1  1088 111 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2   683  29 BRAIN PLASTICITY AND COGNITIVE FUNCTIONS AFTER ETHANOL CONSUMPTION IN C57BL/6J MICE. ACUTE OR CHRONIC ADMINISTRATIONS OF HIGH DOSES OF ETHANOL IN MICE ARE KNOWN TO PRODUCE SEVERE COGNITIVE DEFICITS LINKED TO HIPPOCAMPAL DAMAGE. HOWEVER, WE RECENTLY REPORTED THAT CHRONIC AND MODERATE ETHANOL INTAKE IN C57BL/6J MICE INDUCED CHROMATIN REMODELING WITHIN THE BDNF PROMOTERS, LEADING TO BOTH ENHANCED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND HIPPOCAMPAL NEUROGENESIS UNDER FREE-CHOICE PROTOCOL. WE PERFORMED HERE A SERIES OF CELLULAR AND BEHAVIORAL STUDIES TO ANALYZE THE CONSEQUENCES OF THESE MODIFICATIONS. WE SHOWED THAT A 3-WEEK CHRONIC FREE-CHOICE ETHANOL CONSUMPTION IN C57BL/6J MICE LED TO A DECREASE IN DNA METHYLATION OF THE BDNF GENE WITHIN THE CA1 AND CA3 SUBFIELDS OF THE HIPPOCAMPUS, AND UPREGULATED HIPPOCAMPAL BDNF SIGNALING PATHWAYS MEDIATED BY ERK, AKT AND CREB. HOWEVER, THIS ACTIVATION DID NOT AFFECT LONG-TERM POTENTIATION IN THE CA1. CONVERSELY, ETHANOL INTAKE IMPAIRED LEARNING AND MEMORY CAPACITIES ANALYZED IN THE CONTEXTUAL FEAR CONDITIONING TEST AND THE NOVEL OBJECT RECOGNITION TASK. IN ADDITION, ETHANOL INCREASED BEHAVIORAL PERSEVERATION IN THE BARNES MAZE TEST BUT DID NOT ALTER THE MOUSE OVERALL SPATIAL CAPACITIES. THESE DATA SUGGESTED THAT IN CONDITIONS OF CHRONIC AND MODERATE ETHANOL INTAKE, THE CHROMATIN REMODELING LEADING TO BDNF SIGNALING UPREGULATION IS PROBABLY AN ADAPTIVE PROCESS, ENGAGED VIA EPIGENETIC REGULATIONS, TO COUNTERACT THE COGNITIVE DEFICITS INDUCED BY ETHANOL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  5273  26 PROMOTER METHYLATION AND BDNF AND DAT1 GENE EXPRESSION PROFILES IN PATIENTS WITH DRUG ADDICTION. BACKGROUND: DRUG ADDICTION IS A BRAIN DISORDER THAT HAS NEGATIVE CONSEQUENCES FOR INDIVIDUALS AND SOCIETY. ADDICTIONS ARE CHRONIC RELAPSING DISEASES OF THE BRAIN THAT ARE CAUSED BY DIRECT DRUG-INDUCED EFFECTS AND PERSEVERING NEUROADAPTATIONS AT THE EPIGENETIC, NEUROPEPTIDE AND NEUROTRANSMITTER LEVELS. BECAUSE THE DOPAMINERGIC SYSTEM HAS A SIGNIFICANT ROLE IN DRUG ABUSE, THE PURPOSE OF THIS STUDY WAS TO ANALYZE THE METHYLATION AND EXPRESSION PROFILE OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND DOPAMINE TRANSPORTER (DAT1) GENES IN INDIVIDUALS WITH DRUG ADDICTION. MATERIALS AND METHODS: BDNF AND DAT1 PROMOTER METHYLATION WERE INVESTIGATED WITH A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) TECHNIQUE IN BLOOD SAMPLES FROM 75 INDIVIDUALS WITH DRUG ADDICTION AND 65 HEALTHY CONTROLS. THE EXPRESSION LEVELS OF BDNF AND DAT1 WERE ASSESSED IN 12 MRNA SAMPLES FROM THE BLOOD OF PATIENTS AND COMPARED TO THE SAMPLES OF HEALTHY CONTROLS (N = 12) WITH REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION PCR. RESULTS: NO SIGNIFICANT DIFFERENCES WERE FOUND IN THE METHYLATION OF BDNF AND DAT1 BETWEEN PATIENTS AND CONTROLS, BUT THE RELATIVE LEVELS OF EXPRESSION OF BDNF AND DAT1 MRNA DIFFERED SIGNIFICANTLY IN THE PATIENTS COMPARED TO CONTROLS (P < 0.0001). CONCLUSION: THESE RESULTS SHOWED THAT THE METHYLATION STATUS OF THE BDNF AND DAT1 GENES HAD NO SIGNIFICANT FUNCTION IN THE PROCESSES OF DRUG ADDICTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  4630  32 NEUROEPIGENETIC REGULATION OF PATHOGENIC MEMORIES. OUR UNIQUE COLLECTION OF MEMORIES DETERMINES OUR INDIVIDUALITY AND SHAPES OUR FUTURE INTERACTIONS WITH THE WORLD. REMARKABLE ADVANCES INTO THE NEUROBIOLOGICAL BASIS OF MEMORY HAVE IDENTIFIED KEY EPIGENETIC MECHANISMS THAT SUPPORT THE STABILITY OF MEMORY. VARIOUS FORMS OF EPIGENETIC REGULATION AT THE