1 231 116 ADAPTIVE CARDIORESPIRATORY CHANGES TO CHRONIC CONTINUOUS AND INTERMITTENT HYPOXIA. THIS CHAPTER REVIEWS CARDIORESPIRATORY ADAPTATIONS TO CHRONIC HYPOXIA (CH) EXPERIENCED AT HIGH ALTITUDE AND CARDIORESPIRATORY PATHOLOGIES ELICITED BY CHRONIC INTERMITTENT HYPOXIA (CIH) OCCURRING WITH OBSTRUCTIVE SLEEP APNEA (OSA). SHORT-TERM CH INCREASES BREATHING (VENTILATORY ACCLIMATIZATION TO HYPOXIA) AND BLOOD PRESSURE (BP) THROUGH CAROTID BODY (CB) CHEMO REFLEX. HYPERPLASIA OF GLOMUS CELLS, ALTERATIONS IN ION CHANNELS, AND RECRUITMENT OF ADDITIONAL EXCITATORY MOLECULES ARE IMPLICATED IN THE HEIGHTENED CB CHEMO REFLEX BY CH. TRANSCRIPTIONAL ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1 AND 2) IS A MAJOR MOLECULAR MECHANISM UNDERLYING RESPIRATORY ADAPTATIONS TO SHORT-TERM CH. HIGH-ALTITUDE NATIVES EXPERIENCING LONG-TERM CH EXHIBIT BLUNTED HYPOXIC VENTILATORY RESPONSE (HVR) AND REDUCED BP DUE TO DESENSITIZATION OF CB RESPONSE TO HYPOXIA AND IMPAIRED PROCESSING OF CB SENSORY INFORMATION AT THE CENTRAL NERVOUS SYSTEM. VENTILATORY CHANGES EVOKED BY LONG-TERM CH ARE NOT READILY REVERSED AFTER RETURN TO SEA LEVEL. OSA PATIENTS AND RODENTS SUBJECTED TO CIH EXHIBIT HEIGHTENED CB CHEMO REFLEX, INCREASED HYPOXIC VENTILATORY RESPONSE, AND HYPERTENSION. INCREASED GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IS A MAJOR CELLULAR MECHANISM UNDERLYING CIH-INDUCED ENHANCED CB CHEMO REFLEX AND THE ENSUING CARDIORESPIRATORY PATHOLOGIES. ROS GENERATION BY CIH IS MEDIATED BY NONTRANSCRIPTIONAL, DISRUPTED HIF-1 AND HIF-2-DEPENDENT TRANSCRIPTIONS AS WELL AS EPIGENETIC MECHANISMS. 2022 2 2359 48 EPIGENETIC REGULATION OF REDOX STATE MEDIATES PERSISTENT CARDIORESPIRATORY ABNORMALITIES AFTER LONG-TERM INTERMITTENT HYPOXIA. KEY POINTS: THE EFFECTS OF SHORT-TERM (ST; 10 DAYS) AND LONG-TERM (LT; 30 DAYS) INTERMITTENT HYPOXIA (IH) ON BLOOD PRESSURE (BP), BREATHING AND CAROTID BODY (CB) CHEMOSENSORY REFLEX WERE EXAMINED IN ADULT RATS. ST- AND LT-IH TREATED RATS EXHIBITED HYPERTENSION, IRREGULAR BREATHING WITH APNOEA AND AUGMENTED THE CB CHEMOSENSORY REFLEX, WITH ALL THESE RESPONSES BECOMING NORMALIZED DURING RECOVERY FROM ST- BUT NOT FROM LT-IH. THE PERSISTENT CARDIORESPIRATORY RESPONSES TO LT-IH WERE ASSOCIATED WITH ELEVATED REACTIVE OXYGEN SPECIES (ROS) LEVELS IN THE CB AND ADRENAL MEDULLA, WHICH WERE A RESULT OF DNA METHYLATION-DEPENDENT SUPPRESSION OF GENES ENCODING ANTI-OXIDANT ENZYMES (AOES). TREATING RATS WITH DECITABINE EITHER DURING LT-IH OR DURING RECOVERY FROM LT-IH PREVENTED DNA METHYLATION OF AOE GENES, NORMALIZED THE EXPRESSION OF AOE GENES AND ROS LEVELS, REVERSED THE HEIGHTENED CB CHEMOSENSORY REFLEX AND HYPERTENSION, AND ALSO STABILIZED BREATHING. ABSTRACT: RODENTS EXPOSED TO CHRONIC INTERMITTENT HYPOXIA (IH), SIMULATING BLOOD O(2) SATURATION PROFILES DURING OBSTRUCTIVE SLEEP APNOEA (OSA), HAVE BEEN SHOWN TO EXHIBIT A HEIGHTENED CAROTID BODY (CB) CHEMOSENSORY REFLEX AND HYPERTENSION. CB CHEMOSENSORY REFLEX ACTIVATION ALSO RESULTS IN UNSTABLE BREATHING WITH APNOEAS. HOWEVER, THE EFFECT OF CHRONIC IH ON BREATHING IS NOT KNOWN. IN THE PRESENT STUDY, WE EXAMINED THE EFFECTS OF CHRONIC IH ON BREATHING ALONG WITH BLOOD PRESSURE (BP) AND ASSESSED WHETHER THE AUTONOMIC RESPONSES ARE NORMALIZED AFTER RECOVERY FROM CHRONIC IH. STUDIES WERE PERFORMED ON ADULT, MALE, SPRAGUE-DAWLEY RATS EXPOSED TO EITHER SHORT-TERM (ST; 10 DAYS) OR LONG-TERM (LT, 30 DAYS) IH. RATS EXPOSED TO EITHER ST- OR LT-IH EXHIBITED HYPERTENSION, IRREGULAR BREATHING WITH APNOEAS, AN AUGMENTED CB CHEMOSENSORY REFLEX AS INDICATED BY ELEVATED CB NEURAL ACTIVITY AND PLASMA CATECHOLAMINE LEVELS, AND