1 5201 154 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 2 6602 30 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 3 3325 34 HISTONE DEACETYLASE 2-MEDIATED EPIGENETIC REGULATION IS INVOLVED IN THE EARLY ISOFLURANE EXPOSURE-RELATED INCREASE IN SUSCEPTIBILITY TO ANXIETY-LIKE BEHAVIOUR EVOKED BY CHRONIC VARIABLE STRESS IN MICE. INCREASING STUDIES REPORT THAT PROLONGED OR MULTIPLE ANAESTHETIC EXPOSURES EARLY IN LIFE ARE ASSOCIATED WITH DETRIMENTAL EFFECTS ON BRAIN FUNCTION. ALTHOUGH STUDIES HAVE EVALUATED THE DETRIMENTAL EFFECTS ON NEUROCOGNITIVE FUNCTION, FEW HAVE FOCUSED ON LONG-TERM NEUROPSYCHIATRIC EFFECTS. IN THE PRESENT STUDY, C57BL/6 MICE RECEIVED EITHER THREE NEONATAL ISOFLURANE EXPOSURES OR CONTROL EXPOSURE. STARTING ON POSTNATAL DAY 45, THE MICE WERE EITHER EXPOSED OR NOT TO A CHRONIC VARIABLE STRESS (CVS) PARADIGM, AND CVS-RELATED NEUROPSYCHIATRIC PERFORMANCE WAS EVALUATED USING A SERIES OF BEHAVIOURAL TESTS. THE EXPRESSION LEVELS OF HISTONE 3 LYSINE 9 ACETYLATION (ACETYL-H3K9), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN, AND HISTONE DEACETYLASES 1-4 IN THE AMYGDALA WERE MEASURED BY IMMUNOBLOTTING OR IMMUNOHISTOCHEMISTRY ANALYSIS. IN MICE WITH NEONATAL ISOFLURANE EXPOSURE, THE EFFECTS OF SODIUM BUTYRATE (NAB), A COMMONLY USED HDAC INHIBITOR, WERE EXAMINED ON CVS-RELATED BEHAVIOURAL AND MOLECULAR ALTERATIONS. THE RESULTS SHOWED THAT REPEATED NEONATAL ISOFLURANE EXPOSURE DID NOT AFFECT INNATE DEPRESSION-LIKE AND ANXIETY-LIKE BEHAVIOURS UNDER NON-STRESS CONDITIONS BUT FACILITATED THE CVS-INDUCED ANXIETY-LIKE BEHAVIOURAL PHENOTYPE. INCREASED HDAC2 EXPRESSION IN THE AMYGDALA WAS ASSOCIATED WITH AN INCREASE IN THE CVS-INDUCED REPRESSION OF ACETYL-H3K9 AND BDNF EXPRESSION AND AN ENHANCED CVS-EVOKED ANXIETY-LIKE BEHAVIOURAL PHENOTYPE IN MICE NEONATAL ISOFLURANE EXPOSURE. NAB SIGNIFICANTLY DECREASED THE CVS-INDUCED ANXIETY LEVEL BY ELEVATING ACETYL-H3K9 AND BDNF EXPRESSION. THESE RESULTS SUGGESTED THAT EARLY ANAESTHESIA EXPOSURE FACILITATED CHRONIC STRESS-INDUCED NEUROPSYCHIATRIC OUTCOMES, AND THE HDAC2-RELATED EPIGENETIC DYSREGULATION OF BDNF GENE EXPRESSION IS INVOLVED IN THE UNDERLYING MECHANISM. 2021 4 1330 38 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 5 5152 31 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 6 5838 35 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 7 4499 37 MORPHINE WITHDRAWAL PRODUCES ERK-DEPENDENT AND ERK-INDEPENDENT EPIGENETIC MARKS IN NEURONS OF THE NUCLEUS ACCUMBENS AND LATERAL SEPTUM. EPIGENETIC CHANGES SUCH AS COVALENT MODIFICATIONS OF HISTONE PROTEINS REPRESENT COMPLEX MOLECULAR SIGNATURES THAT PROVIDE A CELLULAR MEMORY OF PREVIOUSLY EXPERIENCED