1 5503 108 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 2 5838 28 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 3 856 26 CHROMATIN ACCESSIBILITY MAPPING OF THE STRIATUM IDENTIFIES TYROSINE KINASE FYN AS A THERAPEUTIC TARGET FOR HEROIN USE DISORDER. THE CURRENT OPIOID EPIDEMIC NECESSITATES A BETTER UNDERSTANDING OF HUMAN ADDICTION NEUROBIOLOGY TO DEVELOP EFFICACIOUS TREATMENT APPROACHES. HERE, WE PERFORM GENOME-WIDE ASSESSMENT OF CHROMATIN ACCESSIBILITY OF THE HUMAN STRIATUM IN HEROIN USERS AND MATCHED CONTROLS. OUR STUDY REVEALS DISTINCT NEURONAL AND NON-NEURONAL EPIGENETIC SIGNATURES, AND IDENTIFIES A LOCUS IN THE PROXIMITY OF THE GENE ENCODING TYROSINE KINASE FYN AS THE MOST AFFECTED REGION IN NEURONS. FYN EXPRESSION, KINASE ACTIVITY AND THE PHOSPHORYLATION OF ITS TARGET TAU ARE INCREASED BY HEROIN USE IN THE POST-MORTEM HUMAN STRIATUM, AS WELL AS IN RATS TRAINED TO SELF-ADMINISTER HEROIN AND PRIMARY STRIATAL NEURONS TREATED WITH CHRONIC MORPHINE IN VITRO. PHARMACOLOGICAL OR GENETIC MANIPULATION OF FYN ACTIVITY SIGNIFICANTLY ATTENUATES HEROIN SELF-ADMINISTRATION AND RESPONDING FOR DRUG-PAIRED CUES IN RODENTS. OUR FINDINGS SUGGEST THAT STRIATAL FYN IS AN IMPORTANT DRIVER OF HEROIN-RELATED NEURODEGENERATIVE-LIKE PATHOLOGY AND DRUG-TAKING BEHAVIOR, MAKING FYN A PROMISING THERAPEUTIC TARGET FOR HEROIN USE DISORDER. 2020 4 195 19 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 5 3002 29 GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS FOR TREATMENT OF MAJOR DEPRESSION: THE 5-HT1A RECEPTOR GENE AS A PARADIGM. MAJOR DEPRESSION AND ANXIETY ARE HIGHLY PREVALENT AND INVOLVE CHRONIC DYSREGULATION OF SEROTONIN, BUT THEY REMAIN POORLY UNDERSTOOD. HERE, WE REVIEW NOVEL TRANSCRIPTIONAL (GENETIC, EPIGENETIC) AND POSTTRANSCRIPTIONAL (MICRORNA, ALTERNATIVE SPLICING) MECHANISMS IMPLICATED IN MENTAL ILLNESS, FOCUSING ON A KEY SEROTONIN-RELATED REGULATOR, THE SEROTONIN 1A (5-HT1A) RECEPTOR. FUNCTIONAL SINGLE-NUCLEOTIDE POLYMORPHISMS AND STRESS-INDUCED DNA METHYLATION OF THE 5-HT1A PROMOTER CONVERGE TO DIFFERENTIALLY ALTER PRE- AND POSTSYNAPTIC 5-HT1A RECEPTOR EXPRESSION ASSOCIATED WITH MAJOR DEPRESSION AND REDUCED THERAPEUTIC RESPONSE TO SEROTONERGIC ANTIDEPRESSANTS. MAJOR DEPRESSION IS ALSO ASSOCIATED WITH ALTERED LEVELS OF SPLICE FACTORS AND MICRORNA, POSTTRANSCRIPTIONAL MECHANISMS THAT REGULATE RNA STABILITY. THE HUMAN 5-HT1A 3'-UNTRANSLATED REGION IS ALTERNATIVELY SPLICED, REMOVING MICRORNA SITES AND INCREASING 5-HT1A EXPRESSION, WHICH IS REDUCED IN MAJOR DEPRESSION AND MAY BE GENOTYPE-DEPENDENT. THUS, THE 5-HT1A RECEPTOR GENE ILLUSTRATES THE CONVERGENCE OF GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS IN GENE EXPRESSION, NEURODEVELOPMENT AND NEUROPLASTICITY, AND MAJOR DEPRESSION. UNDERSTANDING GENE REGULATORY MECHANISMS COULD ENHANCE THE DETECTION, CATEGORIZATION AND PERSONALIZED TREATMENT OF MAJOR DEPRESSION. 