ELEVATED REACTIVE OXYGEN SPECIES (ROS) LEVELS IN THE CB AND ADRENAL MEDULLA (AM). ALL THESE EFFECTS WERE NORMALIZED AFTER RECOVERY FROM ST-IH BUT NOT FROM LT-IH. ANALYSIS OF THE MOLECULAR MECHANISMS UNDERLYING THE PERSISTENT EFFECTS OF LT-IH REVEALED INCREASED DNA METHYLATION OF GENES ENCODING ANTI-OXIDANT ENZYMES (AOES). TREATMENT WITH DECITABINE, A DNA METHYLATION INHIBITOR, EITHER DURING LT-IH OR DURING RECOVERY FROM LT-IH, PREVENTED DNA METHYLATION, NORMALIZED THE EXPRESSION OF AOE GENES, ROS LEVELS, CB CHEMOSENSORY REFLEX AND BP, AND ALSO STABILIZED BREATHING. THESE RESULTS SUGGEST THAT PERSISTENT CARDIORESPIRATORY ABNORMALITIES CAUSED BY LT-IH ARE MEDIATED BY EPIGENETIC RE-PROGRAMMING OF THE REDOX STATE IN THE CB CHEMOSENSORY REFLEX PATHWAY. 2017 3 803 27 CENTRAL CONTROL OF VISCERAL PAIN AND URINARY TRACT FUNCTION. AFFERENT INPUT FROM ADELTA AND C-FIBRES INNERVATING THE URINARY BLADDER ARE PROCESSED DIFFERENTLY BY THE BRAIN, AND HAVE DIFFERENT ROLES IN SIGNALING BLADDER SENSATION. ADELTA FIBRES THAT SIGNAL BLADDER FILLING ACTIVATE A SPINO-BULBO-SPINAL LOOP, WHICH RELAYS IN THE MIDBRAIN PERIAQUEDUCTAL GREY (PAG) AND PONTINE MICTURITION CENTRE (PMC). THE EXCITABILITY OF THIS CIRCUITRY IS REGULATED BY TONIC GABAERGIC INHIBITORY PROCESSES. IN HUMANS AND SOCIALISED ANIMALS MICTURITION IS NORMALLY UNDER VOLITIONAL CONTROL AND INFLUENCED BY A HOST OF PSYCHOSOCIAL FACTORS. HIGHER NERVOUS DECISION-MAKING IN A SOCIAL CONTEXT TO 'GO NOW' OR 'DO NOT GO' PROBABLY RESIDES IN FRONTAL CORTICAL AREAS, WHICH ACT AS A CENTRAL CONTROL SWITCH FOR MICTURITION. EXPOSURE TO PSYCHOSOCIAL STRESS CAN HAVE PROFOUNDLY DISRUPTIVE INFLUENCE ON THE PROCESS AND LEAD TO MALADAPTIVE CHANGES IN THE BLADDER. DURING SLEEPING THE VOIDING REFLEX THRESHOLD APPEARS TO BE RESET TO A HIGHER LEVEL TO PROMOTE URINARY CONTINENCE. UNDER PHYSIOLOGICAL CONDITIONS C-FIBRE BLADDER AFFERENTS ARE NORMALLY SILENT BUT ARE ACTIVATED IN INFLAMMATORY BLADDER STATES AND BY INTENSE DISTENDING PRESSURE. FOLLOWING PROLONGED STIMULATION VISCERAL NOCICEPTORS SENSITISE, LEADING TO A LOWERED THRESHOLD AND HEIGHTENED SENSITIVITY. IN ADDITION, SENSITIZATION MAY OCCUR WITHIN THE CENTRAL PAIN PROCESSING CIRCUITRY, WHICH OUTLASTS THE ORIGINAL NOCICEPTIVE INSULT. VISCERAL NOCICEPTION MAY ALSO BE INFLUENCED BY GENETIC AND ENVIRONMENTAL INFLUENCES. A PERIOD OF CHRONIC STRESS CAN PRODUCE INCREASED SENSITIVITY TO VISCERAL PAIN THAT LASTS FOR MONTHS. ADVERSE EARLY LIFE EVENTS CAN PRODUCE EVEN LONGER LASTING EPIGENETIC CHANGES, WHICH INCREASE THE INDIVIDUAL'S SUSCEPTIBILITY TO DEVELOPING VISCERAL PAIN STATES IN ADULTHOOD. 2016 4 3346 25 HISTONE DEACETYLASES MEDIATE GABA(A) RECEPTOR EXPRESSION, PHYSIOLOGY, AND BEHAVIORAL MALADAPTATIONS IN RAT MODELS OF ALCOHOL DEPENDENCE. ALCOHOL USE DISORDERS ARE CHRONIC DEBILITATING DISEASES CHARACTERIZED BY SEVERE WITHDRAWAL SYMPTOMS THAT CONTRIBUTE TO MORBIDITY AND RELAPSE. GABA(A) RECEPTOR (GABA(A)R) ADAPTATIONS HAVE LONG BEEN IMPLICATED IN THE CHRONIC EFFECTS OF ALCOHOL AND CONTRIBUTE TO MANY WITHDRAWAL SYMPTOMS ASSOCIATED WITH ALCOHOL DEPENDENCE. IN RODENTS, GABA(A)R HYPOFUNCTION RESULTS FROM DECREASES IN GABRA1 EXPRESSION, ALTHOUGH THE UNDERLYING MECHANISM CONTROLLING GABRA1 EXPRESSION AFTER CHRONIC ETHANOL EXPOSURE IS STILL UNKNOWN. WE FOUND THAT CHRONIC ETHANOL EXPOSURE USING EITHER ETHANOL GAVAGE OR TWO-BOTTLE CHOICE VOLUNTARY ACCESS PARADIGMS DECREASED GABRA1 EXPRESSION AND INCREASED HDAC2 AND HDAC3 EXPRESSION. ADMINISTRATION OF THE HDAC INHIBITOR TRICHOSTATIN A (TSA) AFTER CHRONIC ETHANOL EXPOSURE PREVENTS THE DECREASE IN GABRA1 EXPRESSION AND FUNCTION AS WELL AS THE INCREASE