LEVELS OF DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNAS (NCRNAS) CAN MODULATE TRANSCRIPTIONAL AND TRANSLATIONAL EVENTS REQUIRED FOR MEMORY PROCESSES. BY CHANGING THE CELLULAR PROFILE IN THE BRAIN'S EMOTIONAL, REWARD, AND MEMORY CIRCUITS, THESE EPIGENETIC MODIFICATIONS HAVE ALSO BEEN LINKED TO PERSEVERANT, PATHOGENIC MEMORIES. IN THIS REVIEW, WE WILL DELVE INTO THE RELEVANCE OF EPIGENETIC DYSREGULATION TO PATHOGENIC MEMORY MECHANISMS BY FOCUSING ON TWO NEUROPSYCHIATRIC DISORDERS PERPETUATED BY ABERRANT MEMORY ASSOCIATIONS: SUBSTANCE USE DISORDER (SUD) AND POST-TRAUMATIC STRESS DISORDER (PTSD). AS OUR UNDERSTANDING IMPROVES, NEUROEPIGENETIC MECHANISMS MAY SOMEDAY BE HARNESSED TO DEVELOP NOVEL THERAPEUTIC TARGETS FOR THE TREATMENT OF THESE CHRONIC, RELAPSING DISORDERS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  5201  29 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  2672  27 ETHANOL-INDUCED EPIGENETIC REGULATIONS AT THE BDNF GENE IN C57BL/6J MICE. HIGH ETHANOL INTAKE IS WELL KNOWN TO INDUCE BOTH ANXIOLYTIC AND ANXIOGENIC EFFECTS, IN CORRELATION WITH CHROMATIN REMODELING IN THE AMYGDALOID BRAIN REGION AND DEFICITS IN CELL PROLIFERATION AND SURVIVAL IN THE HIPPOCAMPUS OF RODENTS. WHETHER ONLY MODERATE BUT CHRONIC ETHANOL INTAKE IN C57BL/6J MICE COULD ALSO HAVE AN IMPACT ON CHROMATIN REMODELING AND NEUROPLASTICITY WAS ADDRESSED HERE. CHRONIC ETHANOL CONSUMPTION IN A FREE CHOICE PARADIGM WAS FOUND TO INDUCE MARKED CHANGES IN THE EXPRESSION OF GENES IMPLICATED IN NEURAL DEVELOPMENT AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN THE MOUSE HIPPOCAMPUS. TRANSCRIPTS ENCODING NEURAL BHLH ACTIVATORS AND THOSE FROM BDNF EXONS II, III AND VI WERE UPREGULATED, WHEREAS THOSE FROM BDNF EXON VIII AND HDACS WERE DOWNREGULATED BY ETHANOL COMPARED WITH WATER CONSUMPTION. THESE ETHANOL-INDUCED CHANGES WERE ASSOCIATED WITH ENRICHMENT IN BOTH ACETYLATED H3 AT BDNF PROMOTER PVI AND TRIMETHYLATED H3 AT PII AND PIII. CONVERSELY, ACETYLATED H3 AT PIII AND PVIII AND TRIMETHYLATED H3 AT PVIII WERE DECREASED IN ETHANOL-EXPOSED MICE. IN PARALLEL, HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND TRKB-MEDIATED NEUROGENESIS IN THE DENTATE GYRUS WERE SIGNIFICANTLY ENHANCED BY ETHANOL CONSUMPTION. THESE RESULTS SUGGEST THAT, IN C57BL/6J MICE, CHRONIC AND MODERATE ETHANOL INTAKE PRODUCES MARKED EPIGENETIC CHANGES UNDERLYING BDNF OVEREXPRESSION AND DOWNSTREAM HIPPOCAMPAL NEUROGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  3650  28 INCREASED TRANSCRIPTION OF TSPO, HDAC2, AND HDAC6 IN THE AMYGDALA OF MALES WITH ALCOHOL USE DISORDER. INTRODUCTION: REPEATED EXPOSURE TO HIGH DOSES OF ALCOHOL TRIGGERS NEUROINFLAMMATORY PROCESSES THAT CONTRIBUTE TO CRAVING AND MOOD DYSFUNCTION IN ALCOHOL USE DISORDER (AUD). THE UPREGULATION OF THE TRANSLOCATOR PROTEIN (TSPO) IS CONSIDERED A BIOMARKER OF NEUROINFLAMMATION, AND TSPO LIGANDS HAVE BEEN USED AS NEUROIMAGING BIOMARKERS OF NEUROINFLAMMATION. EPIGENETIC MECHANISMS ARE ALSO IMPLICATED IN NEUROINFLAMMATORY RESPONSES TO ALCOHOL, AND ELEVATED EXPRESSION OF HDAC2 AND HDAC6 HAS BEEN REPORTED IN THE BRAIN OF ANIMALS EXPOSED TO CHRONIC ALCOHOL. METHODS: THE PRESENT STUDY EXAMINED THE TRANSCRIPTIONAL REGULATION OF TSPO, HDAC2, AND HDAC6 IN HUMAN POSTMORTEM BRAIN TISSUE FROM MALES PREVIOUSLY DIAGNOSED WITH AUD (N = 11) COMPARED TO AGE-MATCHED NONDEPENDENT MALES (N = 13) IN FOUR BRAIN REGIONS RELEVANT TO AUD: PREFRONTAL CORTEX (PFC), NUCLEUS ACCUMBENS (NAC), HIPPOCAMPUS (HPP), AND AMYGDALA (AMY). RESULTS: TRANSLOCATOR PROTEIN MRNA LEVELS IN AMY AND PFC AND HDAC2 AND HDAC6 MRNA LEVELS IN AMY WERE UPREGULATED IN AUD COMPARED TO CONTROLS. IN AMY, TSPO MRNA LEVELS WERE POSITIVELY ASSOCIATED WITH HDAC2 AND HDAC6 MRNA LEVELS, SUGGESTING A POSSIBLE REGULATION OF TSPO BY HDAC2 AND HDAC6 IN THIS BRAIN REGION. IN CONTRAST, THERE WERE NO GROUP DIFFERENCES FOR TSPO, HDAC2, AND HDAC6 IN NAC AND HPP. CONCLUSION: OUR STUDY IS THE FIRST TO FIND UPREGULATED TSPO MRNA LEVELS IN AMY AND PFC IN POSTMORTEM BRAINS FROM AUD CONSISTENT WITH NEUROINFLAMMATION, AND IN THE AMYGDALA, THEY IMPLICATE EPIGENETIC REGULATION OF TSPO BY HDAC2 AND HDAC6.