STIMULI WITHOUT IRREVERSIBLE CHANGES OF THE GENETIC CODE. IN THIS STUDY WE SHOW THAT NEW GENE EXPRESSION INDUCED IN VIVO BY MORPHINE WITHDRAWAL OCCURS WITH CONCOMITANT EPIGENETIC MODIFICATIONS IN BRAIN REGIONS CRITICALLY INVOLVED IN DRUG-DEPENDENT BEHAVIORS. WE FOUND THAT NALOXONE-PRECIPITATED WITHDRAWAL, BUT NOT CHRONIC MORPHINE ADMINISTRATION, CAUSED A STRONG INDUCTION OF PHOSPHO-HISTONE H3 IMMUNOREACTIVITY IN THE NUCLEUS ACCUMBENS (NAC) SHELL/CORE AND IN THE LATERAL SEPTUM (LS), A CHANGE THAT WAS ACCOMPANIED BY AUGMENTED H3 ACETYLATION (LYS14) IN NEURONS OF THE NAC SHELL. MORPHINE WITHDRAWAL INDUCED THE PHOSPHORYLATION OF THE EPIGENETIC FACTOR METHYL-CPG-BINDING PROTEIN 2 (MECP2) IN SER421 BOTH IN THE LS AND THE NAC SHELL. THESE EPIGENETIC CHANGES WERE ACCOMPANIED BY THE ACTIVATION OF MEMBERS OF THE ERK PATHWAY AS WELL AS INCREASED EXPRESSION OF THE IMMEDIATE EARLY GENES (IEG) C-FOS AND ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN (ARC/ARG3.1). USING A PHARMACOLOGICAL APPROACH, WE FOUND THAT H3 PHOSPHORYLATION AND IEG EXPRESSION WERE PARTIALLY DEPENDENT ON ERK ACTIVATION, WHILE MECP2 PHOSPHORYLATION WAS FULLY ERK-INDEPENDENT. THESE FINDINGS PROVIDE NEW IMPORTANT INFORMATION ON THE ROLE OF THE ERK PATHWAY IN THE REGULATION OF EPIGENETIC MARKS AND GENE EXPRESSION THAT MAY CONCUR TO REGULATE IN VIVO THE CELLULAR CHANGES UNDERLYING THE ONSET OF THE OPIOID WITHDRAWAL SYNDROME. 2013 8 1706 43 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 9 879 34 CHRONIC CHEMOGENETIC STIMULATION OF THE NUCLEUS ACCUMBENS PRODUCES LASTING REDUCTIONS IN BINGE DRINKING AND AMELIORATES ALCOHOL-RELATED MORPHOLOGICAL AND TRANSCRIPTIONAL CHANGES. BINGE DRINKING IS A DANGEROUS PATTERN OF BEHAVIOR. WE TESTED WHETHER CHRONICALLY MANIPULATING NUCLEUS ACCUMBENS (NAC) ACTIVITY (VIA CLOZAPINE-N-OXIDE (CNO) AND DESIGNER RECEPTORS EXCLUSIVELY ACTIVATED BY DESIGNER DRUGS (DREADD)) COULD PRODUCE LASTING EFFECTS ON ETHANOL BINGE-LIKE DRINKING IN MICE SELECTIVELY BRED TO DRINK TO INTOXICATION. WE FOUND CHRONICALLY INCREASING NAC ACTIVITY (4 WEEKS, VIA CNO AND THE EXCITATORY DREADD, HM3DQ) DECREASED BINGE-LIKE DRINKING, BUT DID NOT OBSERVE CNO-INDUCED CHANGES IN DRINKING WITH THE INHIBITORY DREADD, HM4DI. THE CNO/HM3DQ-INDUCED REDUCTION IN ETHANOL DRINKING PERSISTED FOR AT LEAST ONE WEEK, SUGGESTING ADAPTIVE NEUROPLASTICITY VIA TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS. THEREFORE, WE DEFINED THIS PLASTICITY AT THE MORPHOLOGICAL AND TRANSCRIPTOMIC LEVELS. WE FOUND THAT CHRONIC BINGE DRINKING (6 WEEKS) ALTERED NEURONAL MORPHOLOGY IN THE NAC, AN EFFECT THAT WAS AMELIORATED WITH CNO/HM3DQ. MOREOVER, WE DETECTED SIGNIFICANT CHANGES IN EXPRESSION OF SEVERAL PLASTICITY-RELATED GENES WITH BINGE DRINKING THAT WERE AMELIORATED WITH CNO TREATMENT (E.G., HDAC4). LASTLY, WE FOUND THAT LMK235, AN HDAC4/5 INHIBITOR, REDUCED BINGE-LIKE DRINKING. THUS, WE WERE ABLE TO TARGET SPECIFIC MOLECULAR PATHWAYS USING PHARMACOLOGY TO MIMIC THE BEHAVIORAL EFFECTS OF DREADDS. 