2019 6 4499 33 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 7 984 34 CHRONIC PSYCHOLOGICAL STRESS ALTERS GENE EXPRESSION IN RAT COLON EPITHELIAL CELLS PROMOTING CHROMATIN REMODELING, BARRIER DYSFUNCTION AND INFLAMMATION. CHRONIC STRESS IS COMMONLY ASSOCIATED WITH ENHANCED ABDOMINAL PAIN (VISCERAL HYPERSENSITIVITY), BUT THE CELLULAR MECHANISMS UNDERLYING HOW CHRONIC STRESS INDUCES VISCERAL HYPERSENSITIVITY ARE POORLY UNDERSTOOD. IN THIS STUDY, WE EXAMINED CHANGES IN GENE EXPRESSION IN COLON EPITHELIAL CELLS FROM A RAT MODEL USING RNA-SEQUENCING TO EXAMINE STRESS-INDUCED CHANGES TO THE TRANSCRIPTOME. FOLLOWING CHRONIC STRESS, THE MOST SIGNIFICANTLY UP-REGULATED GENES INCLUDED ATG16L1, COQ10B, DCAF13, NAT2, PTBP2, RRAS2, SPINK4 AND DOWN-REGULATED GENES INCLUDING ABAT, CITED2, CNNM2, DAB2IP, PLEKHM1, SCD2, AND TAB2. THE PRIMARY ALTERED BIOLOGICAL PROCESSES REVEALED BY NETWORK ENRICHMENT ANALYSIS WERE INFLAMMATION/IMMUNE RESPONSE, TISSUE MORPHOGENESIS AND DEVELOPMENT, AND NUCLEOSOME/CHROMATIN ASSEMBLY. THE MOST SIGNIFICANTLY DOWN-REGULATED PROCESS WAS THE DIGESTIVE SYSTEM DEVELOPMENT/FUNCTION, WHEREAS THE MOST SIGNIFICANTLY UP-REGULATED PROCESSES WERE INFLAMMATORY RESPONSE, ORGANISMAL INJURY, AND CHROMATIN REMODELING MEDIATED BY H3K9 METHYLATION. FURTHERMORE, A SUBPOPULATION OF STRESSED RATS DEMONSTRATED VERY SIGNIFICANTLY ALTERED GENE EXPRESSION AND TRANSCRIPT ISOFORMS, ENRICHED FOR THE DIFFERENTIAL EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY RESPONSE, INCLUDING UPREGULATION OF CYTOKINE AND CHEMOKINE RECEPTOR GENE EXPRESSION COUPLED WITH DOWNREGULATION OF EPITHELIAL ADHERENS AND TIGHT JUNCTION MRNAS. IN SUMMARY, THESE FINDINGS SUPPORT THAT CHRONIC STRESS IS ASSOCIATED WITH INCREASED LEVELS OF CYTOKINES AND CHEMOKINES, THEIR DOWNSTREAM SIGNALING PATHWAYS COUPLED TO DYSREGULATION OF INTESTINAL CELL DEVELOPMENT AND FUNCTION. EPIGENETIC REGULATION OF CHROMATIN REMODELING LIKELY PLAYS A PROMINENT ROLE IN THIS PROCESS. RESULTS ALSO SUGGEST THAT SUPER ENHANCERS PLAY A PRIMARY ROLE IN CHRONIC STRESS-ASSOCIATED INTESTINAL BARRIER DYSFUNCTION. 