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8  5152  26 PPM1F IN DENTATE GYRUS MODULATES ANXIETY-RELATED BEHAVIORS BY REGULATING BDNF EXPRESSION VIA AKT/JNK/P-H3S10 PATHWAY. ANXIETY IS A SERIOUS PSYCHIATRIC DISORDER, WITH A HIGHER INCIDENCE RATE IN WOMEN THAN IN MEN. PROTEIN PHOSPHATASE MG(2+)/MN(2+)-DEPENDENT 1F (PPM1F), A SERINE/THREONINE PHOSPHATASE, HAS BEEN SHOWN TO HAVE MULTIPLE BIOLOGICAL AND CELLULAR FUNCTIONS. HOWEVER, THE EFFECTS OF PPM1F AND ITS NEURONAL SUBSTRATES ON ANXIETY REMAIN LARGELY UNCLEAR. IN THIS STUDY, WE SHOWED THAT CHRONIC RESTRAINT STRESS (CRS) INDUCED ANXIETY-RELATED BEHAVIORS ONLY IN FEMALE MICE, WHILE ACUTE RESTRAINT STRESS (ARS) PRODUCED ANXIETY-RELATED BEHAVIORS IN BOTH MALE AND FEMALE MICE IN LIGHT-DARK AND ELEVATED PLUS MAZE TESTS AND INDUCED UPREGULATION OF PPM1F AND DOWNREGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION IN THE HIPPOCAMPUS. ADENO-ASSOCIATED VIRUS-MEDIATED OVEREXPRESSION OF PPM1F OR CONDITIONAL KNOCKOUT OF BDNF IN DENTATE GYRUS (DG) LED TO A MORE PRONOUNCED ANXIETY-RELATED BEHAVIOR IN FEMALE THAN IN MALE MICE AS INDICATED BY THE BEHAVIORAL EVALUATIONS. MEANWHILE, OVEREXPRESSION OF PPM1F IN THE DG DECREASED TOTAL BDNF EXON-SPECIFIC MESSENGER RNA EXPRESSION IN THE HIPPOCAMPUS WITH THE DECREASED BINDING ACTIVITY OF PHOSPHORYLATED H3S10 TO ITS INDIVIDUAL PROMOTERS IN FEMALE MICE. FURTHERMORE, WE IDENTIFIED THAT OVEREXPRESSION OF PPM1F DECREASED THE PHOSPHORYLATION LEVELS OF AKT AND JNK IN THE HIPPOCAMPUS OF FEMALE MICE. THESE RESULTS MAY SUGGEST THAT PPM1F REGULATES ANXIETY-RELATED BEHAVIORS BY MODULATING BDNF EXPRESSION AND H3S10 PHOSPHORYLATION-MEDIATED EPIGENETIC MODIFICATION, WHICH MAY BE SERVED AS POTENTIALLY PATHOLOGICAL GENES ASSOCIATED WITH ANXIETY OR OTHER MENTAL DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9  6602  25 TWO KINDS OF TRANSCRIPTION FACTORS MEDIATE CHRONIC MORPHINE-INDUCED DECREASE IN MIR-105 IN MEDIAL PREFRONTAL CORTEX OF RATS. CHRONIC MORPHINE ADMINISTRATION ALTERS GENE EXPRESSION IN DIFFERENT BRAIN REGIONS, AN EFFECT WHICH MAY CONTRIBUTE TO PLASTIC CHANGES ASSOCIATED WITH ADDICTIVE BEHAVIOR. THIS CHANGE IN GENE EXPRESSION IS MOST POSSIBLY MEDIATED BY ADDICTIVE DRUG-INDUCED EPIGENETIC REMODELING OF GENE EXPRESSION PROGRAMS. OUR PREVIOUS STUDIES SHOWED THAT CHRONIC MORPHINE-INDUCED DECREASE OF MIR-105 IN THE MEDIAL PREFRONTAL CORTEX (MPFC) CONTRIBUTED TO CONTEXT-INDUCED RETRIEVAL OF MORPHINE WITHDRAWAL MEMORY. HOWEVER, HOW CHRONIC MORPHINE TREATMENT DECREASES MIR-105 IN THE MPFC STILL REMAINS UNKNOWN. THE PRESENT STUDY SHOWS THAT CHRONIC MORPHINE INDUCES ADDICTION-RELATED CHANGE IN MIR-105 IN THE MPFC VIA TWO KINDS OF TRANSCRIPTION FACTORS: THE FIRST TRANSCRIPTION FACTOR IS CREB ACTIVATED BY MU RECEPTORS-ERK-P90RSK SIGNALING PATHWAY AND THE SECOND TRANSCRIPTION FACTOR IS GLUCOCORTICOID RECEPTOR (GR), WHICH AS A NEGATIVE TRANSCRIPTION FACTOR, MEDIATES CHRONIC MORPHINE-INDUCED DECREASE IN MIR-105 IN THE MPFC OF RATS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  3126  33 GINSENOSIDE REDUCES COGNITIVE IMPAIRMENT DURING CHRONIC CEREBRAL