1 4603 159 NEGATIVE ALLOSTERIC MODULATION OF MGLUR5 PARTIALLY CORRECTS PATHOPHYSIOLOGY IN A MOUSE MODEL OF RETT SYNDROME. RETT SYNDROME (RTT) IS CAUSED BY MUTATIONS IN THE GENE ENCODING METHYL-CPG BINDING PROTEIN 2 (MECP2), AN EPIGENETIC REGULATOR OF MRNA TRANSCRIPTION. HERE, WE REPORT A TEST OF THE HYPOTHESIS OF SHARED PATHOPHYSIOLOGY OF RTT AND FRAGILE X, ANOTHER MONOGENIC CAUSE OF AUTISM AND INTELLECTUAL DISABILITY. IN FRAGILE X, THE LOSS OF THE MRNA TRANSLATIONAL REPRESSOR FMRP LEADS TO EXAGGERATED PROTEIN SYNTHESIS DOWNSTREAM OF METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5). WE FOUND THAT MGLUR5- AND PROTEIN-SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY WERE SIMILARLY ALTERED IN AREA CA1 OF MECP2 KO MICE. CA1 PYRAMIDAL CELL-TYPE-SPECIFIC, GENOME-WIDE PROFILING OF RIBOSOME-BOUND MRNAS WAS PERFORMED IN WILD-TYPE AND MECP2 KO HIPPOCAMPAL CA1 NEURONS TO REVEAL THE MECP2-REGULATED "TRANSLATOME." WE FOUND SIGNIFICANT OVERLAP BETWEEN RIBOSOME-BOUND TRANSCRIPTS OVEREXPRESSED IN THE MECP2 KO AND FMRP MRNA TARGETS. THESE TENDED TO ENCODE LONG GENES THAT WERE FUNCTIONALLY RELATED TO EITHER CYTOSKELETON ORGANIZATION OR THE DEVELOPMENT OF NEURONAL CONNECTIVITY. IN THE FMR1 KO MOUSE, CHRONIC TREATMENT WITH MGLUR5-NEGATIVE ALLOSTERIC MODULATORS (NAMS) HAS BEEN SHOWN TO AMELIORATE MANY MUTANT PHENOTYPES BY CORRECTING EXCESSIVE PROTEIN SYNTHESIS. IN MECP2 KO MICE, WE FOUND THAT MGLUR5 NAM TREATMENT SIGNIFICANTLY REDUCED THE LEVEL OF OVEREXPRESSED RIBOSOME-ASSOCIATED TRANSCRIPTS, PARTICULARLY THOSE THAT WERE ALSO FMRP TARGETS. SOME RETT PHENOTYPES WERE ALSO AMELIORATED BY TREATMENT, MOST NOTABLY HIPPOCAMPAL CELL SIZE AND LIFESPAN. TOGETHER, THESE RESULTS SUGGEST A POTENTIAL MECHANISTIC LINK BETWEEN MECP2-MEDIATED TRANSCRIPTION REGULATION AND MGLUR5/FMRP-MEDIATED PROTEIN TRANSLATION REGULATION THROUGH COREGULATION OF A SUBSET OF GENES RELEVANT TO SYNAPTIC FUNCTIONS. SIGNIFICANCE STATEMENT: ALTERED REGULATION OF SYNAPTIC PROTEIN SYNTHESIS HAS BEEN HYPOTHESIZED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY THAT UNDERLIES MULTIPLE FORMS OF INTELLECTUAL DISABILITY AND AUTISM SPECTRUM DISORDER. HERE, WE SHOW IN A MOUSE MODEL OF RETT SYNDROME (MECP2 KO) THAT METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5)- AND PROTEIN-SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY ARE ABNORMAL IN THE HIPPOCAMPUS. WE FOUND THAT A SUBSET OF RIBOSOME-BOUND MRNAS WAS ABERRANTLY UPREGULATED IN HIPPOCAMPAL CA1 NEURONS OF MECP2 KO MICE, THAT THESE SIGNIFICANTLY OVERLAPPED WITH FMRP DIRECT TARGETS AND/OR SFARI HUMAN AUTISM GENES, AND THAT CHRONIC TREATMENT OF MECP2 KO MICE WITH AN MGLUR5-NEGATIVE ALLOSTERIC MODULATOR TUNES DOWN UPREGULATED RIBOSOME-BOUND MRNAS AND PARTIALLY IMPROVES MUTANT MICE PHENOTYPES. 2016 2 346 31 ALTERED CARBON DIOXIDE METABOLISM AND CREATINE ABNORMALITIES IN RETT SYNDROME. DESPITE THEIR GOOD APPETITE, MANY FEMALES WITH RETT SYNDROME (RTT) MEET THE CRITERIA FOR MODERATE TO SEVERE MALNUTRITION. ALTHOUGH FEEDING DIFFICULTIES MAY PLAY A PART IN THIS, OTHER CONSTITUTIONAL FACTORS SUCH AS ALTERED METABOLIC PROCESSES ARE SUSPECTED. IRREGULAR BREATHING IS A COMMON CLINICAL FEATURE, LEADING TO CHRONIC RESPIRATORY ALKALOSIS OR ACIDOSIS. WE ASSUMED THAT THESE CHANGES IN INTRACELLULAR PH CAUSE DISTURBANCES IN THE METABOLIC EQUILIBRIUM, WITH IMPORTANT NUTRITIONAL CONSEQUENCES. THE STUDY POPULATION CONSISTED OF A GROUP OF THIRTEEN WELL-DEFINED RTT GIRLS WITH EXTENDED CLINICAL, MOLECULAR AND NEUROPHYSIOLOGICAL ASSESSMENTS. DESPITE NORMAL LEVELS OF TOTAL DIETARY ENERGY AND PROTEIN INTAKES, MALNUTRITION WAS CONFIRMED BASED ON SIGNIFICANTLY LOW FAT-FREE MASS INDEX (FFMI) VALUES. BIOCHEMICAL SCREENING OF MULTIPLE METABOLIC PATHWAYS SHOWED SIGNIFICANTLY ELEVATED PLASMA CREATINE CONCENTRATIONS AND INCREASED URINARY CREATINE/CREATININE RATIO IN FIVE RTT GIRLS. FOUR GIRLS, 10 YEARS AND OLDER, WERE FORCEFUL BREATHERS, ONE 13-YEAR-OLD GIRL HAD AN UNDETERMINED