IN HDAC2 AND HDAC3 EXPRESSION IN BOTH THE CORTEX AND THE MEDIAL PREFRONTAL CORTEX (MPFC). CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL, BUT NOT ACUTE ETHANOL EXPOSURE OR ACUTE WITHDRAWAL, CAUSE A SELECTIVE UPREGULATION OF HDAC2 AND HDAC3 ASSOCIATED WITH THE GABRA1 PROMOTER THAT ACCOMPANIES A DECREASE IN H3 ACETYLATION OF THE GABRA1 PROMOTER AND THE REDUCTION IN GABA(A)R ALPHA1 SUBUNIT EXPRESSION. TSA ADMINISTRATION PREVENTED EACH OF THESE MOLECULAR EVENTS AS WELL AS BEHAVIORAL MANIFESTATIONS OF ETHANOL DEPENDENCE, INCLUDING TOLERANCE TO ZOLPIDEM-INDUCED LOSS OF RIGHTING REFLEX, REDUCED OPEN-ARM TIME IN THE ELEVATED PLUS MAZE, REDUCED CENTER-TIME AND LOCOMOTOR ACTIVITY IN THE OPEN-FIELD ASSAY, AND TSA REDUCED VOLUNTARY ETHANOL CONSUMPTION. THE RESULTS SHOW HOW CHRONIC ETHANOL EXPOSURE REGULATES THE HIGHLY PROMINENT GABA(A)R ALPHA1 SUBUNIT BY AN EPIGENETIC MECHANISM THAT REPRESENTS A POTENTIAL TREATMENT MODALITY FOR ALCOHOL DEPENDENCE. 2018 5 1088 18 COCAINE DIRECTLY IMPAIRS MEMORY EXTINCTION AND ALTERS BRAIN DNA METHYLATION DYNAMICS IN HONEY BEES. DRUG ADDICTION IS A CHRONIC RELAPSING BEHAVIORAL DISORDER. THE HIGH RELAPSE RATE HAS OFTEN BEEN ATTRIBUTED TO THE PERSEVERANCE OF DRUG-ASSOCIATED MEMORIES DUE TO HIGH INCENTIVE SALIENCE OF STIMULI LEARNT UNDER THE INFLUENCE OF DRUGS. DRUG ADDICTION HAS ALSO BEEN INTERPRETED AS A MEMORY DISORDER SINCE DRUG ASSOCIATED MEMORIES ARE UNUSUALLY ENDURING AND SOME DRUGS, SUCH AS COCAINE, INTERFERE WITH NEUROEPIGENETIC MACHINERY KNOWN TO BE INVOLVED IN MEMORY PROCESSING. HERE WE USED THE HONEY BEE (AN ESTABLISHED INVERTEBRATE MODEL FOR EPIGENOMICS AND BEHAVIORAL STUDIES) TO EXAMINE WHETHER OR NOT COCAINE AFFECTS MEMORY PROCESSING INDEPENDENTLY OF ITS EFFECT ON INCENTIVE SALIENCE. USING THE PROBOSCIS EXTENSION REFLEX TRAINING PARADIGM WE FOUND THAT COCAINE STRONGLY IMPAIRS CONSOLIDATION OF EXTINCTION MEMORY. BASED ON CORRELATION BETWEEN THE OBSERVED EFFECT OF COCAINE ON LEARNING AND EXPRESSION OF EPIGENETIC PROCESSES, WE PROPOSE THAT COCAINE INTERFERES WITH MEMORY PROCESSING INDEPENDENTLY OF INCENTIVE SALIENCE BY DIRECTLY ALTERING DNA METHYLATION DYNAMICS. OUR FINDINGS EMPHASIZE THE IMPACT OF COCAINE ON MEMORY SYSTEMS, WITH RELEVANCE FOR UNDERSTANDING HOW COCAINE CAN HAVE SUCH AN ENDURING IMPACT ON BEHAVIOR. 2018 6 4138 34 MECHANISMS OF MICROGLIAL ACTIVATION IN MODELS OF INFLAMMATION AND HYPOXIA: IMPLICATIONS FOR CHRONIC INTERMITTENT HYPOXIA. CHRONIC INTERMITTENT HYPOXIA (CIH) IS A HALLMARK OF SLEEP APNOEA, A CONDITION ASSOCIATED WITH DIVERSE CLINICAL DISORDERS. CIH AND SLEEP APNOEA ARE CHARACTERIZED BY INCREASED REACTIVE OXYGEN SPECIES FORMATION, PERIPHERAL AND CNS INFLAMMATION, NEURONAL DEATH AND NEUROCOGNITIVE DEFICITS. FEW STUDIES HAVE EXAMINED THE ROLE OF MICROGLIA, THE RESIDENT CNS IMMUNE CELLS, IN MODELS OF CIH. THUS, LITTLE IS KNOWN CONCERNING THEIR DIRECT CONTRIBUTIONS TO NEUROPATHOLOGY OR THE CELLULAR MECHANISMS REGULATING THEIR ACTIVITIES DURING OR FOLLOWING PATHOLOGICAL CIH. IN THIS REVIEW, WE IDENTIFY GAPS IN KNOWLEDGE REGARDING CIH-INDUCED MICROGLIAL ACTIVATION, AND PROPOSE MECHANISMS BASED ON DATA FROM RELATED MODELS OF HYPOXIA AND/OR HYPOXIA-REOXYGENATION. CIH MAY DIRECTLY AFFECT MICROGLIA, OR MAY HAVE INDIRECT EFFECTS VIA THE PERIPHERY OR OTHER CNS CELLS. PERIPHERAL INFLAMMATION MAY INDIRECTLY ACTIVATE MICROGLIA VIA ENTRY OF PRO-INFLAMMATORY MOLECULES INTO THE CNS, AND/OR ACTIVATION OF VAGAL AFFERENTS THAT TRIGGER CNS INFLAMMATION. CIH-INDUCED RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS FROM INJURED CNS CELLS MAY ALSO ACTIVATE MICROGLIA VIA INTERACTIONS WITH PATTERN RECOGNITION