1 6388 134 THE ROLE OF SIRT1 IN THE BASOLATERAL AMYGDALA IN DEPRESSION-LIKE BEHAVIORS IN MICE. PREVIOUS INVESTIGATIONS HAVE IMPLICATED THE BASOLATERAL AMYGDALA (BLA) EPIGENETIC MECHANISMS IN THE PATHOPHYSIOLOGY OF DEPRESSION. SIRT1 IS A NAD+-DEPENDENT CLASS III HISTONE DEACETYLASE, WIDELY EXPRESSES IN BLA. HOWEVER, EPIGENETIC MECHANISMS IN THE BLA UNDER THE REGULATION OF SIRT1 IN THE DEPRESSION ARE LARGELY UNCHARACTERIZED. UNDER THE CHRONIC UNPREDICTABLE CHRONIC MILD STRESS (CUMS) MOUSE MODEL, WE USED ADENO-ASSOCIATED VIRAL VECTORS (AAV) THAT ENCODED SIRT1-SHRNA OR SIRT1 TO SPECIFICALLY KNOCKDOWN OR OVEREXPRESS SIRT1 IN BLA NEURONS, RESPECTIVELY. CUMS PROCEDURE INDUCED SIGNIFICANT DEPRESSION SYMPTOMS INCLUDING THE DECREASED SUCROSE PREFERENCE, THE LESS BODYWEIGHT GAINED, THE DECREASED IMMOBILE LATENCY AND THE INCREASED IMMOBILE TIME BOTH IN FORCED SWIM TEST (FST) AND TAIL SUSPENSION TEST (TST). KNOCKDOWN OF SIRT1 IN BLA GLUTAMATERGIC NEURONS REVERSED THESE DEPRESSION-LIKE BEHAVIORS AND RESTORED THE SYNAPTIC ABNORMALITIES. OVEREXPRESSION OF SIRT1 IN BLA GLUTAMATERGIC NEURONS INDUCED DEPRESSION-LIKE BEHAVIORS IN NON-STRESSED CONTROL MICE. THE RESULT OF PROTEIN EXPRESSIONS AND ULTRASTRUCTURAL CHANGES WERE CONSISTENT WITH THE BEHAVIORAL RESULTS. OUR STUDY SUGGESTED THAT DOWNREGULATION OF SIRT1 IN BLA HAS CERTAIN BENEFICIAL EFFECT ON CUMS-INDUCED DEPRESSION-LIKE BEHAVIORS SUCH AS ANOREXIA, ANHEDONIA, HOPELESSNESS AND DESPAIR. IN ADDITION, THE INCREASED EXPRESSION OF SIRT1 MAY BE THE IMMEDIATE CAUSE OF DEPRESSIVE-LIKE SYMPTOMS. THE ABNORMAL EXPRESSION OF SIRT1 MAY AFFECT THE TRANSCRIPTIONAL REGULATION MECHANISM AND SIGNALING PROTEIN ACETYLATION, AFFECTING NEUROPLASTICITY AND ULTIMATELY CONTRIBUTE TO MDD. IN THE STRESS-SUSCEPTIBLE MICE, THESE TWO MECHANISMS MAY CO-EXIST, BUT THE SPECIFIC MECHANISM NEEDS FURTHER RESEARCH. 2021 2 5020 37 PERSISTENT OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 ATTENUATING GABAERGIC INHIBITION IN BASOLATERAL AMYGDALA ACCOUNTS FOR ANXIETY IN RAT OFFSPRING EXPOSED PERINATALLY TO LOW-DOSE BISPHENOL A. SUBSTANTIAL EVIDENCE INDICATES THAT PREDISPOSITION TO DISEASES CAN BE ACQUIRED DURING EARLY STAGES OF DEVELOPMENT AND INTERACTIONS BETWEEN ENVIRONMENTAL AND GENETIC FACTORS MAY BE IMPLICATED IN THE ONSET OF MANY PATHOLOGICAL CONDITIONS. WE HAVE SHOWN THAT PERINATAL EXPOSURE TO BISPHENOL A (BPA) AT ENVIRONMENTAL DOSE LEVEL CAUSES LONG-TERM ANXIETY-LIKE BEHAVIORS IN RATS. THE AIM OF THIS STUDY WAS TO EXAMINE EPIGENETIC REPROGRAMMING EFFECT OF BPA ON ANXIETY-RELATED NEUROBEHAVIOR IN THE RAT OFFSPRING. THE RESULTS OF REAL-TIME RT-PCR DISPLAYED THAT THE OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 (DNMT1) MRNA WAS ACCOMPANIED BY THE REDUCTION OF GLUTAMIC ACID DECARBOXYLASE 67 (GAD67) MRNA LEVEL IN THE BASOLATERAL AMYGDALA (BLA) OF POSTNATAL DAY 45 BPA-EXPOSED FEMALE RATS. CHRONIC INTRO-BLA INJECTION WITH 5-ADA-CDR COULD RECTIFY THE GAD67 MRNA EXPRESSION. BEHAVIORAL DATA SHOWED THAT THE ANXIETY-LIKE BEHAVIORS IN BPA-EXPOSED RATS WERE REVERSED BY INTRO-BLA TREATMENT WITH 5-ADA-CDR WHICH COULD BE FURTHER BLOCKED BY PTX. ELECTROPHYSIOLOGICAL STUDY REVEALED BEHAVIORAL ALTERATIONS WERE ASSOCIATED WITH THE INCREASE OF POSTSYNAPTIC NEURONAL EXCITABILITY IN THE CORTICAL-BLA PATHWAY WHICH APPEARED AS MULTISPIKE RESPONSES, PAIRED-PULSE FACILITATION INSTEAD OF PAIRED-PULSE INHIBITION AND LONG-TERM POTENTIATION AND 5-AZA-CDR TREATMENT RESTORED THE INCREASED SYNAPTIC TRANSMISSION IN THE BLA VIA IMPROVING GABAERGIC SYSTEM. THE ABOVE RESULTS SUGGEST THAT THE OVEREXPRESSION OF DNMT1 IN THE BLA IS RESPONSIBLE FOR THE ETIOLOGY OF ANXIETY ASSOCIATED WITH BPA EXPOSURE VIA GABAERGIC DISINHIBITION. IN ADDITION, WE ALSO FIND THESE LONG-TERM NEUROBEHAVIORAL EFFECTS OF DEVELOPMENTAL BPA EXPOSURE ARE REVERSIBLE IN ADOLESCENT PERIOD. 2013 3 5749 37 SOCIAL DEFEAT INDUCES CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VENTRAL HIPPOCAMPUS, PREFRONTAL CORTEX, AND DORSAL RAPHE NUCLEUS. CHRONIC EXPOSURE TO STRESS IS ASSOCIATED WITH A NUMBER OF PSYCHIATRIC DISORDERS, BUT LITTLE IS KNOWN ABOUT THE EPIGENETIC MECHANISMS THAT UNDERLIE THE STRESS RESPONSE OR RESILIENCE TO CHRONIC STRESS. WE INVESTIGATED HISTONE ACETYLATION IN SEVEN DIFFERENT BRAIN REGIONS OF RATS EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS: THE DORSAL HIPPOCAMPUS (DHPC), VENTRAL HIPPOCAMPUS (VHPC), MEDIAL PREFRONTAL CORTEX (MPFC), BASOLATERAL AMYGDALA (BLA), LOCUS COERULEUS (LC), PARAVENTRICULAR THALAMUS (PVT), AND DORSAL RAPHE (DR) NUCLEUS. THIS STRESS PARADIGM WAS UNIQUE IN THAT IT ALLOWED RATS TO DISPLAY RESILIENCE IN THE FORM OF AN ACTIVE COPING MECHANISM. WE FOUND THAT THERE WAS AN INCREASE IN ACETYLATION OF H3K9/14 (H3K9/14AC) AND BULK ACETYLATION OF H4K5,8,12,16 (H4K5,8,12,16AC) IN THE DR NUCLEUS OF RATS THAT WERE LESS RESILIENT. LESS RESILIENT RATS ALSO DISPLAYED INCREASED LEVELS OF H3K18 ACETYLATION (H3K18AC) IN THE MPFC WHEN COMPARED TO NON-STRESSED CONTROLS. IN THE VHPC, THERE WAS AN INCREASE IN H3K18AC AND H4K12 (H4K12AC) IN RATS THAT WERE LESS RESILIENT WHEN COMPARED TO NON-STRESSED CONTROL RATS. IN ADDITION, THERE WAS A DECREASE IN LEVELS OF H4K8 ACETYLATION (H4K8AC) IN BOTH RESILIENT AND NON-RESILIENT RATS AS COMPARED TO CONTROLS. WE ASSESSED EXPRESSION OF HISTONE MODIFYING ENZYMES IN THE VHPC AND THE MPFC USING QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (PCR) AND FOUND CHANGES IN EXPRESSION OF A NUMBER OF TARGETS. THESE INCLUDED CHANGES IN SIRT1 AND SIRT2 IN THE VHPC AND CHANGES IN KAT5 IN THE MPFC. OVERALL, THESE RESULTS SUGGEST THAT CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE MODIFYING