CARDIORESPIRATORY PHENOTYPE. AN ISOLATED INCREASE OF THE URINARY CREATINE/CREATININE RATIO WAS SEEN IN TWO GIRLS, A 9-YEAR OLD FORCEFUL AND A 4-YEAR OLD FEEBLE BREATHER. GIVEN THAT THE YOUNG GIRLS ARE FEEBLE BREATHERS AND THE OLDER GIRLS ARE FORCEFUL BREATHERS, IT IS IMPOSSIBLE TO DETERMINE WHETHER THE ELEVATED CREATINE CONCENTRATIONS ARE DUE TO INCREASING AGE OR CARDIORESPIRATORY PHENOTYPE. FURTHERMORE, MECP2 DEFICIENCY MAY CAUSE EPIGENETIC ABERRATIONS AFFECTING THE EXPRESSION OF THE CREATINE-TRANSPORTER GENE, WHICH IS LOCATED AT XQ28. FURTHER STUDIES ARE REQUIRED TO CONFIRM THESE FINDINGS AND TO PROVIDE GREATER INSIGHT INTO THE PATHOGENESIS OF THE ABNORMAL CREATINE METABOLISM IN RTT. 2012 3 2266 30 EPIGENETIC PROGRAMMING OF MU-OPIOID RECEPTOR GENE IN MOUSE BRAIN IS REGULATED BY MECP2 AND BRG1 CHROMATIN REMODELLING FACTOR. THE PHARMACOLOGICAL ACTION OF MORPHINE AS A PAIN MEDICATION IS MEDIATED PRIMARILY THROUGH THE MU-OPIOID RECEPTOR (MOR). WITH FEW EXCEPTIONS, MOR IS EXPRESSED IN BRAIN REGIONS WHERE OPIOID ACTIONS TAKE PLACE. THE BASIS FOR THIS UNIQUE SPATIAL EXPRESSION OF MOR REMAINS UNDETERMINED. RECENTLY, WE REPORTED THAT DNA METHYLATION OF THE MOR PROMOTER PLAYS AN IMPORTANT ROLE IN REGULATING MOR IN P19 CELLS. IN THIS STUDY, WE SHOW THAT THE DIFFERENTIAL EXPRESSION OF MOR IN MICRODISSECTED MOUSE BRAIN REGIONS COINCIDES WITH DNA METHYLATION AND HISTONE MODIFICATIONS. MOR EXPRESSION COULD BE INDUCED BY A DEMETHYLATING AGENT OR A HISTONE DEACETYLASE INHIBITOR IN MOR-NEGATIVE CELLS, SUGGESTING THAT THE MOR GENE CAN BE SILENCED UNDER EPIGENETIC CONTROL. INCREASES IN THE IN VIVO INTERACTION OF METHYL-CPG-BINDING PROTEIN 2 (MECP2) WERE OBSERVED IN THE CEREBELLUM, IN WHICH THE MOR PROMOTER WAS HYPERMETHYLATED AND MOR EXPRESSION WAS THE LOWEST AMONG ALL BRAIN REGIONS TESTED. MECP2 IS ASSOCIATED CLOSELY WITH RETT SYNDROME, A NEURODEVELOPMENTAL DISORDER. WE ALSO ESTABLISHED NOVEL EVIDENCE FOR A FUNCTIONAL ROLE FOR MECP2'S ASSOCIATION WITH THE CHROMATIN-REMODELLING FACTOR BRG1 AND DNA METHYLTRANSFERASE DNMT1, SUGGESTING A POSSIBLE ROLE FOR MECP2 IN CHROMATIN REMODELLING DURING MOR GENE REGULATION. WE CONCLUDE THAT MOR GENE EXPRESSION IS EPIGENETICALLY PROGRAMMED IN VARIOUS BRAIN REGIONS AND THAT MECP2 ASSISTS THE EPIGENETIC PROGRAM DURING DNA METHYLATION AND CHROMATIN REMODELLING OF THE MOR PROMOTER. 2009 4 3082 48 GENOME-WIDE REDISTRIBUTION OF MECP2 IN DORSAL ROOT GANGLIA AFTER PERIPHERAL NERVE INJURY. BACKGROUND: METHYL-CPG-BINDING PROTEIN 2 (MECP2), A PROTEIN WITH AFFINITY FOR METHYLATED CYTOSINES, IS CRUCIAL FOR NEURONAL DEVELOPMENT AND FUNCTION. MECP2 REGULATES GENE EXPRESSION THROUGH ACTIVATION, REPRESSION AND CHROMATIN REMODELING. MUTATIONS IN MECP2 CAUSE RETT SYNDROME, AND THESE PATIENTS DISPLAY IMPAIRED NOCICEPTION. WE OBSERVED AN INCREASE IN MECP2 EXPRESSION IN MOUSE DORSAL ROOT GANGLIA (DRG) AFTER PERIPHERAL NERVE INJURY. THE FUNCTIONAL IMPLICATION OF INCREASED MECP2 IS LARGELY UNKNOWN. TO IDENTIFY REGIONS OF THE GENOME BOUND BY MECP2 IN THE DRG AND THE CHANGES INDUCED BY NERVE INJURY, A CHROMATIN IMMUNOPRECIPITATION OF MECP2 FOLLOWED BY SEQUENCING (CHIP-SEQ) WAS PERFORMED 4 WEEKS AFTER SPARED NERVE INJURY (SNI). RESULTS: WHILE THE NUMBER OF BINDING SITES ACROSS THE GENOME REMAINED SIMILAR IN THE SNI MODEL AND SHAM CONTROL, SNI INDUCED THE REDISTRIBUTION OF MECP2 TO TRANSCRIPTIONALLY RELEVANT REGIONS. TO DETERMINE HOW DIFFERENTIAL BINDING OF MECP2 CAN AFFECT GENE EXPRESSION IN THE DRG, WE INVESTIGATED MMU-MIR-126, A MICRORNA LOCUS THAT HAD ENRICHED MECP2 BINDING IN THE SNI MODEL. ENRICHED MECP2 BINDING TO MIR-126 LOCUS AFTER NERVE INJURY REPRESSED MIR-126 EXPRESSION, AND THIS WAS NOT MEDIATED BY ALTERATIONS IN METHYLATION PATTERN AT THE MIR-126 LOCUS. DOWNREGULATION OF MIR-126 RESULTED IN THE UPREGULATION OF ITS TWO TARGET GENES DNMT1 AND VEGFA IN NEURO 2A CELLS AND IN SNI MODEL COMPARED TO CONTROL. THESE TARGET GENES WERE SIGNIFICANTLY DOWNREGULATED IN MECP2-NULL