RECEPTORS EXPRESSED ON MICROGLIA. FOR EXAMPLE, TOLL-LIKE RECEPTORS ACTIVATE MITOGEN-ACTIVATED PROTEIN KINASE/TRANSCRIPTION FACTOR PATHWAYS REQUIRED FOR MICROGLIAL INFLAMMATORY GENE EXPRESSION. ALTHOUGH EPIGENETIC EFFECTS FROM CIH HAVE NOT YET BEEN STUDIED IN MICROGLIA, POTENTIAL EPIGENETIC MECHANISMS IN MICROGLIAL REGULATION ARE DISCUSSED, INCLUDING MICRORNAS, HISTONE MODIFICATIONS AND DNA METHYLATION. EPIGENETIC EFFECTS CAN OCCUR DURING CIH, OR LONG AFTER IT HAS ENDED. A BETTER UNDERSTANDING OF CIH EFFECTS ON MICROGLIAL ACTIVITIES MAY BE IMPORTANT TO REVERSE CIH-INDUCED NEUROPATHOLOGY IN PATIENTS WITH SLEEP DISORDERED BREATHING. 2016 7 1177 34 CONTROL OF BREATHING AND THE CIRCULATION IN HIGH-ALTITUDE MAMMALS AND BIRDS. HYPOXIA IS AN UNREMITTING STRESSOR AT HIGH ALTITUDES THAT PLACES A PREMIUM ON OXYGEN TRANSPORT BY THE RESPIRATORY AND CARDIOVASCULAR SYSTEMS. PHENOTYPIC PLASTICITY AND GENOTYPIC ADAPTATION AT VARIOUS STEPS IN THE O2 CASCADE COULD HELP OFFSET THE EFFECTS OF HYPOXIA ON CELLULAR O2 SUPPLY IN HIGH-ALTITUDE NATIVES. IN THIS REVIEW, WE WILL DISCUSS THE UNIQUE MECHANISMS BY WHICH VENTILATION, CARDIAC OUTPUT, AND BLOOD FLOW ARE CONTROLLED IN HIGH-ALTITUDE MAMMALS AND BIRDS. ACCLIMATIZATION TO HIGH ALTITUDES LEADS TO SOME CHANGES IN RESPIRATORY AND CARDIOVASCULAR CONTROL THAT INCREASE O2 TRANSPORT IN HYPOXIA (E.G., VENTILATORY ACCLIMATIZATION TO HYPOXIA). HOWEVER, ACCLIMATIZATION OR DEVELOPMENT IN HYPOXIA CAN ALSO MODIFY CARDIORESPIRATORY CONTROL IN WAYS THAT ARE MALADAPTIVE FOR O2 TRANSPORT. HYPOXIA RESPONSES THAT AROSE AS SHORT-TERM SOLUTIONS TO O2 DEPRIVATION (E.G., PERIPHERAL VASOCONSTRICTION) OR REGIONAL VARIATION IN O2 LEVELS IN THE LUNGS (I.E., HYPOXIC PULMONARY VASOCONSTRICTION) ARE DETRIMENTAL AT IN CHRONIC HIGH-ALTITUDE HYPOXIA. EVOLVED CHANGES IN CARDIORESPIRATORY CONTROL HAVE ARISEN IN MANY HIGH-ALTITUDE TAXA, INCLUDING INCREASES IN EFFECTIVE VENTILATION, ATTENUATION OF HYPOXIC PULMONARY VASOCONSTRICTION, AND CHANGES IN CATECHOLAMINE SENSITIVITY OF THE HEART AND SYSTEMIC VASCULATURE. PARALLEL EVOLUTION OF SOME OF THESE CHANGES IN INDEPENDENT HIGHLAND LINEAGES SUPPORTS THEIR ADAPTIVE SIGNIFICANCE. MUCH LESS IS KNOWN ABOUT THE GENOMIC BASES AND POTENTIAL INTERACTIVE EFFECTS OF ADAPTATION, ACCLIMATIZATION, DEVELOPMENTAL PLASTICITY, AND TRANS-GENERATIONAL EPIGENETIC TRANSFER ON CARDIORESPIRATORY CONTROL. FUTURE WORK TO UNDERSTAND THESE VARIOUS INFLUENCES ON BREATHING AND CIRCULATION IN HIGH-ALTITUDE NATIVES WILL HELP ELUCIDATE HOW COMPLEX PHYSIOLOGICAL SYSTEMS CAN BE PUSHED TO THEIR LIMITS TO MAINTAIN CELLULAR FUNCTION IN HYPOXIA. 2015 8 4643 17 NEUROPATHIC PAIN AS A TRIGGER FOR HISTONE MODIFICATIONS IN LIMBIC CIRCUITRY. CHRONIC PAIN INVOLVES BOTH CENTRAL AND PERIPHERAL NEURONAL PLASTICITY THAT ENCOMPASSES CHANGES IN THE BRAIN, SPINAL CORD, AND PERIPHERAL NOCICEPTORS. WITHIN THE FOREBRAIN, MESOCORTICOLIMBIC REGIONS ASSOCIATED WITH EMOTIONAL REGULATION HAVE RECENTLY BEEN SHOWN TO EXHIBIT LASTING GENE EXPRESSION CHANGES IN MODELS OF CHRONIC PAIN. TO BETTER UNDERSTAND HOW SUCH ENDURING TRANSCRIPTIONAL CHANGES MIGHT BE REGULATED WITHIN BRAIN STRUCTURES ASSOCIATED WITH PROCESSING OF PAIN OR AFFECT, WE EXAMINED EPIGENETIC MODIFICATIONS INVOLVED WITH ACTIVE OR PERMISSIVE TRANSCRIPTIONAL STATES (HISTONE H3 LYSINE 4 MONO AND TRIMETHYLATION, AND HISTONE H3 LYSINE 27 ACETYLATION) IN PERIAQUEDUCTAL GRAY (PAG), LATERAL HYPOTHALAMUS (LH), NUCLEUS ACCUMBENS (NAC), AND VENTRAL TEGMENTAL AREA (VTA) 5 WEEKS AFTER SCIATIC NERVE INJURY IN MICE TO MODEL CHRONIC PAIN. FOR BOTH MALE AND FEMALE MICE IN CHRONIC PAIN, WE OBSERVED AN OVERALL TREND FOR A REDUCTION OF THESE EPIGENETIC MARKERS IN PERIAQUEDUCTAL GRAY, LH, AND NAC, BUT NOT VTA. MOREOVER, WE DISCOVERED THAT SOME EPIGENETIC MODIFICATIONS EXHIBITED CHANGES ASSOCIATED WITH PAIN HISTORY, WHILE OTHERS WERE ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY. WHEN TAKEN TOGETHER, THESE RESULTS SUGGEST THAT NERVE INJURY LEADS TO CHRONIC CHROMATIN-MEDIATED SUPPRESSION OF TRANSCRIPTION IN KEY LIMBIC BRAIN STRUCTURES AND CIRCUITS, WHICH MAY UNDERLIE ENDURING CHANGES IN PAIN PROCESSING AND SENSITIVITY WITHIN THESE SYSTEMS. 