2022 8 6690 27 VALPROIC ACID SILENCING OF ASCL1B/ASCL1 RESULTS IN THE FAILURE OF SEROTONERGIC DIFFERENTIATION IN A ZEBRAFISH MODEL OF FETAL VALPROATE SYNDROME. FETAL VALPROATE SYNDROME (FVS) IS CAUSED BY IN UTERO EXPOSURE TO THE DRUG SODIUM VALPROATE. VALPROATE IS USED WORLDWIDE FOR THE TREATMENT OF EPILEPSY, AS A MOOD STABILISER AND FOR ITS PAIN-RELIEVING PROPERTIES. IN ADDITION TO BIRTH DEFECTS, FVS IS ASSOCIATED WITH AN INCREASED RISK OF AUTISM SPECTRUM DISORDER (ASD), WHICH IS CHARACTERISED BY ABNORMAL BEHAVIOURS. VALPROATE PERTURBS MULTIPLE BIOCHEMICAL PATHWAYS AND ALTERS GENE EXPRESSION THROUGH ITS INHIBITION OF HISTONE DEACETYLASES. WHICH, IF ANY, OF THESE MECHANISMS IS RELEVANT TO THE GENESIS OF ITS BEHAVIOURAL SIDE EFFECTS IS UNCLEAR. NEUROANATOMICAL CHANGES ASSOCIATED WITH FVS HAVE BEEN REPORTED AND, AMONG THESE, ALTERED SEROTONERGIC NEURONAL DIFFERENTIATION IS A CONSISTENT FINDING. ALTERED SEROTONIN HOMEOSTASIS IS ALSO ASSOCIATED WITH AUTISM. HERE WE HAVE USED A CHEMICAL-GENETICS APPROACH TO INVESTIGATE THE UNDERLYING MOLECULAR DEFECT IN A ZEBRAFISH FVS MODEL. VALPROATE CAUSES THE SELECTIVE FAILURE OF ZEBRAFISH CENTRAL SEROTONIN EXPRESSION. IT DOES SO BY DOWNREGULATING THE PRONEURAL GENE ASCL1B, AN ORTHOLOG OF MAMMALIAN ASCL1, WHICH IS A KNOWN DETERMINANT OF SEROTONERGIC IDENTITY IN THE MAMMALIAN BRAINSTEM. ASCL1B IS SUFFICIENT TO RESCUE SEROTONIN EXPRESSION IN VALPROATE-TREATED EMBRYOS. CHEMICAL AND GENETIC BLOCKADE OF THE HISTONE DEACETYLASE HDAC1 DOWNREGULATES ASCL1B, CONSISTENT WITH THE HDAC1-MEDIATED SILENCING OF ASCL1B EXPRESSION BY VALPROATE. MOREOVER, TONIC NOTCH SIGNALLING IS CRUCIAL FOR ASCL1B REPRESSION BY VALPROATE. CONCOMITANT BLOCKADE OF NOTCH SIGNALLING RESTORES ASCL1B EXPRESSION AND SEROTONIN EXPRESSION IN BOTH VALPROATE-EXPOSED AND HDAC1 MUTANT EMBRYOS. TOGETHER, THESE DATA PROVIDE A MOLECULAR EXPLANATION FOR SEROTONERGIC DEFECTS IN FVS AND HIGHLIGHT AN EPIGENETIC MECHANISM FOR GENOME-ENVIRONMENT INTERACTION IN DISEASE. 2014 9 2246 24 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS. 2018 10 889 24 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 11 1330 32 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 12 3465 31 HYPOTHESIS: REGULATION OF NEUROPLASTICITY MAY INVOLVE I-MOTIF AND G-QUADRUPLEX DNA FORMATION MODULATED BY EPIGENETIC MECHANISMS. RECENT STUDIES DEMONSTRATED THE EXISTENCE IN VIVO OF VARIOUS FUNCTIONAL DNA STRUCTURES THAT DIFFER FROM THE DOUBLE HELIX. THE G-QUADRUPLEX (G4) AND INTERCALATED MOTIF (I-MOTIF OR IM) DNA STRUCTURES ARE FORMED AS KNOTS WHERE, CORRESPONDINGLY, GUANINES OR CYTOSINES ON THE SAME STRAND OF DNA BIND TO EACH OTHER. THERE ARE GROUNDS TO BELIEVE THAT G4 AND IM SEQUENCES PLAY A SIGNIFICANT ROLE IN REGULATING GENE EXPRESSION CONSIDERING THEIR TENDENCY TO BE FOUND IN OR NEAR REGULATORY SITES (SUCH AS PROMOTERS, ENHANCERS, AND TELOMERES) AS WELL AS THE CORRELATION BETWEEN THE PREVALENCE OF G4 OR IM CONFORMATIONS AND SPECIFIC PHASES OF CELL CYCLE. NOTABLY, G4 