MICE COMPARED TO WILD-TYPE LITTERMATES, INDICATING A REGULATORY ROLE FOR MECP2 IN ACTIVATING DNMT1 AND VEGFA EXPRESSION. INTRATHECAL DELIVERY OF MIR-126 WAS NOT SUFFICIENT TO REVERSE NERVE INJURY-INDUCED MECHANICAL AND THERMAL HYPERSENSITIVITY, BUT DECREASED DNMT1 AND VEGFA EXPRESSION IN THE DRG. CONCLUSIONS: OUR STUDY SHOWS A REGULATORY ROLE FOR MECP2 IN THAT CHANGES IN GLOBAL REDISTRIBUTION CAN RESULT IN DIRECT AND INDIRECT MODULATION OF GENE EXPRESSION IN THE DRG. ALTERATIONS IN GENOME-WIDE BINDING OF MECP2 THEREFORE PROVIDE A MOLECULAR BASIS FOR A BETTER UNDERSTANDING OF EPIGENETIC REGULATION-INDUCED MOLECULAR CHANGES UNDERLYING NERVE INJURY. 2016 5 6577 26 TREATMENT STRATEGIES FOR COMPLEX BEHAVIORAL INSOMNIA IN CHILDREN WITH NEURODEVELOPMENTAL DISORDERS. PURPOSE OF REVIEW: THIS REVIEW DESCRIBES RECENT RESEARCH IN PEDIATRIC BEHAVIORAL INSOMNIAS IN NEURODEVELOPMENTAL DISORDERS AND THEIR TREATMENT. RECENT FINDINGS: INSOMNIA IN CHILDREN WITH AUTISM SPECTRUM DISORDER (ASD) AND OTHER NEURODEVELOPMENTAL DISORDERS (NDDS) IS TYPICALLY COMPLEX, CHRONIC, AND DIFFICULT TO ADEQUATELY CONTROL. ABNORMALITIES IN GENETIC AND/OR EPIGENETIC REGULATION OF SLEEP/WAKEFULNESS AND ITS TIMING PREDISPOSE PATIENTS WITH NDD TO INSOMNIA, ALTHOUGH POOR SLEEP HYGIENE, MALADAPTIVE ASSOCIATIONS, AND LIMIT-SETTING ARE LIKELY TO CONTRIBUTE. PARENTS ARE AGENTS FOR CHANGE IN PROBLEMATIC SLEEP BEHAVIORS IN PATIENTS WITH NDD. WE REVIEW THE BENEFITS OF BEHAVIORAL THERAPIES AND MELATONIN TO TREAT SLEEP PROBLEMS IN CHILDREN WITH NDD. PROBLEMATIC SLEEP IS SO PREVALENT IN SOME NEURODEVELOPMENTAL SYNDROMES (RETT, ANGELMAN, WILLIAMS, AND SMITH-MAGENIS) THAT IT IS PART OF THEIR DIAGNOSTIC CRITERIA. SUMMARY: CHILDREN AND ADOLESCENTS WITH NEUROLOGICAL DISORDERS FREQUENTLY HAVE COMPLEX SLEEP DISORDERS THAT REQUIRE TREATMENT. UNDERSTANDING THE BASIC PATHOLOGY AND TREATMENT STRATEGIES PROVIDES AN OPPORTUNITY TO IMPROVE WELL BEING AND QUALITY OF LIFE IN THOSE AFFECTED BY NDD AND THEIR FAMILIES. 2013 6 4161 39 MECP2 REGULATES ETHANOL SENSITIVITY AND INTAKE. WE HAVE INVESTIGATED THE EXPRESSION OF CHROMATIN-REGULATING GENES IN THE PREFRONTAL CORTEX AND IN THE SHELL SUBDIVISION OF THE NUCLEUS ACCUMBENS DURING PROTRACTED WITHDRAWAL IN MICE WITH INCREASED ETHANOL DRINKING AFTER CHRONIC INTERMITTENT ETHANOL (CIE) VAPOR EXPOSURE AND IN MICE WITH A HISTORY OF NON-DEPENDENT DRINKING. WE OBSERVED THAT THE METHYL-CPG BINDING PROTEIN 2 (MECP2) WAS ONE OF THE FEW CHROMATIN-REGULATING GENES TO BE DIFFERENTIALLY REGULATED BY A HISTORY OF DEPENDENCE. AS MECP2 HAS THE POTENTIAL OF ACTING AS A BROAD GENE REGULATOR, WE INVESTIGATED SENSITIVITY TO ETHANOL AND ETHANOL DRINKING IN MECP2(308/) (Y) MICE, WHICH HARBOR A TRUNCATED MECP2 ALLELE BUT HAVE A MILDER PHENOTYPE THAN MECP2 NULL MICE. WE OBSERVED THAT MECP2(308/) (Y) MICE WERE MORE SENSITIVE TO ETHANOL'S STIMULATORY AND SEDATIVE EFFECTS THAN WILD-TYPE (WT) MICE, DRANK LESS ETHANOL IN A LIMITED ACCESS 2 BOTTLE CHOICE PARADIGM AND DID NOT SHOW INCREASED DRINKING AFTER INDUCTION OF DEPENDENCE WITH EXPOSURE TO CIE VAPORS. ALCOHOL METABOLISM DID NOT DIFFER IN MECP2(308/) (Y) AND WT MICE. ADDITIONALLY, MECP2(308/) (Y) MICE DID NOT DIFFER FROM WT MICE IN ETHANOL PREFERENCE IN A 24-HOUR PARADIGM NOR IN THEIR INTAKE OF GRADED SOLUTIONS OF SACCHARIN OR QUININE, SUGGESTING THAT THE MECP2(308/) (Y) MUTATION DID NOT ALTER TASTE FUNCTION. LASTLY, USING THE GENE SET ENRICHMENT ANALYSIS ALGORITHM, WE FOUND A SIGNIFICANT OVERLAP IN THE GENES REGULATED BY ALCOHOL AND BY MECP2. TOGETHER, THESE RESULTS SUGGEST THAT MECP2 CONTRIBUTES TO THE REGULATION OF ETHANOL SENSITIVITY AND DRINKING. 