OXALIPLATIN TREATMENT WAS SIGNIFICANTLY SUPPRESSED BY ACTIVATION OF SIRT1 WITH RESVERATROL. MOREOVER, BOTH THE EXPRESSION OF NAV1.7 AND HISTONE H3 ACETYLATION AT THE NAV1.7 PROMOTER WERE UPREGULATED IN THE DRG BY LOCAL KNOCKDOWN OF SIRT1 WITH SIRT1 SIRNA IN NAIVE RATS. LIMITATIONS: MORE UNDERLYING MECHANISM(S) OF SIRT1 REDUCTION AFTER OXALIPLATIN TREATMENT NEEDS TO BE EXPLORED IN FUTURE RESEARCH. CONCLUSIONS: THESE FINDINGS SUGGEST THAT REDUCTION OF SIRT1-MEDIATED EPIGENETIC UPREGULATION OF NAV1.7 IN THE DRG CONTRIBUTES TO THE DEVELOPMENT OF OXALIPLATIN-INDUCED NEUROPATHIC PAIN IN RATS. THE INTRATHECAL DRUG DELIVERY TREATMENT OF ACTIVATING SIRT1 MIGHT BE A NOVEL THERAPEUTIC OPTION FOR OXALIPLATIN-INDUCED NEUROPATHIC PAIN. 2023 15 3810 36 INTRATHECAL 5-AZACYTIDINE INHIBITS GLOBAL DNA METHYLATION AND METHYL- CPG-BINDING PROTEIN 2 EXPRESSION AND ALLEVIATES NEUROPATHIC PAIN IN RATS FOLLOWING CHRONIC CONSTRICTION INJURY. THE PATHOGENESIS OF NEUROPATHIC PAIN REMAINS LARGELY UNKNOWN. EPIGENETIC MECHANISMS MAY PLAY A MAJOR ROLE IN REGULATING EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM IN VERTEBRATES, AND METHYL- CPG-BINDING PROTEIN 2 (MECP2) IS DIRECTLY INVOLVED IN METHYLATION-MEDIATED GENE SILENCING. TO DETERMINE HOW CHANGES IN GLOBAL DNA METHYLATION AND MECP2 EXPRESSION OCCUR FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) AND HOW REPRESSION OF DNA METHYLATION AFFECTS THESE CHANGES AND ATTENUATES NEUROPATHIC PAIN, WE USED INTRATHECAL 5-AZACYTIDINE, A DNA METHYLTRANSFERASE INHIBITOR, IN CCI RATS. RATS RECEIVED 0.9% SALINE OR 5-AZACYTIDINE (10MUMOL.D(-1)) VIA SPINAL INJECTION ONCE DAILY FROM DAY 3 TO DAY 14 AFTER CCI SURGERY. GLOBAL DNA METHYLATION AND MECP2 EXPRESSION INCREASED IN THE SPINAL CORD IN CCI RATS ON DAY 14 AFTER CCI SURGERY. MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA INDUCED BY CCI WERE ATTENUATED BY INTRATHECAL 5-AZACYTIDINE FROM DAY 5 TO DAY 14 AFTER CCI SURGERY. THE INCREASES IN GLOBAL DNA METHYLATION AND MECP2 EXPRESSION IN THE SPINAL CORD IN CCI RATS WERE ALSO SIGNIFICANTLY INHIBITED BY INTRATHECAL 5-AZACYTIDINE. THESE RESULTS DEMONSTRATE THAT INCREASED GLOBAL DNA METHYLATION AND MECP2 EXPRESSION IN THE SPINAL CORD AFTER NERVE DAMAGE MAY PLAY AN IMPORTANT ROLE IN NEUROPATHIC PAIN. 5-AZACYTIDINE SHOWS POTENTIAL FOR TREATING NEUROPATHIC PAIN. 2011 16 3493 41 IDENTIFICATION OF KEY GENES, PATHWAYS, AND MIRNA/MRNA REGULATORY NETWORKS OF CUMS-INDUCED DEPRESSION IN NUCLEUS ACCUMBENS BY INTEGRATED BIOINFORMATICS ANALYSIS. INTRODUCTION: MAJOR DEPRESSIVE