HYPOPERFUSION THROUGH BRAIN-DERIVED NEUROTROPHIC FACTOR REGULATED BY EPIGENETIC MODULATION. INCREASED EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN ASSOCIATED WITH MEMORY-ENHANCING AND NEUROPROTECTIVE PROPERTIES OF SOME DRUGS UNDER CHRONIC CEREBRAL HYPOPERFUSION (CCH) CONDITION. GINSENOSIDE RD (GSRD), ONE OF THE MAIN ACTIVE INGREDIENTS IN PANAX GINSENG, IS WIDELY USED FOR BRAIN PROTECTION. HOWEVER, IT IS POORLY UNDERSTOOD WHETHER EPIGENETIC MECHANISMS IMPLIED IN THE BDNF MODULATION AFTER GSRD TREATMENT FOR CCH REMAIN ELUSIVE. HERE, WE INVESTIGATED THE NEUROPROTECTIVE EFFECTS OF GSRD AND THE INVOLVED MECHANISMS. WE DEMONSTRATED THAT GSRD ADMINISTRATION AMELIORATED CCH-INDUCED IMPAIRMENT OF LEARNING AND MEMORY BEHAVIORS, EVIDENCED BY DECREASED ESCAPE LATENCY AND INCREASED NUMBER OF CROSSING THE PLATFORM IN MORRIS WATER MAZE TEST. THIS IMPROVEMENT WAS ASSOCIATED WITH PROMOTED NEURON SURVIVAL AND INCREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND PREFRONTAL CORTEX OF CCH MICE. GSRD IMPROVED NEURON SURVIVAL AND DECREASED NEURON APOPTOSIS AND THE LEVEL OF CASPASE-3 UNDER OXYGEN-GLUCOSE DEPRIVATION/REOXYGENATION (OGD/R) BY UPREGULATION OF BDNF AS WELL AS IN VITRO. THE LEVELS OF ACETYLATED HISTONE H3 (AC-H3) AND HISTONE DEACETYLASE (HISTONE DEACETYLASE 2 (HDAC2)) WERE ALTERED UNDER OGD/R IN A TIME-DEPENDENT MANNER, AND GSRD REESTABLISHED THE BALANCE BETWEEN AC-H3 AND HDAC2 WHICH RESULTED IN UPREGULATION OF BDNF AND INCREASED NEURON SURVIVAL. MS-275, AN INHIBITOR OF CLASS I HDACS, ABOLISHED THE LEVELS OF AC-H3 AT THE BDNF PROMOTERS AND ENHANCED UPREGULATION OF BDNF AFTER GSRD ADMINISTRATION, SUGGESTING A SYNERGISTIC EFFECT BETWEEN GSRD AND MS-275. ALL THE DATA SUGGESTED THAT GSRD PROVIDED NEUROPROTECTION BY EPIGENETIC MODULATION WHICH ACCOUNTED FOR THE REGULATION OF BDNF IN CCH MICE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  1706  26 DYNORPHIN/KOP AND NOCICEPTIN/NOP GENE EXPRESSION AND EPIGENETIC CHANGES BY COCAINE IN RAT STRIATUM AND NUCLEUS ACCUMBENS. COCAINE INDUCES NEUROCHEMICAL CHANGES OF ENDOGENOUS PRODYNORPHIN-KAPPA OPIOID RECEPTOR (PDYN-KOP) AND PRONOCICEPTIN/ORPHANINFQ-NOCICEPTIN RECEPTOR (PN/OFQ-NOP) SYSTEMS. BOTH SYSTEMS PLAY AN IMPORTANT ROLE IN REWARDING MECHANISMS AND ADDICTIVE STIMULUS PROCESSING BY MODULATING DRUG-INDUCED DOPAMINERGIC ACTIVATION IN THE MESOCORTICO-LIMBIC BRAIN AREAS. THEY ARE ALSO INVOLVED IN REGULATING STRESS MECHANISMS RELATED TO ADDICTION. THE AIM OF THIS STUDY WAS TO INVESTIGATE POSSIBLE CHANGES OF GENE EXPRESSION OF THE DYNORPHINERGIC AND NOCICEPTINERGIC SYSTEM COMPONENTS IN THE NUCLEUS ACCUMBENS (NA) AND IN MEDIAL AND LATERAL CAUDATE PUTAMEN (MCPU AND LCPU, RESPECTIVELY) OF RATS, FOLLOWING CHRONIC SUBCUTANEOUS INFUSION OF COCAINE. IN ADDITION, THE EPIGENETIC HISTONE MODIFICATIONS H3K4ME3 AND H3K27ME3 (AN ACTIVATING AND A REPRESSIVE MARKER, RESPECTIVELY) AT THE PROMOTER LEVEL OF THE PDYN, KOP, PN/OFQ AND NOP GENES WERE INVESTIGATED. RESULTS SHOWED THAT COCAINE INDUCED PDYN GENE EXPRESSION UP-REGULATION IN THE NA AND LCPU, AND ITS DOWN-REGULATION IN THE MCPU, WHEREAS KOP MRNA LEVELS WERE UNCHANGED. MOREOVER, COCAINE EXPOSURE DECREASED PN/OFQ GENE EXPRESSION IN THE NA AND LCPU, WHILE NOP MRNA LEVELS APPEARED SIGNIFICANTLY INCREASED IN THE NA AND DECREASED IN THE LCPU. SPECIFIC CHANGES OF THE H3K4ME3 AND H3K27ME3 LEVELS WERE FOUND AT PDYN, PN/OFQ, AND NOP GENE PROMOTER, CONSISTENT WITH THE OBSERVED GENE EXPRESSION ALTERATIONS. THE PRESENT FINDINGS CONTRIBUTE TO BETTER DEFINE THE ROLE OF ENDOGENOUS PDYN-KOP AND PN/OFQ-NOP SYSTEMS IN NEUROPLASTICITY MECHANISMS FOLLOWING CHRONIC COCAINE