2020 10 5339 26 QUETIAPINE TREATMENT REVERSES DEPRESSIVE-LIKE BEHAVIOR AND REDUCES DNA METHYLTRANSFERASE ACTIVITY INDUCED BY MATERNAL DEPRIVATION. STRESS IN EARLY LIFE HAS BEEN APPOINTED AS AN IMPORTANT PHENOMENON IN THE ONSET OF DEPRESSION AND POOR RESPONSE TO TREATMENT WITH CLASSICAL ANTIDEPRESSANTS. FURTHERMORE, CHILDHOOD TRAUMA TRIGGERS EPIGENETIC CHANGES, WHICH ARE ASSOCIATED WITH THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER (MDD). TREATMENT WITH ATYPICAL ANTIPSYCHOTICS SUCH AS QUETIAPINE, EXERTS THERAPEUTIC EFFECT FOR MDD PATIENTS AND INDUCES EPIGENETIC CHANGES. THIS STUDY AIMED TO ANALYZE THE EFFECT OF CHRONIC TREATMENT WITH QUETIAPINE (20MG/KG) ON DEPRESSIVE-LIKE BEHAVIOR OF RATS SUBMITTED TO MATERNAL DEPRIVATION (MD), AS WELL AS THE ACTIVITY OF HISTONE ACETYLATION BY THE ENZYMES HISTONE ACETYL TRANSFERASES (HAT) AND DEACETYLASES (HDAC) AND DNA METHYLATION, THROUGH DNA METHYLTRANSFERASE ENZYME (DNMT) IN THE PREFRONTAL CORTEX (PFC), NUCLEUS ACCUMBENS (NAC) AND HIPPOCAMPUS. MATERNALLY DEPRIVED RATS HAD A DEPRESSIVE-LIKE BEHAVIOR IN THE FORCED SWIMMING TEST AND AN INCREASE IN THE HDAC AND DNMT ACTIVITIES IN THE HIPPOCAMPUS AND NAC. TREATMENT WITH QUETIAPINE REVERSED DEPRESSIVE-LIKE BEHAVIOR AND REDUCED THE DNMT ACTIVITY IN THE HIPPOCAMPUS. THIS IS THE FIRST STUDY TO SHOW THE ANTIDEPRESSANT-LIKE EFFECT OF QUETIAPINE IN ANIMALS SUBJECTED TO MD AND A PROTECTIVE EFFECT BY QUETIAPINE IN REDUCING EPIGENETIC CHANGES INDUCED BY STRESS IN EARLY LIFE. THESE RESULTS REINFORCE AN IMPORTANT ROLE OF QUETIAPINE AS THERAPY FOR MDD. 2017 11 889 35 CHRONIC DIETARY ADMINISTRATION OF VALPROIC ACID PROTECTS NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS FROM IBOTENIC ACID NEUROTOXICITY. VALPROIC ACID (VPA) HAS BEEN USED FOR MANY YEARS AS A DRUG OF CHOICE FOR EPILEPSY AND MOOD DISORDERS. RECENTLY, EVIDENCE HAS BEEN PROPOSED FOR A WIDE SPECTRUM OF ACTIONS OF THIS DRUG, INCLUDING ANTITUMORAL AND NEUROPROTECTIVE PROPERTIES. VALPROIC ACID-MEDIATED NEUROPROTECTION IN VIVO HAS BEEN SO FAR DEMONSTRATED IN A LIMITED NUMBER OF EXPERIMENTAL MODELS. IN THIS STUDY, WE HAVE TESTED THE NEUROPROTECTIVE POTENTIAL OF CHRONIC (4 + 1 WEEKS) DIETARY ADMINISTRATION OF VPA ON DEGENERATION OF CHOLINERGIC AND GABAERGIC NEURONS OF THE RAT NUCLEUS BASALIS MAGNOCELLULARIS (NBM), INJECTED WITH THE EXCITOTOXIN, IBOTENIC ACID (IBO), AN