2023 9 6352 19 THE ROLE OF GABA(A) RECEPTORS IN THE DEVELOPMENT OF ALCOHOLISM. ALCOHOLISM IS A COMMON, HERITABLE, CHRONIC RELAPSING DISORDER. GABA(A) RECEPTORS UNDERGO ALLOSTERIC MODULATION BY ETHANOL, ANESTHETICS, BENZODIAZEPINES AND NEUROSTEROIDS AND HAVE BEEN IMPLICATED IN THE ACUTE AS WELL AS THE CHRONIC EFFECTS OF ETHANOL INCLUDING TOLERANCE, DEPENDENCE AND WITHDRAWAL. MEDICATIONS TARGETING GABA(A) RECEPTORS AMELIORATE THE SYMPTOMS OF ACUTE WITHDRAWAL. ETHANOL INDUCES PLASTICITY IN GABA(A) RECEPTORS: TOLERANCE IS ASSOCIATED WITH GENERALLY DECREASED GABA(A) RECEPTOR ACTIVATION AND DIFFERENTIALLY ALTERED SUBUNIT EXPRESSION. THE DOPAMINE (DA) MESOLIMBIC REWARD PATHWAY ORIGINATING IN THE VENTRAL TEGMENTAL AREA (VTA), AND INTERACTING STRESS CIRCUITRY PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT OF ADDICTION. VTA GABAERGIC INTERNEURONS ARE THE PRIMARY INHIBITORY REGULATORS OF DA NEURONS AND A SUBSET OF VTA GABA(A) RECEPTORS MAY BE IMPLICATED IN THE SWITCH FROM HEAVY DRINKING TO DEPENDENCE. GABA(A) RECEPTORS MODULATE ANXIETY AND RESPONSE TO STRESS; IMPORTANT ELEMENTS OF SUSTAINED DRINKING AND RELAPSE. THE GABA(A) RECEPTOR SUBUNIT GENES CLUSTERED ON CHROMOSOME 4 ARE HIGHLY EXPRESSED IN THE REWARD PATHWAY. SEVERAL RECENT STUDIES HAVE PROVIDED STRONG EVIDENCE THAT ONE OF THESE GENES, GABRA2, IS IMPLICATED IN ALCOHOLISM IN HUMANS. THE INFLUENCE OF THE INTERACTION BETWEEN ETHANOL AND GABA(A) RECEPTORS IN THE REWARD PATHWAY ON THE DEVELOPMENT OF ALCOHOLISM TOGETHER WITH GENETIC AND EPIGENETIC VULNERABILITIES WILL BE EXPLORED IN THIS REVIEW. 2008 10 2358 23 EPIGENETIC REGULATION OF RAC1 INDUCES SYNAPTIC REMODELING IN STRESS DISORDERS AND DEPRESSION. DEPRESSION INDUCES STRUCTURAL AND FUNCTIONAL SYNAPTIC PLASTICITY IN BRAIN REWARD CIRCUITS, ALTHOUGH THE MECHANISMS PROMOTING THESE CHANGES AND THEIR RELEVANCE TO BEHAVIORAL OUTCOMES ARE UNKNOWN. TRANSCRIPTIONAL PROFILING OF THE NUCLEUS ACCUMBENS (NAC) FOR RHO GTPASE-RELATED GENES, WHICH ARE KNOWN REGULATORS OF SYNAPTIC STRUCTURE, REVEALED A SUSTAINED REDUCTION IN RAS-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1 (RAC1) EXPRESSION AFTER CHRONIC SOCIAL DEFEAT STRESS. THIS WAS ASSOCIATED WITH A REPRESSIVE CHROMATIN STATE SURROUNDING THE PROXIMAL PROMOTER OF RAC1. INHIBITION OF CLASS 1 HISTONE DEACETYLASES (HDACS) WITH MS-275 RESCUED BOTH THE DECREASE IN RAC1 TRANSCRIPTION AFTER SOCIAL DEFEAT STRESS AND DEPRESSION-RELATED BEHAVIOR, SUCH AS SOCIAL AVOIDANCE. WE FOUND A SIMILAR REPRESSIVE CHROMATIN STATE SURROUNDING THE RAC1 PROMOTER IN THE NAC OF SUBJECTS WITH DEPRESSION, WHICH CORRESPONDED WITH REDUCED RAC1 TRANSCRIPTION. VIRAL-MEDIATED REDUCTION OF RAC1 EXPRESSION OR INHIBITION OF RAC1 ACTIVITY IN THE NAC INCREASES SOCIAL DEFEAT-INDUCED SOCIAL AVOIDANCE AND ANHEDONIA IN MICE. CHRONIC SOCIAL DEFEAT STRESS INDUCES THE FORMATION OF STUBBY EXCITATORY SPINES THROUGH A RAC1-DEPENDENT MECHANISM INVOLVING THE REDISTRIBUTION OF SYNAPTIC COFILIN, AN ACTIN-SEVERING PROTEIN DOWNSTREAM OF RAC1. OVEREXPRESSION OF CONSTITUTIVELY ACTIVE RAC1 IN THE NAC OF MICE AFTER CHRONIC SOCIAL DEFEAT STRESS REVERSES DEPRESSION-RELATED BEHAVIORS AND PRUNES STUBBY SPINES. TAKEN TOGETHER, OUR DATA IDENTIFY EPIGENETIC REGULATION OF RAC1 IN THE NAC AS A DISEASE MECHANISM IN DEPRESSION AND REVEAL A FUNCTIONAL ROLE FOR RAC1 IN RODENTS IN REGULATING STRESS-RELATED BEHAVIORS. 