AND IM CAPABLE SEQUENCES TEND TO BE FOUND ON THE OPPOSITE STRANDS OF THE SAME DNA SITE WITH AT MOST ONE OF THE TWO STRUCTURES FORMED AT ANY GIVEN TIME. THE RECENT EVIDENCE THAT K(+), MG(2+) CONCENTRATIONS DIRECTLY AFFECT IM FORMATION (AND LIKELY G4 FORMATION INDIRECTLY) LEAD US TO BELIEVE THAT THESE STRUCTURES MAY PLAY A MAJOR ROLE IN SYNAPTIC PLASTICITY OF NEURONS, AND, THEREFORE, IN A VARIETY OF CENTRAL NERVOUS SYSTEM (CNS) FUNCTIONS INCLUDING MEMORY, LEARNING, HABITUAL BEHAVIORS, PAIN PERCEPTION AND OTHERS. FURTHERMORE, EPIGENETIC MECHANISMS, WHICH HAVE AN IMPORTANT ROLE IN SYNAPTIC PLASTICITY AND MEMORY FORMATION, WERE ALSO SHOWN TO INFLUENCE FORMATION AND STABILITY OF G4S AND IMS. OUR HYPOTHESIS IS THAT NON-CANONICAL DNA AND RNA STRUCTURES COULD BE AN INTEGRAL PART OF NEUROPLASTICITY CONTROL VIA GENE EXPRESSION REGULATION AT THE LEVEL OF TRANSCRIPTION, TRANSLATION AND SPLICING. WE PROPOSE THAT THE REGULATORY ACTIVITY OF DNA IM AND G4 STRUCTURES IS MODULATED BY DNA METHYLATION/DEMETHYLATION OF THE IM AND/OR G4 SEQUENCES, WHICH FACILITATES THE SWITCH BETWEEN CANONICAL AND NON-CANONICAL CONFORMATION. OTHER NEURONAL MECHANISMS INTERACTING WITH THE FORMATION AND REGULATORY ACTIVITY OF NON-CANONICAL DNA AND RNA STRUCTURES, PARTICULARLY G4, IM AND TRIPLEXES, MAY INVOLVE MICRORNAS AS WELL AS ION AND PROTON FLUXES. WE ARE PROPOSING EXPERIMENTS IN ACUTE BRAIN SLICES AND IN VIVO TO TEST OUR HYPOTHESIS. THE PROPOSED STUDIES WOULD PROVIDE NEW INSIGHTS INTO FUNDAMENTAL NEURONAL MECHANISMS IN HEALTH AND DISEASE AND POTENTIALLY OPEN NEW AVENUES FOR TREATING MENTAL HEALTH DISORDERS. 2019 13 5713 27 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 14 6012 23 THE APKC-CBP PATHWAY REGULATES POST-STROKE NEUROVASCULAR REMODELING AND FUNCTIONAL RECOVERY. EPIGENETIC MODIFICATIONS HAVE EMERGED AS ATTRACTIVE MOLECULAR SUBSTRATES THAT INTEGRATE EXTRINSIC CHANGES INTO THE DETERMINATION OF CELL IDENTITY. SINCE STROKE-RELATED BRAIN DAMAGE RELEASES MICRO-ENVIRONMENTAL CUES, WE EXAMINED THE ROLE OF A SIGNALING-INDUCED EPIGENETIC PATHWAY, AN ATYPICAL PROTEIN KINASE C (APKC)-MEDIATED PHOSPHORYLATION OF CREB-BINDING PROTEIN (CBP), IN POST-STROKE NEUROVASCULAR REMODELING. USING A KNOCKIN MOUSE STRAIN (CBPS436A) WHERE THE APKC-CBP PATHWAY WAS DEFECTIVE, WE SHOW THAT DISRUPTION OF THE APKC-CBP PATHWAY IN A MURINE FOCAL ISCHEMIC STROKE MODEL INCREASES THE REPROGRAMMING EFFICIENCY OF ISCHEMIA-ACTIVATED PERICYTES (I-PERICYTES) TO NEURAL PRECURSORS. AS A CONSEQUENCE OF ENHANCED CELLULAR REPROGRAMMING, CBPS436A MICE SHOW AN INCREASED TRANSIENT POPULATION OF LOCALLY DERIVED NEURAL PRECURSORS AFTER STROKE, WHILE DISPLAYING A REDUCED NUMBER OF I-PERICYTES, IMPAIRED VASCULAR REMODELING, AND PERTURBED MOTOR RECOVERY DURING THE CHRONIC PHASE OF STROKE. TOGETHER, THIS STUDY ELUCIDATES THE ROLE OF THE APKC-CBP PATHWAY IN MODULATING NEUROVASCULAR REMODELING AND FUNCTIONAL RECOVERY FOLLOWING FOCAL ISCHEMIC STROKE. 