ANIMAL MODELS THAT IS RELEVANT FOR ALZHEIMER'S DISEASE-LIKE NEURODEGENERATION. WE SHOW THAT VPA TREATMENT SIGNIFICANTLY PROTECTS BOTH CHOLINERGIC AND GABAERGIC NEURONS PRESENT IN THE INJECTED AREA FROM THE EXCITOTOXIC INSULT. A SIGNIFICANT LEVEL OF NEUROPROTECTION, IN PARTICULAR, IS EXERTED TOWARDS THE CHOLINERGIC NEURONS OF THE NBM PROJECTING TO THE CORTEX, AS DEMONSTRATED BY THE SUBSTANTIALLY HIGHER LEVELS OF CHOLINERGIC MARKERS MAINTAINED IN THE TARGET CORTICAL AREA OF VPA-TREATED RATS AFTER IBO INJECTION IN THE NBM. WE FURTHER SHOW THAT CHRONIC VPA ADMINISTRATION RESULTS IN INCREASED ACETYLATION OF HISTONE H3 IN BRAIN, CONSISTENT WITH THE HISTONE DEACETYLASE INHIBITORY ACTION OF VPA AND PUTATIVELY LINKED TO A NEUROPROTECTIVE ACTION OF THE DRUG MEDIATED AT THE EPIGENETIC LEVEL. 2009 12 5503 30 RGS9-2--CONTROLLED ADAPTATIONS IN THE STRIATUM DETERMINE THE ONSET OF ACTION AND EFFICACY OF ANTIDEPRESSANTS IN NEUROPATHIC PAIN STATES. THE STRIATAL PROTEIN REGULATOR OF G-PROTEIN SIGNALING 9-2 (RGS9-2) PLAYS A KEY MODULATORY ROLE IN OPIOID, MONOAMINE, AND OTHER G-PROTEIN-COUPLED RECEPTOR RESPONSES. HERE, WE USE THE MURINE SPARED-NERVE INJURY MODEL OF NEUROPATHIC PAIN TO INVESTIGATE THE MECHANISM BY WHICH RGS9-2 IN THE NUCLEUS ACCUMBENS (NAC), A BRAIN REGION INVOLVED IN MOOD, REWARD, AND MOTIVATION, MODULATES THE ACTIONS OF TRICYCLIC ANTIDEPRESSANTS (TCAS). PREVENTION OF RGS9-2 ACTION IN THE NAC INCREASES THE EFFICACY OF THE TCA DESIPRAMINE AND DRAMATICALLY ACCELERATES ITS ONSET OF ACTION. BY CONTROLLING THE ACTIVATION OF EFFECTOR MOLECULES BY G PROTEIN ALPHA AND BETAGAMMA SUBUNITS, RGS9-2 AFFECTS SEVERAL PROTEIN INTERACTIONS, PHOSPHOPROTEIN LEVELS, AND THE FUNCTION OF THE EPIGENETIC MODIFIER HISTONE DEACETYLASE 5, WHICH ARE IMPORTANT FOR TCA RESPONSIVENESS. FURTHERMORE, INFORMATION FROM RNA-SEQUENCING ANALYSIS REVEALS THAT RGS9-2 IN THE NAC AFFECTS THE EXPRESSION OF MANY GENES KNOWN TO BE INVOLVED IN NOCICEPTION, ANALGESIA, AND ANTIDEPRESSANT DRUG ACTIONS. OUR FINDINGS PROVIDE NOVEL INFORMATION ON NAC-SPECIFIC CELLULAR MECHANISMS THAT MEDIATE THE ACTIONS OF TCAS IN NEUROPATHIC PAIN STATES. 2015 13 2886 27 GABA-AALPHA5 MIGHT BE INVOLVED IN LEARNING-MEMORY DYSFUNCTION IN THE OFFSPRINGS OF CHRONIC ETHANOL-TREATED RATS VIA GABA-AALPHA5 HISTONE H3K9 ACETYLATION. RECENTLY, NUMEROUS STUDIES HAVE BEEN FOCUSED ON THE RELATIONSHIP BETWEEN GABA-A RECEPTORS AND ALCOHOL-INDUCED SPATIAL LEARNING AND MEMORY DEFICITS. GABA-AALPHA5, A SUBUNIT OF GABA-A RECEPTORS, IS CONSIDERED TO PLAY AN IMPORTANT ROLE IN ALCOHOL-INDUCED COGNITIVE IMPAIRMENT, HOWEVER, THE MECHANISM REMAINS OBSCURE. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF GABA-AALPHA5 INCREASED IN RATS TREATED WITH CHRONIC ETHANOL VIA HISTONE H3K9 ACETYLATION. FURTHERMORE, THIS EPIGENETIC MODIFICATION COULD BE INHERITED BY THE NEXT GENERATIONS, WHICH EVENTUALLY EXHIBIT SIMILAR SPATIAL LEARNING AND MEMORY DEFICITS IN THE OFFSPRINGS. IN SUMMARY, OUR RESULTS SUGGESTED THAT GABA-AALPHA5 MIGHT BE INVOLVED IN CHRONIC ETHANOL TREATMENT-INDUCED LEARNING-MEMORY DYSFUNCTION AND FOR THE FIRST TIME PROVED THAT LEARNING-MEMORY DYSFUNCTION COULD BE INHERITED BY THE OFFSPRINGS VIA HISTONE H3K9 ACETYLATION. HOPEFULLY, IN THE NEAR FUTURE, GABA-AALPHA5 INHIBITORS WOULD BE AN EFFECTIVE WAY TO TREAT ALCOHOL-INDUCED COGNITION IMPAIRMENT. 2019 14 5713 30 SIRT2 INHIBITION REVERSES ANHEDONIA IN THE VGLUT1+/- DEPRESSION MODEL. SOME HISTONE DEACETYLASE (HDACS) ENZYMES HAVE BEEN PROPOSED AS EPIGENETIC TARGETS INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION AND ANTIDEPRESSANT-LIKE ACTION. AMONG THEM, WE HAVE RECENTLY IDENTIFIED SIRT2, A CLASS III NAD(+)-DEPENDENT HDAC, AS BEING OPPOSITELY REGULATED BY STRESS AND ANTIDEPRESSANTS. MOREOVER, SIRT2 INHIBITION HAS SHOWN ANTIANHEDONIC-LIKE ACTION IN THE CHRONIC MILD STRESS MODEL OF DEPRESSION. HERE WE HAVE EXTENDED THE STUDY USING AN ALTERNATIVE MODEL OF DEPRESSION BASED IN A GENETIC MANIPULATION OF GLUTAMATE FUNCTION. SPECIFICALLY, MICE HETEROZYGOUS FOR THE VESICULAR GLUTAMATE TRANSPORTER 1 (VGLUT1+/-) WERE USED. FIRSTLY, MRNA EXPRESSION OF THE DIFFERENT MEMBERS OF THE HDAC SUPERFAMILY IN THE PREFRONTAL CORTEX (PFC) OF VGLUT1+/- MICE AND WT LITTERMATES WERE STUDIED BY RT-PCR. SECONDLY, THE EFFECT OF REPEATED TREATMENT WITH THE SELECTIVE SIRT2 INHIBITOR 33I AND THE ANTIDEPRESSANT IMIPRAMINE ON ANHEDONIC BEHAVIOUR OF VGLUT1+/- MICE WAS STUDIED BY WEEKLY MONITORING OF SUCROSE INTAKE. FURTHER, THE INTERACTION OF 33I TOWARDS SPECIFIC MONOAMINERGIC TARGETS SUCH AS SEROTONIN OR NORADRENALINE TRANSPORTERS AS WELL AS THE MONOAMINOOXIDASE ENZYME WAS STUDIED. THE MRNA OCCURANCE OF THE DIFFERENT MEMBERS OF HDAC SUPERFAMILY WAS NOT ALTERED IN THE PFC OF VGLUT1+/- MICE. WHILE REPEATED IMIPRAMINE SHOWED AN ANTI-ANHEDONIC ACTION IN BOTH VGLUT1+/- AND WT, THE SELECTIVE SIRT2 INHIBITOR 33I FULLY REVERSED ANHEDONIA OF VGLUT1+/-. FURTHER, 33I SHOWED NO INTERACTION WITH THE ABOVE MENTIONED MONOAMINERGIC MOLECULAR TARGETS. THESE RESULTS CONFIRM THAT SIRT2 INHIBITION IS ABLE TO REVERSE ANHEDONIA IN DIFFERENT ANIMAL MODELS AND HIGHLIGHT THE NEED TO FURTHER INVESTIGATE THE ROLE OF SIRT2 INHIBITORS AS NEW ANTIDEPRESSANT AGENTS. 