ENZYMES IN THESE REGIONS CORRELATE WITH THE BEHAVIORAL RESPONSE TO STRESS IN SOCIALLY DEFEATED RATS. 2014 4 4500 36 MORPHINE-WITHDRAWAL AVERSIVE MEMORIES AND THEIR EXTINCTION MODULATE H4K5 ACETYLATION AND BRD4 ACTIVATION IN THE RAT HIPPOCAMPUS AND BASOLATERAL AMYGDALA. CHROMATIN MODIFICATION IS A CRUCIAL MECHANISM IN SEVERAL IMPORTANT PHENOMENA IN THE BRAIN, INCLUDING DRUG ADDICTION. PERSISTENCE OF DRUG CRAVING AND RISK OF RELAPSE COULD BE ATTRIBUTED TO DRUG-INDUCED EPIGENETIC MECHANISMS THAT SEEM TO BE CANDIDATES EXPLAINING LONG-LASTING DRUG-INDUCED BEHAVIOUR AND MOLECULAR ALTERATIONS. HISTONE ACETYLATION HAS BEEN PROPOSED TO REGULATE DRUG-SEEKING BEHAVIOURS AND THE EXTINCTION OF REWARDING MEMORY OF DRUG TAKING. IN THIS WORK, WE STUDIED THE EPIGENETIC REGULATION DURING CONDITIONED PLACE AVERSION AND AFTER EXTINCTION OF AVERSIVE MEMORY OF OPIATE WITHDRAWAL. THROUGH IMMUNOFLUORESCENCE ASSAYS, WE ASSESSED SOME EPIGENETIC MARKS (H4K5AC AND P-BRD4) IN CRUCIAL AREAS RELATED TO MEMORY RETRIEVAL -BASOLATERAL AMYGDALA (BLA) AND HIPPOCAMPUS-. ADDITIONALLY, TO TEST THE DEGREE OF TRANSCRIPTIONAL ACTIVATION, WE EVALUATED THE IMMEDIATE EARLY GENES (IEGS) RESPONSE (ARC, BDNF, CREB, EGR-1, FOS AND NFKB) AND SMARCC1 (CHROMATIN REMODELER) THROUGH RT-QPCR IN THESE NUCLEI. OUR RESULTS SHOWED INCREASED P-BRD4 AND H4K5AC LEVELS DURING AVERSIVE MEMORY RETRIEVAL, SUGGESTING A MORE OPEN CHROMATIN STATE. HOWEVER, TRANSCRIPTIONAL ACTIVATION OF THESE IEGS WAS NOT FOUND, THEREFORE SUGGESTING THAT OTHER SECONDARY RESPONSE MAY ALREADY BE HAPPENING. ADDITIONALLY, SMARCC1 LEVELS WERE REDUCED DUE TO MORPHINE CHRONIC ADMINISTRATION IN BLA AND DENTATE GYRUS. THE ACTIVATION MARKERS RETURNED TO CONTROL LEVELS AFTER THE RETRIEVAL OF AVERSIVE MEMORIES, REVEALING A MORE REPRESSED CHROMATIN STATE. TAKEN TOGETHER, OUR RESULTS SHOW A MAJOR ROLE OF THE TANDEM H4K5AC/P-BRD4 DURING THE RETRIEVAL OF AVERSIVE MEMORIES. THESE RESULTS MIGHT BE USEFUL TO ELUCIDATE NEW MOLECULAR TARGETS TO IMPROVE AND DEVELOP PHARMACOLOGICAL TREATMENTS TO ADDRESS ADDICTION AND TO AVOID DRUG RELAPSE. 2023 5 5201 40 PRENATAL MORPHINE EXPOSURE INCREASES GAMMA OSCILLATION AND THETA COHERENCE IN THE RAT REWARD SYSTEM. PREVIOUS STUDIES HAVE FOUND THAT PRENATAL MORPHINE (PNM) EXPOSURE LEADS TO BOTH INCREASED AND DECREASED RISK OF SUBSTANCE ABUSE IN OFFSPRING. UNDERSTANDING MORE ABOUT THE NEUROBIOLOGICAL CHANGES AFTER THE PNM EXPOSURE WOULD HELP TO UNDERSTAND MORE ABOUT THIS ISSUE. SIGNALING FROM DOPAMINE NEURONS OF THE VENTRAL TEGMENTAL AREA (VTA) IN THE MESOACCUMBAL AND MESOCORTICAL PATHWAYS PLAYS A VITAL ROLE IN DRUG DEPENDENCY. TO PROVIDE FURTHER KNOWLEDGE ABOUT THE EFFECTS OF PNM ON DRUG SEEKING BEHAVIOR AND THE DOPAMINE SYSTEM. WE RECORDED LOCAL FIELD POTENTIALS (LFP) SIMULTANEOUSLY IN THE VTA, NAC (NUCLEUS ACCUMBENS), BLA (BASOLATERAL AMYGDALA) AND MPFC (MEDIAL PREFRONTAL CORTEX) IN MALE ADULT RATS PRENATALLY TREATED WITH SALINE OR MORPHINE. MORPHINE (10 MG/KG) INDUCED CONDITIONED PLACE PREFERENCE (CPP) ESTABLISHMENT, EXTINCTION AND PRIMING WERE TESTED TO INVESTIGATE THE EFFECTS OF PNM ON ADDICTIVE-LIKE BEHAVIOR. IN ADDITION, THE EXPRESSION OF NUCLEAR HISTONE DEACETYLASES (HDAC4, HDAC5), WHICH PLAYS ESSENTIAL EPIGENETIC ROLES IN NEUROPLASTICITY AFTER DRUG USE WERE ALSO TESTED IN VTA AND NAC. THE RESULTS SHOWED THAT PNM DID NOT CHANGE THE ACQUISITION OF MORPHINE CPP IN MALE RATS, BUT IMPAIRED CPP EXTINCTION AND MORPHINE (5 MG/KG) - PRIMED REINSTATEMENT OF CPP AFTER EXTINCTION. PNM INCREASED THE LOW GAMMA (30-60 HZ) AND HIGH (60-90 HZ) GAMMA LFP POWERS IN NAC AND BLA. PNM ALSO LEADS TO INCREASED THETA (4-9 HZ) COHERENCE BETWEEN VTA AND NAC, AND INCREASED HDAC5 EXPRESSION IN VTA. AFTER CHRONIC MORPHINE ADMINISTRATION, COHERENCE BETWEEN VTA-NAC, MPFC-NAC AND MPFC-BLA INCREASED SIGNIFICANTLY IN PNS RATS, BUT NO CHANGES WERE FIND IN PNM RATS, INDICATING IMPAIRED PLASTICITY IN BRAIN CIRCUITS. ALL THESE RESULTS SUGGEST THAT PNM EXPOSURE INCREASED REWARD PROCESSING IN ADULT MALE RATS, BUT IMPAIRED MORPHINE CPP EXTINCTION AND REINSTATEMENT, WHICH RELATE TO DECREASES NETWORK PLASTICITY AND INCREASED HDAC5 EXPRESSION IN THE REWARD SYSTEM. 2022 6 6108 52 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 69 35 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 8 3177 45 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 9 611 32 BIDIRECTIONAL RESCUE OF EXTREME GENETIC PREDISPOSITIONS TO ANXIETY: IMPACT OF CRH RECEPTOR 1 AS EPIGENETIC PLASTICITY GENE IN THE AMYGDALA. THE CONTINUUM OF PHYSIOLOGICAL ANXIETY UP TO PSYCHOPATHOLOGY IS NOT MERELY DEPENDENT ON GENES, BUT IS ORCHESTRATED BY THE INTERPLAY OF GENETIC PREDISPOSITION, GENE X ENVIRONMENT AND EPIGENETIC INTERACTIONS. ACCORDINGLY, INBORN ANXIETY IS CONSIDERED A POLYGENIC, MULTIFACTORIAL TRAIT, LIKELY TO BE SHAPED BY ENVIRONMENTALLY DRIVEN PLASTICITY AT THE GENOMIC LEVEL. WE HERE TOOK ADVANTAGE OF THE EXTREME GENETIC PREDISPOSITION OF THE SELECTIVELY BRED HIGH (HAB) AND LOW ANXIETY (LAB) MOUSE MODEL EXHIBITING HIGH VS LOW ANXIETY-RELATED BEHAVIOR AND TESTED WHETHER AND HOW BENEFICIAL (ENRICHED ENVIRONMENT) VS DETRIMENTAL (CHRONIC MILD STRESS) ENVIRONMENTAL MANIPULATIONS ARE CAPABLE OF RESCUING PHENOTYPES FROM BOTH ENDS OF THE ANXIETY CONTINUUM. WE PROVIDE EVIDENCE THAT (I) EVEN INBORN AND SEEMINGLY RIGID BEHAVIORAL AND NEUROENDOCRINE PHENOTYPES CAN BIDIRECTIONALLY BE RESCUED BY APPROPRIATE ENVIRONMENTAL STIMULI, (II) CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1 (CRHR1), CRITICALLY INVOLVED IN TRAIT ANXIETY, SHOWS BIDIRECTIONAL ALTERATIONS IN ITS EXPRESSION IN THE BASOLATERAL AMYGDALA (BLA) UPON ENVIRONMENTAL STIMULATION, (III) THESE ALTERATIONS ARE LINKED TO AN INCREASED METHYLATION STATUS OF ITS PROMOTER AND, FINALLY, (IV) BINDING OF THE TRANSCRIPTION FACTOR YIN YANG 1 (YY1) TO THE CRHR1 PROMOTER CONTRIBUTES TO ITS GENE EXPRESSION IN A METHYLATION-SENSITIVE MANNER. THUS, CRHR1 IN THE BLA IS CRITICALLY INVOLVED AS PLASTICITY GENE IN THE BIDIRECTIONAL EPIGENETIC RESCUE OF EXTREMES IN TRAIT ANXIETY. 