DISORDER (MDD) IS A RECURRENT, DEVASTATING MENTAL DISORDER, WHICH AFFECTS >350 MILLION PEOPLE WORLDWIDE, AND EXERTS SUBSTANTIAL PUBLIC HEALTH AND FINANCIAL COSTS TO SOCIETY. THUS, THERE IS A SIGNIFICANT NEED TO DISCOVER INNOVATIVE THERAPEUTICS TO TREAT DEPRESSION EFFICIENTLY. STRESS-INDUCED DYSFUNCTION IN THE SUBTYPE OF NEURONAL CELLS AND THE CHANGE OF SYNAPTIC PLASTICITY AND STRUCTURAL PLASTICITY OF NUCLEUS ACCUMBENS (NAC) ARE IMPLICATED IN DEPRESSION SYMPTOMOLOGY. HOWEVER, THE MOLECULAR AND EPIGENETIC MECHANISMS AND STRESSES TO THE NAC PATHOLOGICAL CHANGES IN DEPRESSION REMAIN ELUSIVE. MATERIALS AND METHODS: IN THIS STUDY, TREATMENT GROUP MICE WERE TREATED CONTINUALLY WITH THE CHRONIC UNPREDICTABLE MILD STRESS (CUMS) UNTIL EXPRESSION OF DEPRESSION-LIKE BEHAVIORS WERE FOUND. DEPRESSION WAS CONFIRMED WITH SUCROSE PREFERENCE, NOVELTY-SUPPRESSED FEEDING, FORCED SWIMMING, AND TAIL SUSPENSION TESTS. WE APPLIED HIGH-THROUGHPUT RNA SEQUENCING TO ASSESS MICRORNA EXPRESSION AND TRANSCRIPTIONAL PROFILES IN THE NAC TISSUE FROM DEPRESSION-LIKE BEHAVIORS MICE AND CONTROL MICE. THE REGULATORY NETWORK OF MIRNAS/MRNAS WAS CONSTRUCTED BASED ON THE HIGH-THROUGHPUT RNA SEQUENCE AND BIOINFORMATICS SOFTWARE PREDICTIONS. RESULTS: A TOTAL OF 17 MIRNAS AND 10 MRNAS WERE SIGNIFICANTLY UPREGULATED IN THE NAC OF CUMS-INDUCED MICE WITH DEPRESSION-LIKE BEHAVIORS, AND 12 MIRNAS AND 29 MRNAS WERE DOWNREGULATED. A SERIES OF BIOINFORMATICS ANALYSES SHOWED THAT THESE ALTERED MIRNAS PREDICTED TARGET MRNA AND DIFFERENTIALLY EXPRESSED MRNAS WERE SIGNIFICANTLY ENRICHED IN THE MAPK SIGNALING PATHWAY, GABAERGIC SYNAPSE, DOPAMINERGIC SYNAPSE, CYTOKINE-CYTOKINE RECEPTOR INTERACTION, AXON GUIDANCE, REGULATION OF AUTOPHAGY, AND SO ON. FURTHERMORE, DUAL LUCIFERASE REPORT ASSAY AND QRT-PCR RESULTS VALIDATED THE MIRNA/MRNA REGULATORY NETWORK. CONCLUSION: THE DETERIORATIONS OF GABAERGIC SYNAPSES, DOPAMINERGIC SYNAPSES, NEUROTRANSMITTER SYNTHESIS, AS WELL AS AUTOPHAGY-ASSOCIATED APOPTOTIC PATHWAY ARE ASSOCIATED WITH THE MOLECULAR PATHOLOGICAL MECHANISM OF CUMS-INDUCED DEPRESSION. 2019 17 3280 25 HERPES ZOSTER OPHTHALMICUS FOLLOWING ONABOTULINUMTOXINA ADMINISTRATION FOR CHRONIC MIGRAINE: A CASE REPORT AND LITERATURE REVIEW. BACKGROUND: THERE IS A GROWING BODY OF LITERATURE DOCUMENTING LOCAL HERPES ZOSTER OUTBREAK FOLLOWING PROCEDURES. THE MECHANISM UNDERLYING THESE OUTBREAKS REMAINS ELUSIVE. WE PRESENT A CASE OF ZOSTER FOLLOWING ONABOTULINUMTOXINA (BTX) FOR MIGRAINE AND A LITERATURE REVIEW. METHODS: CHART AND LITERATURE REVIEW. CASE: A 