2014 7 4163 27 MECP2 REPRESSION OF G9A IN REGULATION OF PAIN AND MORPHINE REWARD. OPIOIDS ARE COMMONLY USED FOR PAIN RELIEF, BUT THEIR STRONG REWARDING EFFECTS DRIVE OPIOID MISUSE AND ABUSE. HOW PAIN AFFECTS THE LIABILITY OF OPIOID ABUSE IS UNKNOWN AT PRESENT. IN THIS STUDY, WE IDENTIFIED AN EPIGENETIC REGULATING CASCADE ACTIVATED BY BOTH PAIN AND THE OPIOID MORPHINE. BOTH PERSISTENT PAIN AND REPEATED MORPHINE UPREGULATED THE TRANSCRIPTIONAL REGULATOR MECP2 IN MOUSE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT MECP2 BOUND TO AND REPRESSED THE TRANSCRIPTIONAL REPRESSOR HISTONE DIMETHYLTRANSFERASE G9A, REDUCING G9A-CATALYZED REPRESSIVE MARK H3K9ME2 IN CEA. REPRESSION OF G9A ACTIVITY INCREASED EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF). BEHAVIORALLY, PERSISTENT INFLAMMATORY PAIN INCREASED THE SENSITIVITY TO ACQUIRING MORPHINE-INDUCED, REWARD-RELATED BEHAVIOR OF CONDITIONED PLACE PREFERENCE IN MICE. LOCAL VIRAL VECTOR-MEDIATED MECP2 OVEREXPRESSION, CRE-INDUCED G9A KNOCKDOWN, AND CEA APPLICATION OF BDNF MIMICKED, WHEREAS MECP2 KNOCKDOWN INHIBITED, THE PAIN EFFECT. THESE RESULTS SUGGEST THAT MECP2 DIRECTLY REPRESSES G9A AS A SHARED MECHANISM IN CENTRAL AMYGDALA FOR REGULATION OF EMOTIONAL RESPONSES TO PAIN AND OPIOID REWARD, AND FOR THEIR BEHAVIORAL INTERACTION. 2014 8 5021 37 PERSISTENT PAIN MAINTAINS MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL THROUGH REDUCED MECP2 REPRESSION OF GLUA1 IN RAT CENTRAL AMYGDALA. AS LONG-TERM OPIOIDS ARE INCREASINGLY USED FOR CONTROL OF CHRONIC PAIN, HOW PAIN AFFECTS THE REWARDING EFFECT OF OPIOIDS AND HENCE RISK OF PRESCRIPTION OPIOID MISUSE AND ABUSE REMAINS A HEALTHCARE CONCERN AND A CHALLENGING ISSUE IN CURRENT PAIN MANAGEMENT. IN THIS STUDY, USING A RAT MODEL OF MORPHINE SELF-ADMINISTRATION, WE INVESTIGATED THE MOLECULAR MECHANISMS UNDERLYING THE IMPACT OF PAIN ON OPERANT BEHAVIOR OF MORPHINE INTAKE AND MORPHINE SEEKING BEFORE AND AFTER MORPHINE WITHDRAWAL. WE FOUND THAT RATS WITH PERSISTENT PAIN CONSUMED A SIMILAR AMOUNT OF DAILY MORPHINE TO THAT IN CONTROL RATS WITHOUT PAIN, BUT MAINTAINED THEIR LEVEL-PRESSING BEHAVIOR OF MORPHINE SEEKING AFTER ABSTINENCE OF MORPHINE AT 0.2 MG/KG, WHEREAS THIS BEHAVIOR WAS GRADUALLY DIMINISHED IN CONTROL RATS. IN THE CENTRAL NUCLEUS OF AMYGDALA (CEA), A LIMBIC STRUCTURE CRITICALLY INVOLVED IN THE AFFECTIVE DIMENSION OF PAIN, PROTEINS OF GLUA1 SUBUNITS OF GLUTAMATE AMPA RECEPTORS WERE UPREGULATED DURING MORPHINE WITHDRAWAL, AND VIRAL KNOCKDOWN OF CEA GLUA1 ELIMINATED THE MORPHINE-SEEKING BEHAVIOR IN WITHDRAWN RATS OF THE PAIN GROUP. CHROMATIN IMMUNOPRECIPITATION ANALYSIS REVEALED THAT THE METHYL CPG-BINDING PROTEIN 2 (MECP2) WAS ENRICHED IN THE PROMOTER REGION OF GRIA1 ENCODING GLUA1 AND THIS ENRICHMENT WAS SIGNIFICANTLY ATTENUATED IN WITHDRAWN RATS OF THE PAIN GROUP. FURTHERMORE, VIRAL OVEREXPRESSION OF CEA MECP2 REPRESSED THE GLUA1 LEVEL AND ELIMINATED THE MAINTENANCE OF MORPHINE-SEEKING BEHAVIOR AFTER MORPHINE WITHDRAWAL. THESE RESULTS SUGGEST DIRECT MECP2 REPRESSION OF GLUA1 FUNCTION AS A LIKELY MECHANISM FOR MORPHINE-SEEKING BEHAVIOR MAINTAINED BY LONG-LASTING AFFECTIVE PAIN AFTER MORPHINE WITHDRAWAL. 2015 9 917 38 CHRONIC HIGH-FAT DIET DRIVES POSTNATAL EPIGENETIC REGULATION OF MU-OPIOID RECEPTOR IN THE BRAIN. OPIOID SYSTEM DYSREGULATION HAS BEEN OBSERVED IN BOTH GENETIC AND HIGH-FAT DIET (HFD)-INDUCED MODELS OF OBESITY. AN UNDERSTANDING OF THE MOLECULAR MECHANISMS OF MOR TRANSCRIPTIONAL REGULATION, PARTICULARLY WITHIN AN IN VIVO CONTEXT, IS LACKING. USING A DIET-INDUCED MODEL OF OBESITY (DIO), MICE WERE FED A HIGH-FAT DIET (60% CALORIES FROM FAT) FROM WEANING TO >18 WEEKS OF AGE. COMPARED WITH MICE FED THE CONTROL DIET, DIO MICE HAD A DECREASED PREFERENCE FOR SUCROSE. MOR MRNA EXPRESSION WAS DECREASED IN REWARD-RELATED CIRCUITRY (VENTRAL TEGMENTAL AREA (VTA), NUCLEUS ACCUMBENS (NAC), AND PREFRONTAL CORTEX (PFC)) BUT NOT THE HYPOTHALAMUS, IMPORTANT IN THE HOMEOSTATIC REGULATION OF FEEDING. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT LINKS ENVIRONMENTAL EXPOSURES TO ALTERED GENE EXPRESSION. WE FOUND A SIGNIFICANT INCREASE IN DNA METHYLATION IN THE MOR PROMOTER REGION WITHIN THE REWARD-RELATED BRAIN REGIONS. METHYL CPG-BINDING PROTEIN 2 (MECP2) CAN BIND METHYLATED DNA AND REPRESS TRANSCRIPTION, AND DIO MICE SHOWED INCREASED BINDING OF MECP2 TO THE MOR PROMOTER IN REWARD-RELATED REGIONS OF THE BRAIN. FINALLY, USING CHIP ASSAYS WE EXAMINED H3K9 METHYLATION (INACTIVE CHROMATIN) AND H3 ACETYLATION (ACTIVE CHROMATIN) WITHIN THE MOR PROMOTER REGION AND FOUND INCREASED H3K9 METHYLATION AND DECREASED H3 ACETYLATION. THESE DATA ARE THE FIRST TO IDENTIFY DNA METHYLATION, MECP2 RECRUITMENT, AND CHROMATIN REMODELING AS MECHANISMS LEADING TO TRANSCRIPTIONAL REPRESSION OF MOR IN THE BRAINS OF MICE FED A HIGH-FAT DIET. 2011 10 1803 15 EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS ON THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NUCLEI OF HIPPOCAMPAL NEURONS IN RATS WITH DIFFERENT EXCITABILITY OF THE NERVOUS SYSTEM. IN RATS WITH LOW EXCITABILITY THRESHOLD OF THE NERVOUS SYSTEM DEMONSTRATING SIGNIFICANT AND PERSISTENT BEHAVIORAL DISORDERS UNDER STRESS CONDITIONS, THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NEURONAL NUCLEI OF HIPPOCAMPAL FIELD CA3 DECREASED OVER 2 WEEKS AFTER LONG-TERM EMOTIONAL AND PAIN STRESS. IT WAS HYPOTHESIZED THAT PROTEIN MECP2 TRIGGERS EPIGENETIC CHANGES IN DNA THAT UNDERLIE "STRESS MEMORY". 2006 11 2158 34 EPIGENETIC MECHANISMS FOR NUTRITION DETERMINANTS OF LATER HEALTH OUTCOMES. EPIGENETIC MARKING ON GENES CAN DETERMINE WHETHER OR NOT GENES ARE EXPRESSED. EPIGENETIC REGULATION IS MEDIATED BY THE ADDITION OF METHYL GROUPS TO DNA CYTOSINE BASES, OF METHYL AND ACETYL GROUPS TO PROTEINS (HISTONES) AROUND WHICH DNA IS WRAPPED, AND BY SMALL INTERFERING RNA MOLECULES. SOME COMPONENTS OF EPIGENETIC REGULATION HAVE EVOLVED TO PERMIT CONTROL OF WHETHER MATERNAL OR PATERNAL GENES ARE EXPRESSED. THE EPIGENETIC IMPRINTING OF IGF2 EXPRESSION IS AN EXAMPLE OF MATERNAL AND PATERNAL EPIGENETIC MARKING THAT MODULATES FETAL GROWTH AND FETAL SIZE. HOWEVER, EPIGENETIC REGULATION ALSO PERMITS THE FETUS AND THE INFANT TO ADAPT GENE EXPRESSION TO THE ENVIRONMENT IN WHICH IT IS GROWING; SOMETIMES WHEN THIS ADJUSTMENT GOES AWRY, THE RISK OF CHRONIC DISEASE IS INCREASED. RECENT PROGRESS IN THE UNDERSTANDING OF NUTRITIONAL INFLUENCES ON EPIGENETICS SUGGESTS THAT NUTRIENTS THAT ARE PART OF METHYL-GROUP METABOLISM CAN SIGNIFICANTLY INFLUENCE EPIGENETICS. DURING CRITICAL PERIODS IN DEVELOPMENT, DIETARY METHYL-GROUP INTAKE (CHOLINE, METHIONINE, AND FOLATE) CAN ALTER DNA AND HISTONE METHYLATION, WHICH RESULTS IN LIFELONG CHANGES IN GENE EXPRESSION. IN RODENT MODELS, PREGNANT DAMS THAT WERE FED DIETS HIGH IN METHIONINE, FOLIC ACID, AND CHOLINE PRODUCED OFFSPRING WITH DIFFERENT COAT COLORS OR WITH KINKED TAILS. A NUMBER OF SYNDROMES IN HUMANS CAN BE CAUSED BY DEFECTIVE EPIGENETIC REGULATION, INCLUDING RETT SYNDROME. THERE ARE INTERESTING EXAMPLES OF THE EFFECTS OF NUTRITION IN EARLY LIFE THAT RESULT IN ALTERED HEALTH IN ADULTS, AND SOME OF THESE COULD BE THE RESULT OF ALTERED EPIGENETIC REGULATION OF GENE EXPRESSION. 2009 12 3606 26 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 13 4160 36 MECP2 EPIGENETIC SILENCING OF OPRM1 GENE IN PRIMARY SENSORY NEURONS UNDER NEUROPATHIC PAIN CONDITIONS. OPIOIDS ARE THE LAST OPTION FOR THE PHARMACOLOGICAL TREATMENT OF NEUROPATHIC PAIN, BUT THEIR ANTINOCICEPTIVE EFFECTS ARE LIMITED. DECREASED MU OPIOID RECEPTOR (MOR) EXPRESSION IN THE PERIPHERAL NERVOUS SYSTEM MAY CONTRIBUTE TO THIS. HERE, WE SHOWED THAT NERVE INJURY INDUCED HYPERMETHYLATION OF THE OPRM1 GENE PROMOTER AND AN INCREASED EXPRESSION OF METHYL-CPG BINDING PROTEIN 2 (MECP2) IN INJURED DORSAL ROOT GANGLION (DRG). THE DOWNREGULATION OF MOR IN THE DRG IS CLOSELY RELATED TO THE AUGMENTATION OF MECP2, AN EPIGENETIC REPRESSOR, WHICH COULD RECRUIT HDAC1 AND BIND TO THE METHYLATED REGIONS OF THE OPRM1 GENE PROMOTER. MECP2 KNOCKDOWN RESTORED THE EXPRESSION OF MOR IN INJURED DRG AND ENHANCED THE ANALGESIC EFFECT OF MORPHINE, WHILE THE MIMICKING OF THIS INCREASE VIA THE INTRATHECAL INFUSION OF VIRAL VECTOR-MEDIATED MECP2 WAS SUFFICIENT TO REDUCE