2014 10 5651 29 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD. 2020 11 4397 43 MODULATION OF DNA METHYLATION AND GENE EXPRESSION IN RODENT CORTICAL NEUROPLASTICITY PATHWAYS EXERTS RAPID ANTIDEPRESSANT-LIKE EFFECTS. BACKGROUND: STRESS INCREASES DNA METHYLATION, PRIMARILY A SUPPRESSIVE EPIGENETIC MECHANISM CATALYZED BY DNA METHYLTRANSFERASES (DNMT), AND DECREASES THE EXPRESSION OF GENES INVOLVED IN NEURONAL PLASTICITY AND MOOD REGULATION. DESPITE CHRONIC ANTIDEPRESSANT TREATMENT DECREASES STRESS-INDUCED DNA METHYLATION, IT IS NOT KNOWN WHETHER INHIBITION OF DNMT WOULD CONVEY RAPID ANTIDEPRESSANT-LIKE EFFECTS. AIM: THIS WORK TESTED SUCH A HYPOTHESIS AND EVALUATED WHETHER A BEHAVIORAL EFFECT INDUCED BY DNMT INHIBITORS (DNMTI) CORRESPONDS WITH CHANGES IN DNA METHYLATION AND TRANSCRIPT LEVELS IN GENES CONSISTENTLY ASSOCIATED WITH THE NEUROBIOLOGY OF DEPRESSION AND SYNAPTIC PLASTICITY (BDNF, TRKB, 5-HT(1A), NMDA, AND AMPA). METHODS: MALE WISTAR RATS RECEIVED INTRAPERITONEAL (I.P.) INJECTION OF TWO PHARMACOLOGICALLY DIFFERENT DNMTI (5-AZAD 0.2 AND 0.6 MG/KG OR RG108 0.6 MG/KG) OR VEHICLE (1 ML/KG), 1 H OR 7 DAYS BEFORE THE LEARNED HELPLESSNESS TEST (LH). DNA METHYLATION IN TARGET GENES AND THE CORRESPONDENT TRANSCRIPT LEVELS WERE MEASURED IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) USING MEDIP-QPCR. IN PARALLEL SEPARATE GROUPS, THE ANTIDEPRESSANT-LIKE EFFECT OF 5-AZAD AND RG108 WAS INVESTIGATED IN THE FORCED SWIMMING TEST (FST). THE INVOLVEMENT OF CORTICAL BDNF-TRKB-MTOR PATHWAYS WAS ASSESSED BY INTRA-VENTRAL MEDIAL PFC (VMPFC) INJECTIONS OF RAPAMYCIN (MTOR INHIBITOR), K252A (TRKB RECEPTOR ANTAGONIST), OR VEHICLE (0.2 MUL/SIDE). RESULTS: WE FOUND THAT BOTH 5-AZAD AND RG108 ACUTELY AND 7 DAYS BEFORE THE TEST DECREASED ESCAPE FAILURES IN THE LH. LH STRESS INCREASED DNA METHYLATION AND DECREASED TRANSCRIPT LEVELS OF BDNF IV AND TRKB IN THE PFC, EFFECTS THAT WERE NOT SIGNIFICANTLY ATTENUATED BY RG108 TREATMENT. THE SYSTEMIC ADMINISTRATION OF 5-AZAD (0.2 MG/KG) AND RG108 (0.2 MG/KG) INDUCED AN ANTIDEPRESSANT-LIKE EFFECT IN FST, WHICH WAS, HOWEVER, ATTENUATED BY TRKB AND MTOR INHIBITION INTO THE VMPFC. CONCLUSION: THESE FINDINGS SUGGEST THAT ACUTE INHIBITION OF STRESS-INDUCED DNA METHYLATION PROMOTES RAPID AND SUSTAINED ANTIDEPRESSANT EFFECTS ASSOCIATED WITH INCREASED BDNF-TRKB-MTOR SIGNALING IN THE PFC. 2021 12 2827 32 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS. 