TREATMENT. THE EPIGENETIC HISTONE MODIFICATIONS UNDERLYING THE GENE EXPRESSION CHANGES LIKELY MEDIATE THE EFFECTS OF COCAINE ON TRANSCRIPTIONAL REGULATION OF SPECIFIC GENE PROMOTERS THAT RESULT IN LONG-LASTING DRUG-INDUCED PLASTICITY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  5838  29 STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE THE SENSITIVITY TO SOCIAL DEFEAT STRESS IN MICE THROUGH EPIGENETIC REGULATION. THE GLOBAL NUMBER OF PATIENTS WITH DEPRESSION INCREASES IN CORRELATION TO EXPOSURE TO SOCIAL STRESS. CHRONIC STRESS DOES NOT TRIGGER DEPRESSION IN ALL INDIVIDUALS, AS SOME REMAIN RESILIENT. THE UNDERLYING MOLECULAR MECHANISMS THAT CONTRIBUTE TO STRESS SENSITIVITY HAVE BEEN POORLY UNDERSTOOD, ALTHOUGH REVEALING THE REGULATION OF STRESS SENSITIVITY COULD HELP DEVELOP TREATMENTS FOR DEPRESSION. WE PREVIOUSLY FOUND THAT STRIATAL SHATI/NAT8L, AN N-ACETYLTRANSFERASE, WAS INCREASED IN A DEPRESSION MOUSE MODEL. WE INVESTIGATED THE ROLES OF SHATI/NAT8L IN STRESS SENSITIVITY IN MICE AND FOUND THAT SHATI/NAT8L AND BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS IN THE DORSAL STRIATUM WERE INCREASED IN STRESS-SUSCEPTIBLE MICE BUT NOT IN RESILIENT MICE EXPOSED TO REPEATED SOCIAL DEFEAT STRESS (RSDS). KNOCKDOWN OF SHATI/NAT8L IN THE DORSAL STRIATUM INDUCED RESILIENCE TO RSDS. IN ADDITION, BLOCKADE OF BDNF SIGNALING IN THE DORSAL STRIATUM BY ANA-12, A BDNF-SPECIFIC RECEPTOR TROPOMYOSIN-RECEPTOR-KINASE B (TRKB) INHIBITOR, ALSO INDUCED RESILIENCE TO STRESS. SHATI/NAT8L IS CORRELATED WITH BDNF EXPRESSION AFTER RSDS, AND BDNF IS DOWNSTREAM OF SHATI/NAT8L PATHWAYS IN THE DORSAL STRIATUM; SHATI/NAT8L IS EPIGENETICALLY REGULATED BY BDNF VIA HISTONE ACETYLATION. OUR RESULTS DEMONSTRATE THAT STRIATAL SHATI/NAT8L-BDNF PATHWAYS DETERMINE STRESS SENSITIVITY THROUGH EPIGENETIC REGULATION. THE STRIATAL SHATI/NAT8L-BDNF PATHWAY COULD BE A NOVEL TARGET FOR TREATMENTS OF DEPRESSION AND COULD ESTABLISH A NOVEL THERAPEUTIC STRATEGY FOR DEPRESSION PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
13  1330  29 DEPRESSIVE-LIKE BEHAVIORS ARE REGULATED BY NOX1/NADPH OXIDASE BY REDOX MODIFICATION OF NMDA RECEPTOR 1. INVOLVEMENT OF REACTIVE OXYGEN SPECIES (ROS) HAS BEEN SUGGESTED IN THE DEVELOPMENT OF PSYCHIATRIC DISORDERS. NOX1 IS A NONPHAGOCYTIC FORM OF NADPH OXIDASE WHOSE EXPRESSION IN THE NERVOUS SYSTEM IS NEGLIGIBLE COMPARED WITH OTHER NOX ISOFORMS. HOWEVER, NOX1-DERIVED ROS INCREASE INFLAMMATORY PAIN AND TOLERANCE TO OPIOID ANALGESIA. TO CLARIFY THE ROLE OF NOX1 IN THE BRAIN, WE EXAMINED DEPRESSIVE-LIKE BEHAVIORS IN MICE DEFICIENT IN NOX1 (NOX1(-/Y)). DEPRESSIVE-LIKE BEHAVIORS INDUCED BY CHRONIC SOCIAL DEFEAT STRESS OR ADMINISTRATION OF CORTICOSTERONE (CORT) WERE SIGNIFICANTLY AMELIORATED IN NOX1(-/Y) GENERATION OF ROS WAS SIGNIFICANTLY ELEVATED IN THE PREFRONTAL CORTEX (PFC) OF MICE ADMINISTRATED WITH CORT, WHILE NOX1 MRNA WAS UPREGULATED ONLY IN THE VENTRAL TEGMENTAL AREA (VTA) AMONG BRAIN AREAS RESPONSIBLE FOR EMOTIONAL BEHAVIORS. DELIVERY OF MIRNA AGAINST NOX1 TO VTA RESTORED CORT-INDUCED DEPRESSIVE-LIKE BEHAVIORS IN WILD-TYPE (WT) LITTERMATES. ADMINISTRATION OF CORT TO WT, BUT NOT TO NOX1(-/Y), SIGNIFICANTLY REDUCED TRANSCRIPT LEVELS OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WITH A CONCOMITANT INCREASE IN DNA METHYLATION OF THE PROMOTER REGIONS IN BDNF DELIVERY OF MIRNA AGAINST NOX1 TO VTA RESTORED THE LEVEL OF BDNF MRNA IN WT PFC. REDOX PROTEOME ANALYSES DEMONSTRATED THAT NMDA RECEPTOR 1 (NR1) WAS AMONG THE MOLECULES REDOX REGULATED BY NOX1. IN CULTURED CORTICAL NEURONS, HYDROGEN PEROXIDE SIGNIFICANTLY SUPPRESSED NMDA-INDUCED