2017 15 2886 24 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 16 4861 31 ORGANIC ANION TRANSPORTER 1 IS AN HDAC4-REGULATED MEDIATOR OF NOCICEPTIVE HYPERSENSITIVITY IN MICE. PERSISTENT PAIN IS SUSTAINED BY MALADAPTIVE CHANGES IN GENE TRANSCRIPTION RESULTING IN ALTERED FUNCTION OF THE RELEVANT CIRCUITS; THERAPIES ARE STILL UNSATISFACTORY. THE EPIGENETIC MECHANISMS AND AFFECTED GENES LINKING NOCICEPTIVE ACTIVITY TO TRANSCRIPTIONAL CHANGES AND PATHOLOGICAL SENSITIVITY ARE UNCLEAR. HERE, WE FOUND THAT, AMONG SEVERAL HISTONE DEACETYLASES (HDACS), SYNAPTIC ACTIVITY SPECIFICALLY AFFECTS HDAC4 IN MURINE SPINAL CORD DORSAL HORN NEURONS. NOXIOUS STIMULI THAT INDUCE LONG-LASTING INFLAMMATORY HYPERSENSITIVITY CAUSE NUCLEAR EXPORT AND INACTIVATION OF HDAC4. THE DEVELOPMENT OF INFLAMMATION-ASSOCIATED MECHANICAL HYPERSENSITIVITY, BUT NEITHER ACUTE NOR BASAL SENSITIVITY, IS IMPAIRED BY THE EXPRESSION OF A CONSTITUTIVELY NUCLEAR LOCALIZED HDAC4 MUTANT. NEXT GENERATION RNA-SEQUENCING REVEALED AN HDAC4-REGULATED GENE PROGRAM COMPRISING MEDIATORS OF SENSITIZATION INCLUDING THE ORGANIC ANION TRANSPORTER OAT1, KNOWN FOR ITS RENAL TRANSPORT FUNCTION. USING PHARMACOLOGICAL AND MOLECULAR TOOLS TO MODULATE OAT1 ACTIVITY OR EXPRESSION, WE CAUSALLY LINK OAT1 TO PERSISTENT INFLAMMATORY HYPERSENSITIVITY IN MICE. THUS, HDAC4 IS A KEY EPIGENETIC REGULATOR THAT TRANSLATES NOCICEPTIVE ACTIVITY INTO SENSITIZATION BY REGULATING OAT1, WHICH IS A POTENTIAL TARGET FOR PAIN-RELIEVING THERAPIES. 2022 17 5832 24 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 18 786 25 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 19 5474 25 RESTORATION OF HISTONE ACETYLATION AMELIORATES DISEASE AND METABOLIC ABNORMALITIES IN A FUS MOUSE MODEL. DYSREGULATION OF EPIGENETIC MECHANISMS IS EMERGING AS A CENTRAL EVENT IN NEURODEGENERATIVE DISORDERS, INCLUDING AMYOTROPHIC LATERAL SCLEROSIS (ALS). IN MANY MODELS OF NEURODEGENERATION, GLOBAL HISTONE ACETYLATION IS DECREASED IN THE AFFECTED NEURONAL TISSUES. HISTONE ACETYLATION IS CONTROLLED BY THE ANTAGONISTIC ACTIONS OF TWO PROTEIN FAMILIES -THE HISTONE ACETYLTRANSFERASES (HATS) AND THE HISTONE DEACETYLASES (HDACS). DRUGS INHIBITING HDAC ACTIVITY ARE ALREADY USED IN THE CLINIC AS ANTI-CANCER AGENTS. THE AIM OF THIS STUDY WAS TO EXPLORE THE THERAPEUTIC POTENTIAL OF HDAC INHIBITION IN THE CONTEXT OF ALS. WE DISCOVERED THAT TRANSGENIC