2011 13 1005 36 CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD CAUSES DIFFERENTIAL DEPRESSIVE AND ANXIOGENIC EFFECTS IN THE NOVELTY-SEEKING PHENOTYPE: FUNCTIONAL IMPLICATIONS FOR HIPPOCAMPAL AND AMYGDALAR BRAIN-DERIVED NEUROTROPHIC FACTOR AND THE MOSSY FIBRE PLASTICITY. EXPERIMENTALLY NAIVE RATS SHOW VARIANCE IN THEIR LOCOMOTOR REACTIVITY TO NOVELTY, SOME DISPLAYING HIGHER (HR) WHILE OTHERS DISPLAYING LOWER (LR) REACTIVITY, ASSOCIATED WITH VULNERABILITY TO STRESS. WE EMPLOYED A CHRONIC VARIABLE PHYSICAL STRESS REGIMEN INCORPORATING INTERMITTENT AND RANDOM EXPOSURES OF PHYSICAL STRESSORS OR CONTROL HANDLING DURING THE PERIPUBERTAL-JUVENILE PERIOD TO ASSESS INTERACTIONS BETWEEN STRESS AND THE LRHR PHENOTYPE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS ON THE FORCED SWIM AND SOCIAL INTERACTION TESTS, RESPECTIVELY. A DECREASE IN IMMOBILITY IN THE FORCED SWIM TEST ALONG WITH A DECREASE IN SOCIAL CONTACT IN THE SOCIAL INTERACTION TEST WERE OBSERVED IN THE JUVENILE HRS, COUPLED WITH INCREASES IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPUS AND IN THE BASOLATERAL AMYGDALA WITH CHRONIC VARIABLE PHYSICAL STRESS. IN CONTRAST, AN INCREASE IN IMMOBILITY IN THE FORCED SWIM TEST AND A DECREASE IN SOCIAL CONTACT WAS OBSERVED IN THE LR COUNTERPARTS COUPLED WITH AN INCREASE IN THE BDNF MRNA IN THE BASOLATERAL AMYGDALA FOLLOWING CHRONIC VARIABLE PHYSICAL STRESS. FURTHERMORE, CHRONIC PHYSICAL STRESS LED TO INCREASED H3 AND H4 ACETYLATION AT THE P2 AND P4 PROMOTERS OF THE HIPPOCAMPAL BDNF GENE IN THE HR RATS THAT IS ASSOCIATED WITH INCREASED SUPRAPYRAMIDAL MOSSY FIBRE (SP-MF) TERMINAL FIELD VOLUME. IN CONTRAST, CHRONIC VARIABLE PHYSICAL STRESS LED TO DECREASED H4 ACETYLATION AT THE P4 PROMOTER, ASSOCIATED WITH DECREASED SP-MF VOLUME IN THE LR RATS. THESE FINDINGS SHOW DISSOCIATION IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS FOLLOWING CHRONIC VARIABLE PHYSICAL STRESS IN THE JUVENILE HR ANIMALS THAT MAY BE MEDIATED BY INCREASED LEVELS OF BDNF IN THE HIPPOCAMPUS AND IN THE AMYGDALA, RESPECTIVELY. MOREOVER, CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD RESULTS IN OPPOSITE EFFECTS IN DEPRESSIVE-LIKE BEHAVIOR IN THE LRHR RATS BY WAY OF INDUCING DIFFERENTIAL EPIGENETIC REGULATION OF THE HIPPOCAMPAL BDNF GENE THAT, IN TURN, MAY MEDIATE MOSSY FIBRE SPROUTING. 2011 14 3331 34 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 15 5021 34 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 16 949 39 CHRONIC METHAMPHETAMINE TREATMENT REDUCES THE EXPRESSION OF SYNAPTIC PLASTICITY GENES AND CHANGES THEIR DNA METHYLATION STATUS IN THE MOUSE BRAIN. METHAMPHETAMINE (METH) IS A HIGHLY ADDICTIVE PSYCHOSTIMULANT THAT MAY CAUSE LONG-LASTING SYNAPTIC DYSFUNCTION AND ABNORMAL GENE EXPRESSION. WE AIMED TO EXPLORE THE DIFFERENTIAL EXPRESSION