2013 11 69 22 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 12 1163 23 CONTRIBUTION OF AMYGDALA HISTONE ACETYLATION IN EARLY LIFE STRESS-INDUCED VISCERAL HYPERSENSITIVITY AND EMOTIONAL COMORBIDITY. PATIENTS WITH IRRITABLE BOWEL SYNDROME (IBS) EXPERIENCE NOT ONLY ENHANCED VISCERAL PAIN BUT ALSO EMOTIONAL COMORBIDITIES, SUCH AS ANXIETY AND DEPRESSION. EARLY LIFE STRESS (ELS) IS A HIGH-RISK FOR THE DEVELOPMENT OF IBS. LITERATURES HAVE REPORTED AN IMPORTANT EPIGENETIC MODULATION IN SUSTAINING EXTRINSIC PHENOTYPES. THE AMYGDALA IS CLOSELY RELATED TO THE REGULATION OF VISCERAL FUNCTIONS AND EMOTIONAL EXPERIENCES. IN THIS STUDY, WE HYPOTHESIZED THAT ELS-INDUCED REPROGRAMMING INAPPROPRIATE ADAPTATION OF HISTONE ACETYLATION MODIFICATION IN THE AMYGDALA MAY RESULT IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS. TO TEST THIS HYPOTHESIS, THE MODEL OF ELS RATS WAS ESTABLISHED BY NEONATAL COLORECTAL DILATATION (CRD). VISCERAL HYPERSENSITIVITY WAS ASSESSED BASED ON THE ELECTROMYOGRAPHY RESPONSE OF THE ABDOMINAL EXTERNAL OBLIQUE MUSCLE TO CRD. EMOTIONAL COMORBIDITIES WERE EXAMINED USING THE ELEVATED PLUS MAZE TEST, OPEN FIELD TEST, AND SUCROSE PREFERENCE TEST. TRICHOSTATIN A (TSA) AND C646 WERE MICROINJECTED INTO THE CENTRAL AMYGDALA (CEA) INDIVIDUALLY TO INVESTIGATE THE EFFECTS OF DIFFERENT LEVELS OF HISTONE ACETYLATION MODIFICATION ON VISCERAL HYPERSENSITIVITY AND EMOTION. WE FOUND NEONATAL CRD RESULTED IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS AFTER ADULTHOOD. INHIBITING HISTONE DEACETYLASES (HDACS) IN THE CEA BY TSA ENHANCED VISCERAL SENSITIVITY BUT DID NOT AFFECT ANXIETY-LIKE BEHAVIORS, WHEREAS INHIBITING HAT BY C646 ATTENUATED VISCERAL HYPERSENSITIVITY IN ELS RATS. INTERESTINGLY, CEA TREATMENT WITH TSA INDUCED VISCERAL SENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN THE CONTROL RATS. WESTERN BLOT SHOWED THAT THE EXPRESSIONS OF ACETYLATED 9 RESIDUE OF HISTONE 3 (H3K9) AND PROTEIN KINASE C ZETA TYPE (PKMZETA) WERE HIGHER IN THE ELS RATS COMPARED TO THOSE OF THE CONTROLS. THE ADMINISTRATION OF THE PKMZETA INHIBITOR ZIP INTO THE CEA ATTENUATED VISCERAL HYPERSENSITIVITY OF ELS RATS. FURTHERMORE, THE EXPRESSION OF AMYGDALA PKMZETA WAS ENHANCED BY TSA TREATMENT IN CONTROL RATS. FINALLY, WESTERN BLOT AND IMMUNOFLUORESCENCE RESULTS INDICATED THE DECREASE OF HDAC1 AND HDAC2 EXPRESSIONS, BUT NOT HDAC3 EXPRESSION, CONTRIBUTED TO THE ENHANCEMENT OF HISTONE ACETYLATION IN ELS RATS. OUR RESULTS SUPPORT OUR HYPOTHESIS THAT AMYGDALA-ENHANCED HISTONE ACETYLATION INDUCED BY STRESS IN EARLY LIFE RESULTS IN VISCERAL HYPERSENSITIVITY AND ANXIETY-LIKE BEHAVIORS IN ELS RATS, AND REVERSING THE ABNORMAL EPIGENETIC MECHANISMS MAY BE CRUCIAL TO RELIEVE CHRONIC SYMPTOMS IN ELS RATS. 2022 13 3977 19 LONG-TERM EFFECT OF POST-TRAUMATIC STRESS IN ADOLESCENCE ON DENDRITE DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN MALE RAT HIPPOCAMPUS AND PREFRONTAL CORTEX. EXPOSURE TO A HARSH ENVIRONMENT IN EARLY LIFE INCREASES IN THE RISK OF POST-TRAUMATIC STRESS DISORDER (PTSD) OF AN INDIVIDUAL. BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) PLAYS AN IMPORTANT ROLE IN NEURODEVELOPMENT IN DEVELOPMENTAL STAGES. BOTH CHRONIC AND TRAUMATIC STRESSES INDUCE A DECREASE IN THE LEVEL OF BDNF AND REDUCE NEURAL PLASTICITY, WHICH IS LINKED TO THE PATHOGENESIS OF PTSD. ALSO, STUDIES HAVE SHOWN THAT