72-YEAR-OLD WOMAN WITH CHRONIC MIGRAINE RECEIVED BTX INJECTIONS FOR 3 YEARS WITHOUT INCIDENT. SHE HAD A HISTORY OF THORACIC ZOSTER WITH SUBSEQUENT POST-HERPETIC NEURALGIA. IN AUGUST 2013, 48 HOURS AFTER RECEIVING BTX INJECTIONS, SHE DEVELOPED A PAINFUL RASH IN THE RIGHT V1 DISTRIBUTION CONSISTENT WITH HERPES ZOSTER OPHTHALMICUS. ONE WEEK LATER THE RASH HAD RESOLVED WITHOUT TREATMENT. LITERATURE REVIEW: WE IDENTIFIED 65 (INCLUDING 2 FROM JUEL-JENSON) CASES OF ZOSTER REACTIVATION FOLLOWING MINOR PROCEDURES. THESE CASES TEND TO BE IN YOUNG PATIENTS WITHOUT SPECIFIC RISK FACTORS. OUTBREAKS CHARACTERISTICALLY OCCUR AT THE LEVEL OF EXPOSURE TO LOCAL TRAUMA. DISCUSSION: OUR REVIEW SUGGESTS THAT LOCAL TRAUMA, REGARDLESS OF THE NATURE OF STIMULI, MAY BE SUFFICIENT FOR ZOSTER REACTIVATION. WE HYPOTHESIZE THAT THE STRESSORS IN THESE REPORTED CASES EXERT A LOCAL EPIGENETIC INFLUENCE ON VIRAL TRANSCRIPTION, ALLOWING FOR VIRAL REACTIVATION. CONCLUSION: ZOSTER IS A POTENTIAL COMPLICATION OF BTX ADMINISTRATION FOR CHRONIC MIGRAINE IN ADULTS. PHYSICIAN AWARENESS CAN REDUCE THE SIGNIFICANT MORBIDITY ASSOCIATED WITH THIS DISEASE. 2015 18 745 39 CANNABIS ALTERS EPIGENETIC INTEGRITY AND ENDOCANNABINOID SIGNALLING IN THE HUMAN FOLLICULAR NICHE. STUDY QUESTION: DO PHYTOCANNABINOIDS (PCS) AFFECT FOLLICULAR ENDOCANNABINOID SIGNALLING AND THE EPIGENOME IN THE SURROUNDING GRANULOSA CELLS (GCS)? SUMMARY ANSWER: EXPOSURE TO PCS INCREASES THE EXPRESSION OF ENDOCANNABINOID RECEPTORS AND REDUCES DNA METHYLATION ENZYME EXPRESSION AND GLOBAL DNA METHYLATION IN NAIVE GCS. WHAT IS KNOWN ALREADY: CANNABIS PLANT DERIVATIVES, KNOWN AS PCS, ARE USED FOR MEDICINAL AND RECREATIONAL PURPOSES. THE MAIN PC, TETRAHYDROCANNABINOL (THC), IS THE THIRD MOST COMMONLY USED SUBSTANCE BY WOMEN OF CHILDBEARING AGE, HENCE KNOWLEDGE OF THE EFFECT IT HAS ON REPRODUCTION IS OF UTMOST IMPORTANCE. THC EXERTS ITS EFFECTS VIA RECEPTORS OF THE ENDOCANNABINOID SYSTEM (ECS) AND CAN INTERFERE WITH FOLLICULOGENESIS, OOCYTE DEVELOPMENT AND OVULATION. ENDOCANNABINOIDS HAVE BEEN MEASURED IN FOLLICULAR FLUID (FF) OBTAINED DURING OOCYTE RETRIEVAL AND ARE IMPLICATED IN CONTROLLING FOLLICULOGENESIS. IT HAS BEEN ESTABLISHED THAT IN THE PLACENTA, PCS DISRUPT ENDOCANNABINOID HOMEOSTASIS VIA IMPAIRMENT OF THE SYNTHETIC AND DEGRADING ENZYMES, LEADING TO A NET INCREASE OF ENDOCANNABINOID LEVELS. FINALLY, PREVIOUS STUDIES HAVE SHOWN THAT THC ALTERS METHYLATION AND HISTONE MODIFICATIONS IN SPERM, BRAIN AND BLOOD CELLS. STUDY DESIGN, SIZE, DURATION: THIS STUDY INCLUDED