2017 15 5832 26 STRESS-INDUCED EPIGENETIC CHANGES IN HIPPOCAMPAL MKP-1 PROMOTE PERSISTENT DEPRESSIVE BEHAVIORS. CHRONIC STRESS INDUCES PERSISTENT DEPRESSIVE BEHAVIORS. STRESS-INDUCED TRANSCRIPTIONAL ALTERATION OVER THE HOMEOSTATIC RANGE IN STRESS HORMONE-SENSITIVE BRAIN REGIONS IS BELIEVED TO UNDERLIE LONG-LASTING DEPRESSIVE BEHAVIORS. HOWEVER, THE DETAILED MECHANISMS BY WHICH CHRONIC STRESS CAUSES THOSE ADAPTIVE CHANGES ARE NOT CLEARLY UNDERSTOOD. IN THE PRESENT STUDY, WE INVESTIGATED WHETHER EPIGENETIC CHANGES REGULATE STRESS-INDUCED DEPRESSIVE BEHAVIORS. WE FOUND THAT CHRONIC STRESS IN MICE DOWNREGULATES THE EPIGENETIC FACTORS HDAC2 AND SUV39H1 IN THE HIPPOCAMPUS. A SERIES OF FOLLOW-UP ANALYSES INCLUDING CHIP ASSAY AND SIRNA-MEDIATED FUNCTIONAL ANALYSES REVEAL THAT GLUCOCORTICOIDS RELEASED BY STRESS CUMULATIVELY INCREASE MKP-1 EXPRESSION IN THE HIPPOCAMPUS, AND INCREASED MKP-1 THEN DEBILITATES P-CREB AND PPARGAMMA, WHICH IN TURN SUPPRESS THE EPIGENETIC FACTORS HDAC2 AND SUV39H1. FURTHERMORE, HDAC2 AND SUV39H1 NORMALLY SUPPRESS THE TRANSCRIPTION OF THE MKP-1, AND THEREFORE THE REDUCED EXPRESSION OF HDAC2 AND SUV39H1 INCREASES MKP-1 EXPRESSION. ACCORDINGLY, REPEATED STRESS PROGRESSIVELY STRENGTHENS A VICIOUS CYCLE OF THE MKP-1 SIGNALING CASCADE THAT FACILITATES DEPRESSIVE BEHAVIORS. THESE RESULTS SUGGEST THAT THE HIPPOCAMPAL STRESS ADAPTATION SYSTEM COMPRISING HDAC2/SUV39H1-REGULATED MKP-1 SIGNALING NETWORK DETERMINES THE VULNERABILITY TO CHRONIC STRESS AND THE MAINTENANCE OF DEPRESSIVE BEHAVIORS. 2019 16 786 27 CELL-TYPE-SPECIFIC EPIGENETIC EDITING AT THE FOSB GENE CONTROLS SUSCEPTIBILITY TO SOCIAL DEFEAT STRESS. CHRONIC SOCIAL DEFEAT STRESS REGULATES THE EXPRESSION OF FOSB IN THE NUCLEUS ACCUMBENS (NAC) TO PROMOTE THE CELL-TYPE-SPECIFIC ACCUMULATION OF DELTAFOSB IN THE TWO MEDIUM SPINY NEURON (MSN) SUBTYPES IN THIS REGION. DELTAFOSB IS SELECTIVELY INDUCED IN D1-MSNS IN THE NAC OF RESILIENT MICE, AND IN D2-MSNS OF SUSCEPTIBLE MICE. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENCES OF SUCH SELECTIVE INDUCTION, PARTICULARLY IN D2-MSNS. THIS STUDY EXAMINED HOW CELL-TYPE-SPECIFIC CONTROL OF THE ENDOGENOUS FOSB GENE IN NAC REGULATES SUSCEPTIBILITY TO SOCIAL DEFEAT STRESS. HISTONE POST-TRANSLATIONAL MODIFICATIONS (HPTMS) WERE TARGETED SPECIFICALLY TO FOSB USING ENGINEERED ZINC-FINGER PROTEINS (ZFPS). FOSB-ZFPS WERE FUSED TO EITHER THE TRANSCRIPTIONAL REPRESSOR, G9A, WHICH PROMOTES HISTONE METHYLATION OR THE TRANSCRIPTIONAL ACTIVATOR, P65, WHICH PROMOTES HISTONE ACETYLATION. THESE ZFPS WERE EXPRESSED IN D1- VS D2-MSNS USING CRE-DEPENDENT VIRAL EXPRESSION IN THE NAC OF MICE TRANSGENIC FOR CRE RECOMBINASE IN THESE MSN SUBTYPES. WE FOUND THAT STRESS SUSCEPTIBILITY IS OPPOSITELY REGULATED BY THE SPECIFIC CELL TYPE AND HPTM TARGETED. WE REPORT THAT FOSB-TARGETED HISTONE ACETYLATION IN D2-MSNS OR HISTONE