MICE OVEREXPRESSING WILD-TYPE FUS ("TG FUS+/+"), WHICH RECAPITULATE MANY ASPECTS OF HUMAN ALS, SHOWED REDUCED GLOBAL HISTONE ACETYLATION AND ALTERATIONS IN METABOLIC GENE EXPRESSION, RESULTING IN A DYSREGULATED METABOLIC HOMEOSTASIS. CHRONIC TREATMENT OF TG FUS+/+ MICE WITH ACY-738, A POTENT HDAC INHIBITOR THAT CAN CROSS THE BLOOD-BRAIN BARRIER, AMELIORATED THE MOTOR PHENOTYPE AND SUBSTANTIALLY EXTENDED THE LIFE SPAN OF THE TG FUS+/+ MICE. AT THE MOLECULAR LEVEL, ACY-738 RESTORED GLOBAL HISTONE ACETYLATION AND METABOLIC GENE EXPRESSION, THEREBY RE-ESTABLISHING METABOLITE LEVELS IN THE SPINAL CORD. TAKEN TOGETHER, OUR FINDINGS LINK EPIGENETIC ALTERATIONS TO METABOLIC DYSREGULATION IN ALS PATHOLOGY, AND HIGHLIGHT ACY-738 AS A POTENTIAL THERAPEUTIC STRATEGY TO TREAT THIS DEVASTATING DISEASE. 2019 20 6664 29 UPREGULATION OF LNCRNA71132 IN THE SPINAL CORD REGULATES HYPERSENSITIVITY IN A RAT MODEL OF BONE CANCER PAIN. BONE CANCER PAIN (BCP) IS A PERVASIVE CLINICAL SYMPTOM WHICH IMPAIRS THE QUALITY LIFE. LONG NONCODING RNAS (LNCRNAS) ARE ENRICHED IN THE CENTRAL NERVOUS SYSTEM AND PLAY INDISPENSABLE ROLES IN NUMEROUS BIOLOGICAL PROCESSES, WHILE ITS REGULATORY FUNCTION IN NOCICEPTIVE INFORMATION PROCESSING REMAINS ELUSIVE. HERE, WE REPORTED THAT FUNCTIONAL MODULATORY ROLE OF ENSRNOT00000071132 (LNCRNA71132) IN THE BCP PROCESS AND SPONGING WITH MIR-143 AND ITS DOWNSTREAM GPR85-DEPENDENT SIGNALING CASCADE. SPINAL LNCRNA71132 WAS REMARKABLY INCREASED IN THE RAT MODEL OF BONE CANCER PAIN. THE KNOCKDOWN OF SPINAL LNCRNA71132 REVERTED BCP BEHAVIORS AND SPINAL C-FOS NEURONAL SENSITIZATION. OVEREXPRESSION OF SPINAL LNCRNA71132 IN NAIVE RAT GENERATED PAIN BEHAVIORS, WHICH WERE ACCOMPANIED BY INCREASED SPINAL C-FOS NEURONAL SENSITIZATION. FURTHERMORE, IT WAS FOUND THAT LNCRNA71132 PARTICIPATES IN THE MODULATION OF BCP BY INVERSELY REGULATING THE PROCESSING OF MIR-143-5P. IN ADDITION, AN INCREASE IN EXPRESSION OF SPINAL LNCRNA71132 RESULTED IN THE DECREASE IN EXPRESSION OF MIR-143 UNDER THE BCP STATE. FINALLY, IT WAS FOUND THAT MIR-143-5P REGULATES PAIN BEHAVIORS BY TARGETING GPR85. OVEREXPRESSION OF MIR-143-5P IN THE SPINAL CORD REVERTED THE NOCICEPTIVE BEHAVIORS TRIGGERED BY BCP, ACCOMPANIED BY A DECREASE IN EXPRESSION OF SPINAL GPR85 PROTEIN, BUT NO INFLUENCE ON EXPRESSION OF GPR85 MRNA. THE FINDINGS OF THIS STUDY INDICATE THAT LNCRNA71132 WORKS AS A MIRNA SPONGE IN MIR-143-5P-MEDIATED POSTTRANSCRIPTIONAL MODULATION OF GPR85 EXPRESSION IN BCP. THEREFORE, EPIGENETIC INTERVENTIONS AGAINST LNCRNA71132 MAY POTENTIALLY WORK AS NOVEL TREATMENT AVENUES IN TREATING NOCICEPTIVE HYPERSENSITIVITY TRIGGERED BY BONE CANCER. 2023