AN IN VIVO COHORT ASSESSMENT OF CANNABIS EXPOSURE AND ITS EFFECTS ON THE FOLLICLE AND IN VITRO ASSAYS CONDUCTED TO VALIDATE THE IN VIVO FINDINGS AND TO EXPLORE POSSIBLE MECHANISMS OF ACTION. PARTICIPANTS/MATERIALS, SETTING, METHODS: A TOTAL OF 318 FF SAMPLES, FROM 261 PATIENTS UNDERGOING IVF TREATMENT AT A PRIVATE FERTILITY CLINIC WHO CONSENTED FOR BIOBANKING BIOLOGICAL WASTE MATERIAL BETWEEN JANUARY 2018 AND JULY 2019, WERE INCLUDED IN THIS STUDY. CONCENTRATIONS OF PCS AND ENDOCANNABINOIDS WERE ASSESSED IN FF BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY (LC-MS/MS). EXPOSURE TO PCS WAS DETERMINED BASED ON THESE MEASURED LEVELS. LEVELS OF BOTH ENDOCANNABINOID RECEPTORS (CB1R, CB2R) AND THE DE NOVO DNA METHYLATING ENZYME, DNMT3B, IN GCS WERE ASSESSED BY FLOW CYTOMETRY BOTH IN VITRO AND IN VIVO AND GLOBAL DNA METHYLATION WAS ASSESSED IN VITRO BY ELISA. IN VIVO EFFECTS WERE ASSESSED BY COMPARING SAMPLES POSITIVE FOR AT LEAST ONE PC, WITH SAMPLES NEGATIVE FOR ALL MEASURED PCS. IN VITRO EFFECTS WERE DETERMINED IN NAIVE GCS, OBTAINED CONCURRENTLY WITH FF SAMPLES THAT HAD TESTED NEGATIVE FOR ALL PCS. THESE GCS WERE TREATED WITH DIFFERENT COMBINATIONS OF THE MAIN THREE PCS. MAIN RESULTS AND THE ROLE OF CHANCE: OVERALL, 17 PATIENTS (6.4%) WERE POSITIVE FOR CANNABIS CONSUMPTION. FURTHERMORE, THE PREVALENCE OF CANNABIS POSITIVITY IN THE FF INCREASED FROM 4% OF THE TESTED SAMPLES THAT WERE COLLECTED PRIOR TO NATIONAL LEGALISATION IN OCTOBER 2018 TO 12% OF THOSE COLLECTED FOLLOWING LEGALISATION. OF NOTE, 59% OF PATIENTS WHO TESTED POSITIVE FOR PCS (10 OF 17) REPORTED PREVIOUS OR ONGOING EXPOSURE TO CANNABIS UPON THEIR INITIAL INTAKE. ENDOCANNABINOID LEVELS WERE NOT AFFECTED BY THE PRESENCE OF PCS. CB2R WAS MORE PREVALENT THAN CB1R IN GCS AND ITS EXPRESSION INCREASED FOLLOWING ACUTE AND CHRONIC IN VITRO EXPOSURE TO PCS. THE EXPRESSION OF DNMT3B AND GLOBAL METHYLATION DECREASED FOLLOWING EXPOSURE, SUGGESTING THAT CANNABIS MAY AFFECT THE EPIGENOME IN THE FOLLICULAR NICHE. THE ACUTE CHANGES WERE SUSTAINED THROUGHOUT CHRONIC TREATMENT. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: OUR STUDY IS LIMITED BY LACK OF DETAILS REGARDING MODE, FREQUENCY AND TIMING OF PC CONSUMPTION. MOREOVER, WE WERE NOT ABLE TO ADEQUATELY ASSESS THE EFFECT OF PCS ON IMMEDIATE OR LONG-TERM CLINICAL OUTCOMES, DUE TO THE SMALL SAMPLE SIZE AND THE LACK OF FOLLOW UP. FUTURE, LARGE-SCALE STUDIES SHOULD FOCUS ON ASSESS THE CLINICAL IMPLICATIONS OF CANNABIS EXPOSURE, VALIDATE OUR FINDINGS, AND DETERMINE TO WHAT EXTENT