UPREGULATION OF BDNF TRANSCRIPTS IN NR1-EXPRESSING CELLS BUT NOT IN CELLS HARBORING MUTANT NR1 (C744A). TOGETHER, THESE FINDINGS SUGGEST A KEY ROLE OF NOX1 IN DEPRESSIVE-LIKE BEHAVIORS THROUGH NR1-MEDIATED EPIGENETIC MODIFICATION OF BDNF IN THE MESOPREFRONTAL PROJECTION.SIGNIFICANCE STATEMENT NADPH OXIDASE IS A SOURCE OF REACTIVE OXYGEN SPECIES (ROS) THAT HAVE BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS NEUROLOGICAL DISORDERS. WE PRESENTLY SHOWED THE INVOLVEMENT OF A NONPHAGOCYTIC TYPE OF NADPH OXIDASE, NOX1, IN MAJOR DEPRESSIVE DISORDERS, INCLUDING BEHAVIORAL, BIOCHEMICAL, AND ANATOMICAL CHANGES IN MICE. THE OXIDATION OF NR1 BY NOX1-DERIVED ROS WAS DEMONSTRATED IN PREFRONTAL CORTEX (PFC), WHICH MAY BE CAUSALLY LINKED TO THE DOWNREGULATION OF BDNF, PROMOTING DEPRESSIVE-LIKE BEHAVIORS. GIVEN THAT NOX1 IS UPREGULATED ONLY IN VTA BUT NOT IN PFC, MESOCORTICAL PROJECTIONS APPEAR TO PLAY A CRUCIAL ROLE IN NOX1-DEPENDENT DEPRESSIVE-LIKE BEHAVIORS. OUR STUDY IS THE FIRST TO PRESENT THE POTENTIAL MOLECULAR MECHANISM UNDERLYING THE DEVELOPMENT OF MAJOR DEPRESSION THROUGH THE NOX1-INDUCED OXIDATION OF NR1 AND EPIGENETIC MODIFICATION OF BDNF.	2017	

14  2012  20 EPIGENETIC BASIS OF OPIATE SUPPRESSION OF BDNF GENE EXPRESSION IN THE VENTRAL TEGMENTAL AREA. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS A CRUCIAL ROLE IN MODULATING NEURAL AND BEHAVIORAL PLASTICITY TO DRUGS OF ABUSE. WE FOUND A PERSISTENT DOWNREGULATION OF EXON-SPECIFIC BDNF EXPRESSION IN THE VENTRAL TEGMENTAL AREA (VTA) IN RESPONSE TO CHRONIC OPIATE EXPOSURE, WHICH WAS MEDIATED BY SPECIFIC EPIGENETIC MODIFICATIONS AT THE CORRESPONDING BDNF GENE PROMOTERS. EXPOSURE TO CHRONIC MORPHINE INCREASED STALLING OF RNA POLYMERASE II AT THESE BDNF PROMOTERS IN VTA AND ALTERED PERMISSIVE AND REPRESSIVE HISTONE MODIFICATIONS AND OCCUPANCY OF THEIR REGULATORY PROTEINS AT THE SPECIFIC PROMOTERS. FURTHERMORE, WE FOUND THAT MORPHINE SUPPRESSED BINDING OF PHOSPHO-CREB (CAMP RESPONSE ELEMENT BINDING PROTEIN) TO BDNF PROMOTERS IN VTA, WHICH RESULTED FROM ENRICHMENT OF TRIMETHYLATED H3K27 AT THE PROMOTERS, AND THAT DECREASED NURR1 (NUCLEAR RECEPTOR RELATED-1) EXPRESSION ALSO CONTRIBUTED TO BDNF REPRESSION AND ASSOCIATED BEHAVIORAL PLASTICITY TO MORPHINE. OUR FINDINGS SUGGEST PREVIOUSLY UNKNOWN EPIGENETIC MECHANISMS OF MORPHINE-INDUCED MOLECULAR AND BEHAVIORAL NEUROADAPTATIONS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  1299  24 DECREASED REELIN EXPRESSION IN THE LEFT PREFRONTAL CORTEX (BA9) IN CHRONIC SCHIZOPHRENIA PATIENTS. BACKGROUND: REELIN IS UNDER EPIGENETIC CONTROL AND HAS BEEN REPORTED TO BE DECREASED IN CORTICAL REGIONS IN SCHIZOPHRENIA. METHODS: TO ESTABLISH IF EXPRESSION OF REELIN IS ALTERED IN SPECIFIC CORTICAL, HIPPOCAMPAL OR THALAMIC REGIONS OF SCHIZOPHRENIA PATIENTS, WE MEASURED GENE EXPRESSION OF REELIN IN A POSTMORTEM STUDY OF ELDERLY PATIENTS WITH SCHIZOPHRENIA AND NON-AFFECTED CONTROLS IN BOTH HEMISPHERES DIFFERENTIATING BETWEEN GRAY AND WHITE MATTER. WE COMPARED CEREBRAL POSTMORTEM SAMPLES (DORSOLATERAL PREFRONTAL CORTEX BA9 AND BA46, SUPERIOR TEMPORAL CORTEX BA22, ENTORHINAL CORTEX BA28, SENSORIC CORTEX BA1-3, HIPPOCAMPUS, CA4, MEDIODORSAL NUCLEUS OF THE THALAMUS) FROM 12 SCHIZOPHRENIA PATIENTS WITH 13 NORMAL SUBJECTS INVESTIGATING GENE EXPRESSION OF REELIN IN THE GRAY AND WHITE MATTER OF BOTH HEMISPHERES BY IN SITU-HYBRIDIZATION. RESULTS: THE LEFT PREFRONTAL AREA (BA9) OF SCHIZOPHRENIA PATIENTS REVEALED A DECREASED EXPRESSION OF REELIN-MRNA OF 29.1% IN THE WHITE (P = 0.022) AND 13.6% IN THE GRAY MATTER (P = 0.007) COMPARED TO THE CONTROL GROUP. NONE OF THE OTHER