OF SYNAPTIC PLASTICITY GENES IN CHRONIC METH-TREATED MOUSE BRAIN. WE USED THE RT(2) PROFILER PCR ARRAY AND THE REAL-TIME QUANTITATIVE PCR TO CHARACTERIZE DIFFERENTIALLY EXPRESSED SYNAPTIC PLASTICITY GENES IN THE FRONTAL CORTEX AND THE HIPPOCAMPUS OF CHRONIC METH-TREATED MICE COMPARED WITH NORMAL SALINE-TREATED MICE. WE FURTHER USED PYROSEQUENCING TO ASSESS DNA METHYLATION CHANGES IN THE CPG REGION OF THE FIVE IMMEDIATE EARLY GENES (IEGS) IN CHRONIC METH-TREATED MOUSE BRAIN. WE DETECTED SIX DOWNREGULATED GENES IN THE FRONTAL CORTEX AND THE HIPPOCAMPUS OF CHRONIC METH-TREATED MICE, INCLUDING FIVE IEGS (ARC, EGR2, FOS, KLF10, AND NR4A1) AND ONE NEURONAL RECEPTOR GENE (GRM1), COMPARED WITH NORMAL SALINE-TREATED GROUP, BUT ONLY FOUR GENES (ARC, EGR2, FOS, AND NR4A1) WERE CONFIRMED TO BE DIFFERENT. FURTHERMORE, WE FOUND SEVERAL CPG SITES OF THE ARC AND THE FOS THAT HAD SIGNIFICANT CHANGES IN DNA METHYLATION STATUS IN THE FRONTAL CORTEX OF CHRONIC METH-TREATED MICE, WHILE THE KLF10 AND THE NR4A1 THAT HAD SIGNIFICANT CHANGES IN THE HIPPOCAMPUS. OUR RESULTS SHOW THAT CHRONIC ADMINISTRATION OF METH MAY LEAD TO SIGNIFICANT DOWNREGULATION OF THE IEGS EXPRESSION IN BOTH THE FRONTAL CORTEX AND THE HIPPOCAMPUS, WHICH MAY PARTLY ACCOUNT FOR THE MOLECULAR MECHANISM OF THE ACTION OF METH. FURTHERMORE, THE CHANGES IN DNA METHYLATION STATUS OF THE IEGS IN THE BRAIN INDICATE THAT AN EPIGENETIC MECHANISM-DEPENDENT TRANSCRIPTIONAL REGULATION MAY CONTRIBUTE TO METH ADDICTION, WHICH WARRANTS ADDITIONAL STUDY. 2015 17 4848 29 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021 18 4930 24 PATERNAL ALCOHOL EXPOSURE REDUCES ACQUISITION OF OPERANT ALCOHOL SELF-ADMINISTRATION AND AFFECTS BDNF DNA METHYLATION IN MALE AND FEMALE OFFSPRING. FAMILIAL TRANSMISSION OF ALCOHOL USE DISORDER REFLECTS GENETIC AND ENVIRONMENTAL FACTORS. PATERNAL ALCOHOL EXPOSURE MAY AFFECT RODENT OFFSPRING VIA EPIGENETIC MODIFICATIONS TRANSMITTED THROUGH THE MALE GERM LINE. WHILE SUCH EXPOSURE ALTERS ALCOHOL SENSITIVITY IN MOUSE OFFSPRING, NO STUDIES EXAMINED IF IT IMPACTS THE DEVELOPMENT OF OPERANT ALCOHOL SELF-ADMINISTRATION IN RATS. WE EXPOSED MALE (SIRES) WISTAR RATS TO CHRONIC INTERMITTENT ETHANOL IN VAPOUR CHAMBERS (16 H/DAY; 5 DAYS/WEEK) OR TO AIR FOR 6 WEEKS. EIGHT WEEKS LATER, RATS WERE MATED WITH ALCOHOL-NAIVE FEMALES. ADULT ALCOHOL- AND CONTROL-SIRED F1 OFFSPRING WERE ASSESSED IN ACQUISITION OF ALCOHOL SELF-ADMINISTRATION IN WHICH INCREASING ALCOHOL CONCENTRATIONS (2.5%, 5% AND 10%, V/V) WERE DELIVERED AFTER ONE LEVER PRESS (FIXED RATIO 1 OR FR1). PRIOR TO ALCOHOL SESSIONS, RATS WERE TRAINED TO LEVER PRESS FOR FOOD DELIVERY UNDER AN FR1 SCHEDULE OF REINFORCEMENT. DNA METHYLATION LEVELS OF THE BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) GENE WERE MEASURED IN SPERM, NUCLEUS ACCUMBENS (NAC) AND MEDIAL PREFRONTAL CORTEX (MPFC) IN SIRES AND IN OFFSPRING. ALCOHOL-EXPOSED SIRES HAD LOWER BDNF DNA METHYLATION LEVELS IN NAC AND GREATER METHYLATION LEVELS IN MPFC. ALTHOUGH THIS PATTERN WAS NOT RECAPITULATED IN OFFSPRING, ALCOHOL-SIRED OFFSPRING OF BOTH SEXES DID SHOW ABERRANT BDNF DNA METHYLATION PATTERNS COMPARED TO CONTROL-SIRED OFFSPRING. ALCOHOL-SIRED OFFSPRING SELF-ADMINISTERED LESS ALCOHOL (5% AND 10%) WITH NO GROUP DIFFERENCES IN FOOD RESPONDING. RESULTS INDICATE THAT PATERNAL ALCOHOL EXPOSURE PRIOR TO CONCEPTION PROTECTS AGAINST ALCOHOL'S INITIAL REINFORCING EFFECTS BUT THE PATTERN OF DYSREGULATED BDNF METHYLATION IN REWARD-RELATED CIRCUITRY DID NOT MIMIC CHANGES SEEN IN SIRES. 2022 19 4218 33 METHYL SUPPLEMENTATION ATTENUATES COCAINE-SEEKING BEHAVIORS AND COCAINE-INDUCED C-FOS ACTIVATION IN A DNA METHYLATION-DEPENDENT MANNER. EPIGENETIC MECHANISMS, SUCH AS HISTONE MODIFICATIONS, REGULATE RESPONSIVENESS TO DRUGS OF ABUSE, SUCH AS COCAINE, BUT RELATIVELY LITTLE IS KNOWN ABOUT THE REGULATION OF ADDICTIVE-LIKE BEHAVIORS BY DNA METHYLATION. TO INVESTIGATE THE INFLUENCE OF DNA METHYLATION ON THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ON DRUG-SEEKING BEHAVIOR, RATS RECEIVING METHYL SUPPLEMENTATION VIA CHRONIC L-METHIONINE (MET) UNDERWENT EITHER A SENSITIZATION REGIMEN OF INTERMITTENT COCAINE INJECTIONS OR INTRAVENOUS SELF-ADMINISTRATION OF COCAINE, FOLLOWED BY CUE-INDUCED AND DRUG-PRIMED REINSTATEMENT. MET BLOCKED SENSITIZATION TO THE LOCOMOTOR-ACTIVATING EFFECTS OF COCAINE AND ATTENUATED DRUG-PRIMED REINSTATEMENT, WITH NO EFFECT ON CUE-INDUCED REINSTATEMENT OR SUCROSE SELF-ADMINISTRATION AND REINSTATEMENT. FURTHERMORE, UPREGULATION OF DNA METHYLTRANSFERASE 3A AND 3B AND GLOBAL DNA HYPOMETHYLATION WERE OBSERVED IN THE NUCLEUS ACCUMBENS CORE (NAC), BUT NOT IN THE MEDIAL PREFRONTAL CORTEX (MPFC), OF COCAINE-PRETREATED RATS. GLUTAMATERGIC PROJECTIONS FROM THE MPFC TO THE NAC ARE CRITICALLY INVOLVED IN THE REGULATION OF COCAINE-PRIMED REINSTATEMENT, AND ACTIVATION OF BOTH BRAIN REGIONS IS SEEN IN HUMAN ADDICTS WHEN REEXPOSED TO THE DRUG. WHEN COMPARED WITH VEHICLE-PRETREATED RATS, THE IMMEDIATE EARLY GENE C-FOS (A MARKER OF NEURONAL ACTIVATION) WAS UPREGULATED IN THE NAC AND MPFC OF COCAINE-PRETREATED RATS AFTER COCAINE-PRIMED REINSTATEMENT, AND CHRONIC MET TREATMENT BLOCKED ITS INDUCTION IN BOTH REGIONS. COCAINE-INDUCED C-FOS EXPRESSION IN THE NAC WAS ASSOCIATED WITH REDUCED METHYLATION AT CPG DINUCLEOTIDES IN THE C-FOS GENE PROMOTER, EFFECTS REVERSED BY MET TREATMENT. OVERALL, THESE DATA SUGGEST THAT DRUG-SEEKING BEHAVIORS ARE, IN PART, ATTRIBUTABLE TO A DNA METHYLATION-DEPENDENT PROCESS, LIKELY OCCURRING AT SPECIFIC GENE LOCI (E.G., C-FOS) IN THE REWARD PATHWAY. 2015 20 3977 38 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