CANNABIS AFFECTS THE EPIGENOME OVARIAN FOLLICLE AND THE DEVELOPING OOCYTE. WIDER IMPLICATIONS OF THE FINDINGS: TO OUR KNOWLEDGE, THIS IS THE FIRST STUDY MEASURING PCS IN FF BY LC-MS/MS. WE SHOW THAT CONSUMING CANNABIS ALTERS THE ECS IN THE DEVELOPING FOLLICLE, AND DIRECTLY AFFECTS DNMT EXPRESSION AND GLOBAL DNA METHYLATION LEVELS. CANNABIS LEGALISATION AND USE IS INCREASING WORLDWIDE, THEREFORE FURTHER UNDERSTANDING ITS ROLE IN FEMALE FERTILITY AND FOLLICULOGENESIS IS CRITICAL. STUDY FUNDING/COMPETING INTEREST(S): ALL FUNDING WAS PROVIDED BY CREATE FERTILITY CENTRE THROUGH THE REINVESTMENT OF CLINICAL EARNINGS. THE AUTHORS DECLARE NO COMPETING INTERESTS. 2021 19 325 31 ALLELE-SPECIFIC DNA METHYLATION LEVEL OF FKBP5 IS ASSOCIATED WITH POST-TRAUMATIC STRESS DISORDER. BACKGROUND: FK506-BINDING PROTEIN 5 (FKBP5) BINDS TO GLUCOCORTICOID RECEPTORS AND MODULATES GLUCOCORTICOID SENSITIVITY. THE FKBP5 GENE HAS BEEN IMPLICATED IN THE DYSREGULATION OF HUMAN STRESS RESPONSES, CONTRIBUTING TO THE RISK AND TREATMENT RESPONSE OF STRESS-RELATED DISORDERS. THE PRESENT STUDY EXAMINED WHETHER EPIGENETIC CHANGES IN FKBP5 ARE ASSOCIATED WITH CHRONIC POST-TRAUMATIC STRESS DISORDER (PTSD) STATUS IN THE CONTEXT OF FKBP5 GENETIC VARIATION (RS1360780 POLYMORPHISM) AMONG MALE VETERANS EXPOSED TO COMBAT TRAUMA. METHODS: KOREAN MALE VETERANS WHO SERVED ON ACTIVE DUTY DURING THE VIETNAM WAR WERE CATEGORIZED INTO 2 GROUPS: WITH PTSD (N = 123) AND WITHOUT PTSD (N = 116). THE GENOTYPE OF FKBP5 RS1360780 AND DNA METHYLATION LEVELS OF TWO CPG SITES AT THE FKBP5 INTRON 7 REGION WERE ASSESSED IN PERIPHERAL BLOOD. ANALYSIS OF COVARIANCE WAS PERFORMED TO EXAMINE MAIN AND INTERACTION EFFECTS OF PTSD STATUS AND FKBP5 GENOTYPE ON FKBP5 DNA METHYLATION LEVEL, WITH AGE, TRAUMA LEVELS, AND ALCOHOL USE AS COVARIATES. RESULTS: A SIGNIFICANT MAIN EFFECT OF FKBP5 RS1360780 AND PTSD AND AN INTERACTION EFFECT BETWEEN GENOTYPE AND PTSD STATUS WERE FOUND ON MEAN FKBP5 DNA METHYLATION LEVEL. THE T ALLELE OF RS1360780 WAS ASSOCIATED WITH LOWER FKBP5 METHYLATION LEVEL. IN ADDITION, THE PTSD GROUP SHOWED SIGNIFICANTLY HIGHER METHYLATION THAN DID THE NON-PTSD GROUP AMONG VETERANS CARRYING THE RISK T ALLELE (N = 96), WHILE NO GROUP DIFFERENCE WAS OBSERVED ON METHYLATION LEVELS AMONG VETERANS WITH THE CC GENOTYPE (N = 143). AMONG VETERANS CARRYING THE T ALLELE, FKBP5 METHYLATION LEVELS WERE POSITIVELY CORRELATED WITH THE SEVERITY OF PTSD SYMPTOMS. CONCLUSIONS: THE PRESENT STUDY DEMONSTRATED DIFFERENT FKBP5 METHYLATION LEVELS IN PTSD DEPENDING ON