STRESS ALTERS THE EPIGENETIC MARKER H3K9ME2, WHICH CAN BIND TO THE PROMOTER REGION OF THE BDNF GENE AND REDUCE BDNF PROTEIN LEVEL. HOWEVER, THE LONG-TERM EFFECTS OF TRAUMATIC STRESS DURING ADOLESCENCE ON H3K9ME2, BDNF EXPRESSION AND DENDRITE DEVELOPMENT ARE NOT WELL-KNOWN. THE PRESENT STUDY ESTABLISHED A MODEL OF PTSD IN ADOLESCENT RATS USING AN INESCAPABLE FOOT SHOCK (IFS) PROCEDURE. ANXIETY-LIKE BEHAVIORS, SOCIAL INTERACTION BEHAVIOR AND MEMORY FUNCTION WERE ASSESSED BY THE OPEN FIELD TEST, ELEVATED PLUS MAZE TEST, THREE-CHAMBER SOCIABILITY TEST AND MORRIS WATER MAZE TEST. IN ADDITION, NEURONAL DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN HIPPOCAMPUS (HIP) AND PREFRONTAL CORTEX (PFC) WERE EVALUATED BY GOLGI STAINING, WESTERN BLOTTING, QRT-PCR ANALYSIS AND CHIP-QPCR ANALYSIS. ADDITIONALLY, THE UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (EHMT2) WAS USED FOR INTERVENTION. THE RESULTS SHOWED THAT THE IFS PROCEDURE INDUCED THE PTSD-LIKE BEHAVIORS IN RATS, RESULTED IN FEWER DENDRITE BRANCHES AND SHORTER DENDRITE LENGTH IN CA1 OF HIP AND PFC, INCREASED H3K9ME2 LEVEL AND DECREASED BDNF EXPRESSION IN HIP AND PFC. ALSO, ALTHOUGH ALL THE CHANGES CAN PERSIST TO ADULTHOOD, UNC0642 ADMINISTRATION RELIEVED MOST OF ALTERATIONS. OUR STUDY SUGGESTS THAT TRAUMATIC STRESS IN ADOLESCENCE LEADS TO IMMEDIATE AND LONG-TERM MENTAL DISORDERS, NEURONAL MORPHOLOGICAL CHANGES, LOWER BDNF LEVEL AND INCREASED H3K9ME2 LEVEL IN THE HIP AND PFC, INDICATING THAT H3K9ME2/BDNF DYSFUNCTION PLAYS A KEY ROLE IN PATHOGENESIS OF PTSD. 2020 14 4878 22 OVEREXPRESSION OF THE HISTONE DIMETHYLTRANSFERASE G9A IN NUCLEUS ACCUMBENS SHELL INCREASES COCAINE SELF-ADMINISTRATION, STRESS-INDUCED REINSTATEMENT, AND ANXIETY. REPEATED EXPOSURE TO COCAINE INDUCES LASTING EPIGENETIC CHANGES IN NEURONS THAT PROMOTE THE DEVELOPMENT AND PERSISTENCE OF ADDICTION. ONE EPIGENETIC ALTERATION INVOLVES REDUCTIONS IN LEVELS OF THE HISTONE DIMETHYLTRANSFERASE G9A IN NUCLEUS ACCUMBENS (NAC) AFTER CHRONIC COCAINE ADMINISTRATION. THIS REDUCTION IN G9A MAY ENHANCE COCAINE REWARD BECAUSE OVEREXPRESSING G9A IN THE NAC DECREASES COCAINE-CONDITIONED PLACE PREFERENCE. THEREFORE, WE HYPOTHESIZED THAT HSV-MEDIATED G9A OVEREXPRESSION IN THE NAC SHELL (NACSH) WOULD ATTENUATE COCAINE SELF-ADMINISTRATION (SA) AND COCAINE-SEEKING BEHAVIOR. INSTEAD, WE FOUND THAT G9A OVEREXPRESSION, AND THE RESULTING INCREASE IN HISTONE 3 LYSINE 9 DIMETHYLATION (H3K9ME2), INCREASES SENSITIVITY TO COCAINE REINFORCEMENT AND ENHANCES MOTIVATION FOR COCAINE IN SELF-ADMINISTERING MALE RATS. MOREOVER, WHEN G9A OVEREXPRESSION IS LIMITED TO THE INITIAL 15 D OF COCAINE SA TRAINING, IT PRODUCES AN ENDURING POSTEXPRESSION ENHANCEMENT IN COCAINE SA AND PROLONGED (OVER 5 WEEKS) INCREASES IN REINSTATEMENT OF COCAINE SEEKING INDUCED BY FOOT-SHOCK STRESS, BUT IN THE ABSENCE OF CONTINUED GLOBAL ELEVATIONS IN H3K9ME2. THE INCREASE IN STRESS-INDUCED REINSTATEMENT IS PARALLELED BY HEIGHTENED ANXIETY MEASURES, SUGGESTING THAT COUNTERING THE COCAINE-INDUCED DECREASES IN ENDOGENOUS G9A WITH ECTOPIC G9A OVEREXPRESSION LEADS TO LASTING ANXIOGENIC EFFECTS. FINALLY, WE FOUND AN ENDURING REDUCTION IN PHOSPHORYLATED CAMP-RESPONSE ELEMENT BINDING PROTEIN LEVELS IN THE NACSH THAT COULD ACCOUNT FOR THE INCREASED ANXIETY. THESE DATA DEMONSTRATE A NOVEL ROLE FOR G9A IN PROMOTING COMORBID COCAINE ADDICTION AND ANXIETY AND SUGGEST THAT INCREASED EPIGENETIC REPRESSION OF TRANSCRIPTION THROUGH H3K9 DURING COCAINE USE CAN HAVE LONG-LASTING AND UNEXPECTED NEGATIVE CONSEQUENCES ON BEHAVIOR.SIGNIFICANCE STATEMENT COCAINE ADDICTION IS A NEUROPSYCHIATRIC DISORDER THAT IS