MOR IN THE DRG. MOREOVER, HDAC1 INHIBITION WITH SUBEROYLANILIDE HYDROXAMIC ACID, AN HDAC INHIBITOR, ALSO PREVENTED MOR REDUCTION IN THE DRG OF NEUROPATHIC PAIN MICE, CONTRIBUTING TO THE AUGMENTATION OF MORPHINE ANALGESIA EFFECTS. MECHANISTICALLY, UPREGULATED MECP2 PROMOTES THE BINDING OF A HIGH LEVEL OF HDCA1 TO HYPERMETHYLATED REGIONS OF THE OPRM1 GENE PROMOTER, REDUCES THE ACETYLATION OF HISTONE H3 (ACH3) LEVELS OF THE OPRM1 GENE PROMOTER, AND ATTENUATES OPRM1 TRANSCRIPTION IN INJURED DRG. THUS, UPREGULATED MECP2 AND HDAC1 IN OPRM1 GENE PROMOTER SITES, NEGATIVELY REGULATES MOR EXPRESSION IN INJURED DRG, MITIGATING THE ANALGESIC EFFECT OF THE OPIOIDS. TARGETING MECP2/HDAC1 MAY THUS PROVIDE A NEW SOLUTION FOR IMPROVING THE THERAPEUTIC EFFECT OF OPIOIDS IN A CLINICAL SETTING. 2021 14 1752 38 EARLY LIFE STRESS RESTRICTS TRANSLATIONAL REACTIVITY IN CA3 NEURONS ASSOCIATED WITH ALTERED STRESS RESPONSES IN ADULTHOOD. EARLY LIFE EXPERIENCES PROGRAM BRAIN STRUCTURE AND FUNCTION AND CONTRIBUTE TO BEHAVIORAL ENDOPHENOTYPES IN ADULTHOOD. EPIGENETIC CONTROL OF GENE EXPRESSION BY THOSE EXPERIENCES AFFECT DISCRETE BRAIN REGIONS INVOLVED IN MOOD, COGNITIVE FUNCTION AND REGULATION OF HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. IN RODENTS, ACUTE RESTRAINT STRESS INCREASES THE EXPRESSION OF THE REPRESSIVE HISTONE H3 LYSINE 9 TRI-METHYLATION (H3K9ME3) IN HIPPOCAMPAL FIELDS, INCLUDING THE CA3 PYRAMIDAL NEURONS. THESE CA3 NEURONS ARE CRUCIALLY INVOLVED IN COGNITIVE FUNCTION AND MOOD REGULATION AS WELL AS ACTIVATION OF GLUCOCORTICOID (CORT) SECRETION. CA3 NEURONS ALSO EXHIBIT STRUCTURAL AND FUNCTIONAL CHANGES AFTER EARLY-LIFE STRESS (ELS) AS WELL AS AFTER CHRONIC STRESS IN ADULTHOOD. USING A PROTOCOL OF CHRONIC ELS INDUCED BY LIMITED BEDDING AND NESTING MATERIAL FOLLOWED BY ACUTE-SWIM STRESS (AS) IN ADULTHOOD, WE SHOW THAT MICE WITH A HISTORY OF ELS DISPLAY A BLUNTED CORT RESPONSE TO AS, DESPITE EXHIBITING ACTIVATION OF IMMEDIATE EARLY GENES AFTER STRESS SIMILAR TO THAT FOUND IN CONTROL MICE. WE FIND THAT ELS INDUCED PERSISTENTLY INCREASED EXPRESSION OF THE REPRESSIVE H3K9ME3 HISTONE MARK IN THE CA3 SUBFIELD AT BASELINE THAT WAS SUBSEQUENTLY DECREASED FOLLOWING AS. IN CONTRAST, AS INDUCED A TRANSIENT INCREASE OF THIS MARK IN CONTROL MICE. USING TRANSLATING RIBOSOME AFFINITY PURIFICATION (TRAP) METHOD TO ISOLATE CA3 TRANSLATING MRNAS, WE FOUND THAT EXPRESSION OF GENES OF THE EPIGENETIC GENE FAMILY, GABA/GLUTAMATE FAMILY, AND GLUCOCORTICOID RECEPTORS BINDING GENES WERE DECREASED TRANSIENTLY IN CONTROL MICE BY AS AND SHOWED A PERSISTENT REDUCTION IN ELS MICE. IN MOST CASES, AS IN ELS MICE DID NOT INDUCE GENE EXPRESSION CHANGES. A STRINGENT FILTERING OF GENES AFFECTED BY AS IN CONTROL AND ELS MICE REVEALED A NOTEWORTHY DECREASE IN GENE EXPRESSION CHANGE IN ELS MICE COMPARED TO CONTROL. ONLY 18 GENES WERE SELECTIVELY REGULATED BY AS IN ELS MICE AND ENCOMPASSED PATHWAYS SUCH AS CIRCADIAN RHYTHM, INFLAMMATORY RESPONSE, OPIOID RECEPTORS, AND MORE GENES INCLUDED IN THE GLUCOCORTICOID RECEPTOR BINDING FAMILY. THUS, ELS PROGRAMS A RESTRICTED TRANSLATIONAL RESPONSE TO STRESS IN STRESS-SENSITIVE CA3 NEURONS LEADING TO PERSISTENT CHANGES IN GENE EXPRESSION, SOME OF WHICH MIMIC THE TRANSIENT EFFECTS OF AS IN CONTROL MICE, WHILE LEAVING IN OPERATION THE IMMEDIATE EARLY GENE RESPONSE TO AS. 2019 15 5014 40 PERSISTENCE OF CEREBELLAR ATAXIA DURING CHRONIC ETHANOL EXPOSURE IS ASSOCIATED WITH EPIGENETIC UP-REGULATION OF FMR1 GENE EXPRESSION IN RAT CEREBELLUM. BACKGROUND: ALCOHOL INTOXICATION PRODUCES ATAXIA BY AFFECTING THE CEREBELLUM, WHICH COORDINATES MOVEMENTS. FRAGILE X MENTAL RETARDATION (FMR) PROTEIN IS A COMPLEX REGULATOR OF RNA AND SYNAPTIC PLASTICITY IMPLICATED IN FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME, WHICH FEATURES ATAXIA AND INCREASED FMR1 MRNA EXPRESSION RESULTING FROM EPIGENETIC DYSREGULATION OF FMRP. WE RECENTLY DEMONSTRATED THAT ACUTE ETHANOL-INDUCED ATAXIA IS