REGIONS EXAMINED SHOWED ANY STATISTICALLY SIGNIFICANT DIFFERENCES. CONCLUSION: SINCE REELIN IS RESPONSIBLE FOR MIGRATION AND SYNAPSE FORMATION, THE DECREASED GENE EXPRESSION OF REELIN IN THE LEFT PREFRONTAL AREA OF SCHIZOPHRENIA PATIENTS POINTS TO NEURODEVELOPMENTAL DEFICITS IN NEURONAL MIGRATION AND SYNAPTIC PLASTICITY. HOWEVER, OUR STUDY GROUP WAS SMALL, AND RESULTS SHOULD BE VERIFIED USING LARGER SAMPLES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  1949  26 EPIGENETIC ACTIVATION OF ASCT2 IN THE HIPPOCAMPUS CONTRIBUTES TO DEPRESSION-LIKE BEHAVIOR BY REGULATING D-SERINE IN MICE. THE ROLES OF D-SERINE IN DEPRESSION ARE RAISED CONCERNED RECENTLY AS AN INTRINSIC CO-AGONIST FOR THE NMDA RECEPTOR. HOWEVER, THE MECHANISMS UNDERLYING ITS REGULATION ARE NOT FULLY ELUCIDATED. ASCT2 IS A NA(+)-DEPENDENT D-SERINE TRANSPORTER. WE FOUND THAT DECREASED D-SERINE AND INCREASED HIPPOCAMPAL ASCT2 LEVELS CORRELATED WITH CHRONIC SOCIAL DEFEAT STRESS (CSDS) IN MICE. LENTIVIRUS-MEDIATED SHRNA-MEDIATED KNOCKDOWN OF ASCT2 AND THE ADMINISTRATION OF EXOGENOUS D-SERINE IN THE HIPPOCAMPUS ALLEVIATED CSDS-INDUCED SOCIAL AVOIDANCE AND IMMOBILITY. IN VIVO AND IN VITRO EXPERIMENTS REVEALED THAT UPREGULATION OF ASCT2 EXPRESSION IN CSDS WAS REGULATED THROUGH HISTONE HYPER-ACETYLATION, NOT DNA METHYLATION IN ITS PROMOTER REGION. IMMUNOHISTOCHEMISTRY DEMONSTRATED THE CO-LOCALIZATION OF ASCT2 AND D-SERINE. UPTAKE OF D-SERINE BY ASCT2 WAS DEMONSTRATED BY IN VIVO AND IN VITRO EXPERIMENTS. OUR RESULTS INDICATE THAT CSDS INDUCES ASCT2 EXPRESSION THROUGH EPIGENETIC ACTIVATION AND DECREASES HIPPOCAMPAL D-SERINE LEVELS, LEADING TO SOCIAL AVOIDANCE, AND IMMOBILITY. THUS, TARGETING D-SERINE TRANSPORT REPRESENTS AN ATTRACTIVE NEW STRATEGY FOR TREATING DEPRESSION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  2358  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  1421  23 DIFFERENTIAL BRAIN ADRA2A AND ADRA2C GENE EXPRESSION AND EPIGENETIC REGULATION IN SCHIZOPHRENIA. EFFECT OF ANTIPSYCHOTIC DRUG TREATMENT. POSTSYNAPTIC ALPHA(2A)-ADRENOCEPTOR DENSITY IS ENHANCED IN THE DORSOLATERAL PREFRONTAL CORTEX (DLPFC) OF ANTIPSYCHOTIC-TREATED SCHIZOPHRENIA SUBJECTS. THIS ALTERATION MIGHT BE DUE TO TRANSCRIPTIONAL ACTIVATION, AND COULD BE REGULATED BY EPIGENETIC MECHANISMS SUCH AS HISTONE POSTTRANSLATIONAL MODIFICATIONS (PTMS). THE AIM OF THIS STUDY WAS TO EVALUATE ADRA2A AND ADRA2C GENE EXPRESSION (CODIFYING FOR ALPHA(2)-ADRENOCEPTOR SUBTYPES), AND PERMISSIVE AND REPRESSIVE HISTONE PTMS AT GENE PROMOTER REGIONS IN THE DLPFC OF SUBJECTS WITH SCHIZOPHRENIA AND MATCHED CONTROLS (N = 24 PAIRS). WE STUDIED THE EFFECT OF ANTIPSYCHOTIC (AP) TREATMENT IN AP-FREE (N = 12) AND AP-TREATED (N = 12) SUBGROUPS OF SCHIZOPHRENIA SUBJECTS AND IN RATS ACUTELY AND CHRONICALLY TREATED WITH TYPICAL AND ATYPICAL ANTIPSYCHOTICS. ADRA2A MRNA EXPRESSION WAS SELECTIVELY UPREGULATED IN AP-TREATED SCHIZOPHRENIA SUBJECTS (+93%) WHEREAS ADRA2C MRNA EXPRESSION WAS UPREGULATED IN ALL SCHIZOPHRENIA SUBJECTS (+53%) REGARDLESS OF ANTIPSYCHOTIC TREATMENT. ACUTE AND CHRONIC CLOZAPINE TREATMENT IN RATS DID NOT ALTER BRAIN CORTEX ADRA2A MRNA EXPRESSION BUT INCREASED ADRA2C MRNA EXPRESSION. BOTH ADRA2A AND ADRA2C PROMOTER REGIONS SHOWED EPIGENETIC MODIFICATION BY HISTONE METHYLATION AND ACETYLATION IN HUMAN DLPFC. THE UPREGULATION OF ADRA2A EXPRESSION IN AP-TREATED SCHIZOPHRENIA SUBJECTS MIGHT BE RELATED TO OBSERVED BIVALENT CHROMATIN AT ADRA2A PROMOTER REGION IN SCHIZOPHRENIA (DEPICTED BY INCREASED PERMISSIVE H3K4ME3 AND REPRESSIVE H3K27ME3) AND COULD BE TRIGGERED BY THE ENHANCED H4K16AC AT ADRA2A PROMOTER. IN CONCLUSION, EPIGENETIC