FKBP5 GENETIC VARIATION AMONG VETERANS EXPOSED TO COMBAT TRAUMA. THE PRESENT FINDING SUGGESTS THAT THE GENETIC AND EPIGENETIC MODULATION OF FKBP5 IS INVOLVED IN THE PATHOPHYSIOLOGY OF PTSD. FURTHER LONGITUDINAL RESEARCH INVOLVING PEOPLE EXPOSED TO TRAUMA IS REQUIRED TO UNDERSTAND CAUSAL RELATIONSHIPS OF FKBP5 IN THE DEVELOPMENT AND RECOVERY OF PTSD. 2019 20 6039 38 THE CHEMOKINE RECEPTOR CXCR2 SUPPORTS NOCICEPTIVE SENSITIZATION AFTER TRAUMATIC BRAIN INJURY. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. CHEMOKINE RECEPTORS PLAY AN IMPORTANT ROLE IN BOTH PAIN AND BRAIN INJURY. IN THE CURRENT WORK, WE PURSUED THE HYPOTHESIS THAT THE EPIGENETICALLY REGULATED CXC CHEMOKINE RECEPTOR 2 (CXCR2) IS A CRUCIAL MODULATOR OF NOCICEPTIVE SENSITIZATION INDUCED BY TBI. FOR THESE STUDIES, WE USED THE RAT LATERAL FLUID PERCUSSION MODEL OF TBI. HISTONE ACTYLTRANSFERASE ACTIVITY WAS BLOCKED USING ANACARDIC ACID BEGINNING IMMEDIATELY FOLLOWING INJURY, OR DELAYED FOR SEVEN DAYS PRIOR TO ADMINISTRATION. THE SELECTIVE CXCR2 ANTAGONIST SCH527123 ADMINISTERED SYSTEMICALLY OR INTRATHECALLY WAS USED TO PROBE THE ROLE OF CHEMOKINE SIGNALING ON MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE EXPRESSION OF THE CXCR2 RECEPTOR WAS ACCOMPLISHED USING REAL-TIME PCR, IMMUNOHISTOCHEMISTRY, AND WESTERN BLOTTING, WHILE EPIGENETIC REGULATION WAS ASSESSED USING CHROMATIN IMMUNOPRECIPITATION ASSAY. THE SPINAL LEVELS OF SEVERAL PAIN-RELATED MEDIATORS INCLUDING CXCL1, AN ENDOGENOUS LIGAND FOR CXCR2, AS WELL AS BRAIN-DERIVED NEUROTROPHIC FACTOR AND PRODYNORPHIN WERE MEASURED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. WE OBSERVED THAT ANACARDIC ACID POTENTLY BLOCKED AND REVERSED MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE SAME DRUG WAS ABLE TO PREVENT THE UPREGULATION OF CXCR2 AFTER TBI, BUT DID NOT AFFECT THE SPINAL EXPRESSION OF OTHER PAIN MEDIATORS. ON THE OTHER HAND, BOTH SYSTEMICALLY AND INTRATHECALLY ADMINISTERED SCH527123 REVERSED HINDPAW ALLODYNIA AFTER TBI. MOST OF THE SPINAL CXCR2 APPEARED TO BE EXPRESSED BY SPINAL CORD NEURONS. CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS DEMONSTRATED TBI-ENHANCED ASSOCIATION OF THE CXCR2 PROMOTER WITH ACETYLATED-H3K9 HISTONE PROTEIN THAT WAS ALSO REVERSIBLE USING ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS SUGGESTED THAT TBI CAUSES THE UPREGULATION OF SPINAL CXCR2 THROUGH AN EPIGENETIC MECHANISM ULTIMATELY SUPPORTING NOCICEPTIVE SENSITIZATION. THE USE OF CXCR2 ANTAGONISTS MAY, THEREFORE, BE USEFUL IN PAIN RESULTING FROM TBI. 2017