ASSOCIATED WITH INCREASED CEREBELLAR FMR1 GENE EXPRESSION VIA HISTONE MODIFICATIONS IN RATS, BUT IT IS UNKNOWN WHETHER SIMILAR BEHAVIORAL AND MOLECULAR CHANGES OCCUR FOLLOWING CHRONIC ETHANOL EXPOSURE. HERE, WE INVESTIGATED THE EFFECTS OF CHRONIC ETHANOL EXPOSURE ON ATAXIA AND EPIGENETICALLY REGULATED CHANGES IN FMR1 EXPRESSION IN THE CEREBELLUM. METHODS: MALE ADULT SPRAGUE-DAWLEY RATS WERE TRAINED ON THE ACCELERATING ROTAROD AND THEN FED WITH CHRONIC ETHANOL OR A CONTROL LIEBER-DECARLI DIET WHILE UNDERGOING PERIODIC BEHAVIORAL TESTING FOR ATAXIA DURING ETHANOL EXPOSURE AND WITHDRAWAL. CEREBELLAR TISSUES WERE ANALYZED FOR EXPRESSION OF THE FMR1 GENE AND ITS TARGETS USING A REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. THE EPIGENETIC REGULATION OF FMR1 WAS ALSO INVESTIGATED USING A CHROMATIN IMMUNOPRECIPITATION ASSAY. RESULTS: ATAXIC BEHAVIOR MEASURED BY THE ACCELERATING ROTAROD BEHAVIORAL TEST DEVELOPED DURING CHRONIC ETHANOL TREATMENT AND PERSISTED AT BOTH THE 8-H AND 24-H WITHDRAWAL TIME POINTS COMPARED TO CONTROL DIET-FED RATS. IN ADDITION, CHRONIC ETHANOL TREATMENT RESULTED IN UP-REGULATED EXPRESSION OF FMR1 MRNA AND INCREASED ACTIVATING EPIGENETIC MARKS H3K27 ACETYLATION AND H3K4 TRIMETHYLATION AT 2 SITES WITHIN THE FMR1 PROMOTER. FINALLY, MEASUREMENT OF THE EXPRESSION OF RELEVANT FMRP MRNA TARGETS IN THE CEREBELLUM SHOWED THAT CHRONIC ETHANOL UP-REGULATED CAMP RESPONSE ELEMENT BINDING (CREB) CREB1, PSD95, GRM5, AND GRIN2B MRNA EXPRESSION WITHOUT ALTERING GRIN2A, EAA1, OR HISTONE ACETYLTRANSFERASES CREB BINDING PROTEIN (CBP) OR P300 MRNA TRANSCRIPTS. CONCLUSIONS: THESE RESULTS SUGGEST THAT EPIGENETIC REGULATION OF FMR1 AND SUBSEQUENT FMRP REGULATION OF TARGET MRNA TRANSCRIPTS CONSTITUTE NEUROADAPTATIONS IN THE CEREBELLUM THAT MAY UNDERLIE THE PERSISTENCE OF ATAXIC BEHAVIOR DURING CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL. 2021 16 3810 30 INTRATHECAL 5-AZACYTIDINE INHIBITS GLOBAL DNA METHYLATION AND METHYL- CPG-BINDING PROTEIN 2 EXPRESSION AND ALLEVIATES NEUROPATHIC PAIN IN RATS FOLLOWING CHRONIC CONSTRICTION INJURY. THE PATHOGENESIS OF NEUROPATHIC PAIN REMAINS LARGELY UNKNOWN. EPIGENETIC MECHANISMS MAY PLAY A MAJOR ROLE IN REGULATING EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. DNA METHYLATION IS A MAJOR EPIGENETIC MECHANISM IN VERTEBRATES, AND METHYL- CPG-BINDING PROTEIN 2 (MECP2) IS DIRECTLY INVOLVED IN METHYLATION-MEDIATED GENE SILENCING. TO DETERMINE HOW CHANGES IN GLOBAL DNA METHYLATION AND MECP2 EXPRESSION OCCUR FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) AND HOW REPRESSION OF DNA METHYLATION AFFECTS THESE CHANGES AND ATTENUATES NEUROPATHIC PAIN, WE USED INTRATHECAL 5-AZACYTIDINE, A DNA METHYLTRANSFERASE INHIBITOR, IN CCI RATS. RATS RECEIVED 0.9% SALINE OR 5-AZACYTIDINE (10MUMOL.D(-1)) VIA SPINAL INJECTION ONCE DAILY FROM DAY 3 TO DAY 14 AFTER CCI SURGERY. GLOBAL DNA METHYLATION AND MECP2 EXPRESSION INCREASED IN THE SPINAL CORD IN CCI RATS ON DAY 14 AFTER CCI SURGERY. MECHANICAL ALLODYNIA AND THERMAL HYPERALGESIA INDUCED BY CCI WERE ATTENUATED BY INTRATHECAL 5-AZACYTIDINE FROM DAY 5 TO DAY 14 AFTER CCI SURGERY. THE INCREASES IN GLOBAL DNA METHYLATION AND MECP2 EXPRESSION IN THE SPINAL CORD IN CCI RATS WERE ALSO SIGNIFICANTLY INHIBITED BY INTRATHECAL 5-AZACYTIDINE. THESE RESULTS DEMONSTRATE THAT INCREASED GLOBAL DNA METHYLATION AND MECP2 EXPRESSION IN THE SPINAL CORD AFTER NERVE DAMAGE MAY PLAY AN IMPORTANT ROLE IN NEUROPATHIC PAIN. 5-AZACYTIDINE SHOWS POTENTIAL FOR TREATING NEUROPATHIC PAIN. 2011 17 245 38 ADRENERGIC REPRESSION OF THE EPIGENETIC READER MECP2 FACILITATES CARDIAC ADAPTATION IN CHRONIC HEART FAILURE. RATIONALE: IN CHRONIC HEART FAILURE, INCREASED ADRENERGIC ACTIVATION CONTRIBUTES TO STRUCTURAL REMODELING AND ALTERED GENE EXPRESSION. ALTHOUGH ADRENERGIC SIGNALING ALTERS HISTONE MODIFICATIONS, IT IS UNKNOWN, WHETHER IT ALSO AFFECTS OTHER EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION AND ITS