METHYLATION IN D1-MSNS PROMOTES A STRESS-SUSCEPTIBLE, DEPRESSIVE-LIKE PHENOTYPE, WHILE HISTONE METHYLATION IN D2-MSNS OR HISTONE ACETYLATION IN D1-MSNS INCREASES RESILIENCE TO SOCIAL STRESS AS QUANTIFIED BY SOCIAL INTERACTION BEHAVIOR AND SUCROSE PREFERENCE. THIS WORK PRESENTS THE FIRST DEMONSTRATION OF CELL- AND GENE-SPECIFIC TARGETING OF HISTONE MODIFICATIONS, WHICH MODEL NATURALLY OCCURRING TRANSCRIPTIONAL PHENOMENA THAT CONTROL SOCIAL DEFEAT STRESS BEHAVIOR. THIS EPIGENETIC-EDITING APPROACH, WHICH RECAPITULATES PHYSIOLOGICAL CHANGES IN GENE EXPRESSION, REVEALS CLEAR DIFFERENCES IN THE SOCIAL DEFEAT PHENOTYPE INDUCED BY FOSB GENE MANIPULATION IN MSN SUBTYPES. 2018 17 5205 39 PRENATAL STRESS CHANGES THE GLYCOPROTEIN GPM6A GENE EXPRESSION AND INDUCES EPIGENETIC CHANGES IN RAT OFFSPRING BRAIN. PRENATAL STRESS (PS) EXERTS STRONG IMPACT ON FETAL BRAIN DEVELOPMENT AND ON ADULT OFFSPRING BRAIN FUNCTIONS. PREVIOUS WORK DEMONSTRATED THAT CHRONIC STRESS ALTERS THE MRNA EXPRESSION OF GPM6A, A NEURONAL GLYCOPROTEIN INVOLVED IN FILOPODIUM EXTENSION. IN THIS WORK, WE ANALYZED THE EFFECT OF PS ON GPM6A EXPRESSION AND THE EPIGENETIC MECHANISMS INVOLVED. PREGNANT WISTAR RATS RECEIVED RESTRAINT STRESS DURING THE LAST WEEK OF GESTATION. MALE OFFSPRING WERE SACRIFICED ON POSTNATAL DAYS 28 AND 60. HIPPOCAMPUS AND PREFRONTAL CORTEX SAMPLES WERE ANALYZED FOR GENE EXPRESSION (QPCR FOR MRNAS AND MICRORNAS), METHYLATION STATUS (BISULFITE CONVERSION) AND PROTEIN LEVELS. HIPPOCAMPAL NEURONS IN CULTURE WERE USED TO ANALYZE MICRORNA OVEREXPRESSION EFFECTS. PRENATAL STRESS INDUCED CHANGES IN GPM6A LEVELS IN BOTH TISSUES AND AT BOTH AGES ANALYZED, INDICATING A PERSISTENT EFFECT. TWO CPG ISLANDS IN THE GPM6A GENE WERE IDENTIFIED. VARIATIONS IN THE METHYLATION PATTERN AT THREE SPECIFIC CPGS WERE FOUND IN HIPPOCAMPUS, BUT NOT IN PFC SAMPLES FROM PS OFFSPRING. MICRORNAS PREDICTED TO TARGET GPM6A WERE IDENTIFIED IN SILICO. QPCR MEASUREMENTS SHOWED THAT PS MODIFIED THE EXPRESSION OF SEVERAL MICRORNAS IN BOTH TISSUES, BEING MICRORNA-133B THE MOST SIGNIFICANTLY ALTERED. FURTHER STUDIES OVEREXPRESSING THIS MICRORNA IN NEURONAL CULTURES SHOWED A REDUCTION IN GMP6A MRNA AND PROTEIN LEVEL. MOREOVER FILOPODIUM DENSITY WAS ALSO REDUCED, SUGGESTING THAT GPM6A FUNCTION WAS AFFECTED. GESTATIONAL STRESS AFFECTED GPM6A GENE EXPRESSION IN OFFSPRING LIKELY THROUGH CHANGES IN METHYLATION STATUS AND IN POSTTRANSCRIPTIONAL REGULATION BY MICRORNAS. THUS, OUR FINDINGS PROPOSE GPM6A AS A NOVEL TARGET FOR EPIGENETIC REGULATION DURING PRENATAL STRESS. 