DETRIMENTAL TO SOCIETY AND CURRENTLY HAS NO EFFECTIVE TREATMENTS. THE DIFFICULTY IN TREATING DRUG ADDICTION IS COMPOUNDED BY THE HIGH COMORBIDITY WITH OTHER PSYCHIATRIC ILLNESSES, INCLUDING ANXIETY DISORDERS. HERE, WE DEMONSTRATE THAT G9A, AN EPIGENETIC REPRESSOR OF GENE EXPRESSION, ACTING IN THE NUCLEUS ACCUMBENS, A BRAIN REWARD REGION, IS CAPABLE OF INCREASING BOTH ADDICTION- AND ANXIETY-LIKE BEHAVIORS IN RATS. THESE FINDINGS ARE INTRIGUING BECAUSE REPEATED COCAINE EXPOSURE DECREASES G9A IN THIS REGION AND THEREBY ENHANCES EXPRESSION OF CERTAIN ADDICTION-PROMOTING GENES. HOWEVER, OUR RESULTS SUGGEST THAT COUNTERING THIS COCAINE-INDUCED DECREASE IN G9A ACTIVITY ACTUALLY EXACERBATES ADDICTION AND SENSITIVITY TO RELAPSE UNDER STRESSFUL SITUATIONS. 2018 15 3314 29 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 16 3177 19 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021 17 2448 19 EPIGENETIC SUPPRESSION OF GAD65 EXPRESSION MEDIATES PERSISTENT PAIN. CHRONIC PAIN IS A COMMON NEUROLOGICAL DISEASE INVOLVING LASTING, MULTIFACETED MALADAPTATIONS RANGING FROM GENE MODULATION TO SYNAPTIC DYSFUNCTION AND EMOTIONAL DISORDERS. SUSTAINED PATHOLOGICAL STIMULI IN MANY DISEASES ALTER THE OUTPUT ACTIVITIES OF CERTAIN GENES THROUGH EPIGENETIC MODIFICATIONS, BUT IT IS UNCLEAR HOW EPIGENETIC MECHANISMS OPERATE IN THE DEVELOPMENT OF CHRONIC PAIN. WE SHOW HERE THAT IN THE RAT BRAINSTEM NUCLEUS RAPHE MAGNUS, WHICH IS IMPORTANT FOR CENTRAL MECHANISMS OF CHRONIC PAIN, PERSISTENT INFLAMMATORY AND NEUROPATHIC PAIN EPIGENETICALLY SUPPRESSES GAD2 (ENCODING GLUTAMIC ACID DECARBOXYLASE 65 (GAD65)) TRANSCRIPTION THROUGH HISTONE DEACETYLASE (HDAC)-MEDIATED HISTONE HYPOACETYLATION, RESULTING IN IMPAIRED GAMMA-AMINOBUTYRIC ACID (GABA) SYNAPTIC INHIBITION. GAD2 KNOCKOUT MICE SHOWED SENSITIZED PAIN BEHAVIOR AND IMPAIRED GABA SYNAPTIC FUNCTION IN THEIR BRAINSTEM NEURONS. IN WILD-TYPE BUT NOT GAD2 KNOCKOUT MICE, HDAC INHIBITORS STRONGLY INCREASED GAD65 ACTIVITY, RESTORED GABA SYNAPTIC FUNCTION AND RELIEVED SENSITIZED PAIN BEHAVIOR. THESE FINDINGS SUGGEST GAD65 AND HDACS AS POTENTIAL THERAPEUTIC TARGETS IN AN EPIGENETIC APPROACH TO THE TREATMENT OF CHRONIC PAIN. 2011 18 3331 23 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 19 893 22 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 20 443 29 AORTA MACROPHAGE INFLAMMATORY AND EPIGENETIC CHANGES IN A MURINE MODEL OF OBSTRUCTIVE SLEEP APNEA: POTENTIAL ROLE OF CD36. OBSTRUCTIVE SLEEP APNEA (OSA) AFFECTS 8-10% OF THE POPULATION, IS CHARACTERIZED BY CHRONIC INTERMITTENT HYPOXIA (CIH), AND CAUSALLY ASSOCIATES WITH CARDIOVASCULAR MORBIDITIES. IN CIH-EXPOSED MICE, CLOSELY MIMICKING THE CHRONICITY OF HUMAN OSA, INCREASED ACCUMULATION AND PROLIFERATION OF PRO-INFLAMMATORY METABOLIC M1-LIKE MACROPHAGES HIGHLY EXPRESSING CD36, EMERGED IN AORTA. TRANSCRIPTOMIC AND MEDIP-SEQ APPROACHES IDENTIFIED ACTIVATION OF PRO-ATHEROGENIC PATHWAYS INVOLVING A COMPLEX INTERPLAY OF HISTONE MODIFICATIONS IN FUNCTIONALLY-RELEVANT BIOLOGICAL PATHWAYS, SUCH AS INFLAMMATION AND OXIDATIVE STRESS IN AORTA MACROPHAGES. DISCONTINUATION OF CIH DID NOT ELICIT SIGNIFICANT IMPROVEMENTS IN AORTA WALL MACROPHAGE PHENOTYPE. HOWEVER, CIH-INDUCED AORTA CHANGES WERE ABSENT IN CD36 KNOCKOUT MICE, OUR RESULTS PROVIDE MECHANISTIC INSIGHTS SHOWING THAT CIH EXPOSURES DURING SLEEP IN ABSENCE OF CONCURRENT PRO-ATHEROGENIC SETTINGS (I.E., GENETIC PROPENSITY OR DIETARY MANIPULATION) LEAD TO THE RECRUITMENT OF CD36(+)(HIGH) MACROPHAGES TO THE AORTIC WALL AND TRIGGER ATHEROGENESIS. FURTHERMORE, LONG-TERM CIH-INDUCED CHANGES MAY NOT BE REVERSIBLE WITH USUAL OSA TREATMENT. 2017