PREDISPOSITION DIFFERENTIALLY MODULATED ADRA2A AND ADRA2C MRNA EXPRESSION IN DLPFC OF SCHIZOPHRENIA SUBJECTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  1783  24 EFFECT OF AGOMELATINE ON MEMORY DEFICITS AND HIPPOCAMPAL GENE EXPRESSION INDUCED BY CHRONIC SOCIAL DEFEAT STRESS IN MICE. CHRONIC STRESS IS KNOWN TO INDUCE NOT ONLY ANXIETY AND DEPRESSIVE-LIKE PHENOTYPES IN MICE BUT ALSO COGNITIVE IMPAIRMENTS, FOR WHICH THE ACTION OF CLASSICAL ANTIDEPRESSANT COMPOUNDS REMAINS UNSATISFACTORY. IN THIS CONTEXT, WE INVESTIGATED THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS (CSDS) ON ANXIETY-, SOCIAL- AND COGNITIVE-RELATED BEHAVIORS, AS WELL AS HIPPOCAMPAL BDNF, SYNAPTIC PLASTICITY MARKERS (PSD-95, SYNAPTOPHYSIN, SPINOPHILIN, SYNAPSIN I AND MAP-2), AND EPIGENETIC MODIFYING ENZYMES (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) GENE EXPRESSION IN C57BL/6J MICE. CSDS FOR 10 DAYS PROVOKED LONG-LASTING ANXIOUS-LIKE PHENOTYPE IN THE OPEN FIELD AND EPISODIC MEMORY DEFICITS IN THE NOVEL OBJECT RECOGNITION TEST. WHILE TOTAL BDNF MRNA LEVEL WAS UNCHANGED, BDNF EXON IV, MAP-2, HDAC2, HDAC6 AND MLL3 GENE EXPRESSION WAS SIGNIFICANTLY DECREASED IN THE CSDS MOUSE HIPPOCAMPUS. IN CSDS MICE TREATED 3 WEEKS WITH 50 MG/KG/D AGOMELATINE, AN ANTIDEPRESSANT WITH MELATONERGIC RECEPTOR AGONIST AND 5-HT(2C) RECEPTOR ANTAGONIST PROPERTIES, THE ANXIOUS-LIKE PHENOTYPE WAS NOT REVERSED, BUT THE TREATMENT SUCCESSFULLY PREVENTED THE COGNITIVE IMPAIRMENTS AND HIPPOCAMPAL GENE EXPRESSION MODIFICATIONS. ALTOGETHER, THESE DATA EVIDENCED THAT, IN MICE, AGOMELATINE WAS EFFECTIVE IN ALLEVIATING STRESS-INDUCED ALTERED COGNITIVE FUNCTIONS, POSSIBLY THROUGH A MECHANISM INVOLVING BDNF SIGNALING, SYNAPTIC PLASTICITY AND EPIGENETIC REMODELING.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3986  26 LONG-TERM OVARIECTOMY INCREASES BDNF GENE METHYLATION STATUS IN MOUSE HIPPOCAMPUS. ESTRADIOL (E) HAS BEEN SUGGESTED TO HAVE A NEUROPROTECTIVE EFFECT IN YOUNG ANIMALS BUT HAS NEUTRAL OR HARMFUL EFFECTS WHEN IT IS ADMINISTERED TO AGED ANIMALS. IN THE PRESENT STUDY, WE DETERMINED WHETHER THE POST-OVARIECTOMY (POST-OVX) TIMEFRAME ELAPSED BEFORE THE INITIATION OF CHRONIC E TREATMENT IS CRITICAL FOR THE ESTROGENIC INDUCTION OF NEUROTROPHINS (BRAIN-DERIVED NEUROTROPHIC FACTOR, BDNF, AND SYNAPTOPHYSIN, SYN) IN THE RODENT HIPPOCAMPUS. ADULT MICE WERE OVX AND, A SHORT PERIOD (SHORT-TERM E (STE) ANIMALS) OR A LONG PERIOD (LONG-TERM E (LTE) ANIMALS) AFTER THE OVX, WERE DAILY TREATED WITH E. CONTROL ANIMALS WERE TREATED WITH SESAME OIL (SHORT-TERM CONTROL (STC) AND LONG-TERM CONTROL (LTC) ANIMALS). PROTEIN EXPRESSION WAS DETERMINED USING AN IMMUNOHISTOCHEMICAL APPROACH. TRANSCRIPTIONAL ACTIVITY IN THE HIPPOCAMPUS OF INDIVIDUAL BDNF PROMOTERS WAS ASSESSED BY REAL-TIME QUANTITATIVE RT-PCR, AND THE METHYLATION LEVELS OF REGULATORY REGIONS WERE ANALYZED BY METHYLATION-SPECIFIC PCR AND COMBINED BISULFITE RESTRICTION ANALYSIS. STE ANIMALS SHOWED INCREASED BDNF AND SYN PROTEIN EXPRESSION AND A HIGHER ACTIVITY OF BDNF II, IV, AND V PROMOTERS. IN CONTRAST, LTE ANIMALS DID NOT SHOW E INDUCTION OF NEUROTROPHINS. IN THESE ANIMALS, THE METHYLATION LEVELS OF REGULATORY SEQUENCES OF THE BDNF WERE HIGHER THAN IN THE STE ANIMALS IN A CPG ISLAND OF PROMOTER V AND IN THE CRE REGULATORY SITE LOCATED IN PROMOTER IV. WITH THIS EXPERIMENT, WE DETERMINED THAT A PROLONGED PERIOD OF HYPOESTROGENICITY DISRUPTS THE E-INDUCTION OF NEUROTROPHINS, AND WE POSTULATED THAT DNA METHYLATION IS ONE OF THE EPIGENETIC MECHANISMS THAT COULD EXPLAIN THE E-INSENSITIVITY OF THE BDNF AFTER A LONG PERIOD POST-OVX.	2014