2014 18 3650 32 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 19 905 33 CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE CAUSES LONG-LASTING BEHAVIORAL DEFICITS IN ADULT MICE. REGULAR USE OF MARIJUANA DURING ADOLESCENCE ENHANCES THE RISK OF LONG-LASTING NEUROBIOLOGICAL CHANGES IN ADULTHOOD. THE PRESENT STUDY WAS AIMED AT ASSESSING THE EFFECT OF LONG-TERM ADMINISTRATION OF THE SYNTHETIC CANNABINOID WIN55212.2 DURING ADOLESCENCE IN YOUNG ADULT MICE. ADOLESCENT MICE AGED 5 WEEKS WERE SUBJECTED DAILY TO THE PHARMACOLOGICAL ACTION OF WIN55212.2 FOR 3 WEEKS AND WERE THEN LEFT UNDISTURBED IN THEIR HOME CAGE FOR A 5-WEEK PERIOD AND FINALLY EVALUATED BY BEHAVIORAL TESTING. MICE THAT RECEIVED THE DRUG DURING ADOLESCENCE SHOWED MEMORY IMPAIRMENT IN THE MORRIS WATER MAZE, AS WELL AS A DOSE-DEPENDENT MEMORY IMPAIRMENT IN FEAR CONDITIONING. IN ADDITION, THE ADMINISTRATION OF 3 MG/KG WIN55212.2 IN ADOLESCENCE INCREASED ADULT HIPPOCAMPAL AEA LEVELS AND PROMOTED DNA HYPERMETHYLATION AT THE INTRAGENIC REGION OF THE INTRACELLULAR SIGNALING MODULATOR RGS7, WHICH WAS ACCOMPANIED BY A LOWER RATE OF MRNA TRANSCRIPTION OF THIS GENE, SUGGESTING A POTENTIAL CAUSAL RELATION. ALTHOUGH THE CONCRETE MECHANISMS UNDERLYING THE BEHAVIORAL OBSERVATIONS REMAIN TO BE ELUCIDATED, WE DEMONSTRATE THAT LONG-TERM ADMINISTRATION OF 3 MG/KG OF WIN DURING ADOLESCENCE LEADS TO INCREASED ENDOCANNABINOID LEVELS AND ALTERED RGS7 EXPRESSION IN ADULTHOOD AND ESTABLISH A POTENTIAL LINK TO EPIGENETIC CHANGES. 2017 20 195 22 ACF CHROMATIN-REMODELING COMPLEX MEDIATES STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIOR. IMPROVED TREATMENT FOR MAJOR DEPRESSIVE DISORDER (MDD) REMAINS ELUSIVE BECAUSE OF THE LIMITED UNDERSTANDING OF ITS UNDERLYING BIOLOGICAL MECHANISMS. IT IS LIKELY THAT STRESS-INDUCED MALADAPTIVE TRANSCRIPTIONAL REGULATION IN LIMBIC NEURAL CIRCUITS CONTRIBUTES TO THE DEVELOPMENT OF MDD, POSSIBLY THROUGH EPIGENETIC FACTORS THAT REGULATE CHROMATIN STRUCTURE. WE ESTABLISH THAT PERSISTENT UPREGULATION OF THE ACF (ATP-UTILIZING CHROMATIN ASSEMBLY AND REMODELING FACTOR) ATP-DEPENDENT CHROMATIN-REMODELING COMPLEX, OCCURRING IN THE NUCLEUS ACCUMBENS OF STRESS-SUSCEPTIBLE MICE AND DEPRESSED HUMANS, IS NECESSARY FOR STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS. WE FOUND THAT ALTERED ACF BINDING AFTER CHRONIC STRESS WAS CORRELATED WITH ALTERED NUCLEOSOME POSITIONING, PARTICULARLY AROUND THE TRANSCRIPTION START SITES OF AFFECTED GENES. THESE ALTERATIONS IN ACF BINDING AND NUCLEOSOME POSITIONING WERE ASSOCIATED WITH REPRESSED EXPRESSION OF GENES IMPLICATED IN SUSCEPTIBILITY TO STRESS. TOGETHER, OUR FINDINGS IDENTIFY THE ACF CHROMATIN-REMODELING COMPLEX AS A CRITICAL COMPONENT IN THE DEVELOPMENT OF SUSCEPTIBILITY TO DEPRESSION AND IN REGULATING STRESS-RELATED BEHAVIORS. 2015