RECOGNITION. OBJECTIVE: THE AIM OF THIS STUDY WAS TO IDENTIFY THE MECHANISM OF REGULATION OF THE METHYL-CPG-BINDING PROTEIN 2 (MECP2) AND ITS FUNCTIONAL SIGNIFICANCE DURING CARDIAC PRESSURE OVERLOAD AND UNLOADING. METHODS AND RESULTS: MECP2 WAS IDENTIFIED AS A REVERSIBLY REPRESSED GENE IN MOUSE HEARTS AFTER TRANSVERSE AORTIC CONSTRICTION AND WAS NORMALIZED AFTER REMOVAL OF THE CONSTRICTION. SIMILARLY, MECP2 REPRESSION IN HUMAN FAILING HEARTS RESOLVED AFTER UNLOADING BY A LEFT VENTRICULAR ASSIST DEVICE. THE CLUSTER MIR-212/132 WAS UPREGULATED AFTER TRANSVERSE AORTIC CONSTRICTION OR ON ACTIVATION OF ALPHA1- AND BETA1-ADRENOCEPTORS AND MIR-212/132 LED TO REPRESSION OF MECP2. PREVENTION OF MECP2 REPRESSION BY A CARDIOMYOCYTE-SPECIFIC, DOXYCYCLINE-REGULATABLE TRANSGENIC MOUSE MODEL AGGRAVATED CARDIAC HYPERTROPHY, FIBROSIS, AND CONTRACTILE DYSFUNCTION AFTER TRANSVERSE AORTIC CONSTRICTION. ABLATION OF MECP2 IN CARDIOMYOCYTES FACILITATED RECOVERY OF FAILING HEARTS AFTER REVERSIBLE TRANSVERSE AORTIC CONSTRICTION. GENOME-WIDE EXPRESSION ANALYSIS, CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS, AND DNA METHYLATION ANALYSIS IDENTIFIED MITOCHONDRIAL GENES AND THEIR TRANSCRIPTIONAL REGULATORS AS MECP2 TARGET GENES. COINCIDENT WITH ITS REPRESSION, MECP2 WAS REMOVED FROM ITS TARGET GENES, WHEREAS DNA METHYLATION OF MECP2 TARGET GENES REMAINED STABLE DURING PRESSURE OVERLOAD. CONCLUSIONS: THESE DATA CONNECT ADRENERGIC ACTIVATION WITH A MICRORNA-MECP2 EPIGENETIC PATHWAY THAT IS IMPORTANT FOR CARDIAC ADAPTATION DURING THE DEVELOPMENT AND RECOVERY FROM HEART FAILURE. 2015 18 3315 25 HIPPOCAMPAL MU OPIOID RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN RAT. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCED BY LONG-TERM BRAIN CHANGES. UNDERSTANDING THE NEUROCHEMICAL CHANGES UNDERLYING THE REINFORCING EFFECTS OF THIS DRUG OF ABUSE IS CRITICAL FOR REDUCING THE SOCIETAL BURDEN OF DRUG ADDICTION. THE MU OPIOID RECEPTOR PLAYS A MAJOR ROLE IN DRUG REWARD. THIS RECEPTOR IS MODULATED BY CHRONIC COCAINE TREATMENT IN SPECIFIC BRAIN STRUCTURES, BUT FEW STUDIES INVESTIGATED NEUROCHEMICAL ADAPTATIONS INDUCED BY VOLUNTARY COCAINE INTAKE. IN THIS STUDY, WE INVESTIGATED WHETHER INTRAVENOUS COCAINE-SELF ADMINISTRATION (0.33 MG/KG/INJECTION, FIXED-RATIO 1 [FR1], 10 DAYS) IN RATS INDUCES TRANSCRIPTIONAL AND FUNCTIONAL CHANGES OF THE MU OPIOID RECEPTOR IN REWARD-RELATED BRAIN REGIONS. EPIGENETIC PROCESSES WITH HISTONE MODIFICATIONS WERE EXAMINED FOR TWO ACTIVATING MARKS, H3K4ME3, AND H3K27AC. WE FOUND AN INCREASE OF MU OPIOID RECEPTOR GENE EXPRESSION ALONG WITH A POTENTIATION OF ITS FUNCTIONALITY IN HIPPOCAMPUS OF COCAINE SELF-ADMINISTERING ANIMALS COMPARED TO SALINE CONTROLS. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR REVEALED NO MODIFICATIONS OF THE HISTONE MARK H3K4ME3 AND H3K27AC LEVELS AT MU OPIOID RECEPTOR PROMOTER. OUR STUDY HIGHLIGHTS THE HIPPOCAMPUS AS AN IMPORTANT TARGET TO FURTHER INVESTIGATE NEUROADAPTIVE PROCESSES LEADING TO COCAINE ADDICTION. 2021 19 5712 38 SIRT1 MEDIATES DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS. DEPRESSION IS A RECURRING AND LIFE-THREATENING ILLNESS THAT AFFECTS UP TO 120 MILLION PEOPLE WORLDWIDE. IN THE PRESENT STUDY, WE SHOW THAT CHRONIC SOCIAL DEFEAT STRESS, AN ETHOLOGICALLY VALIDATED MODEL OF DEPRESSION IN MICE, INCREASES SIRT1 LEVELS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. INCREASES IN SIRT1, A WELL CHARACTERIZED CLASS III HISTONE DEACETYLASE, AFTER CHRONIC SOCIAL DEFEAT SUGGEST A ROLE FOR THIS ENZYME IN MEDIATING DEPRESSION-LIKE BEHAVIORS. WHEN RESVERATROL, A PHARMACOLOGICAL ACTIVATOR OF SIRT1, WAS DIRECTLY INFUSED BILATERALLY INTO THE NAC, WE OBSERVED AN INCREASE IN DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. CONVERSELY, INTRA-NAC INFUSIONS OF EX-527, A SIRT1 ANTAGONIST, REDUCED THESE BEHAVIORS; EX-527 ALSO REDUCED ACUTE STRESS RESPONSES IN STRESS-NAIVE MICE. NEXT, WE INCREASED SIRT1 LEVELS DIRECTLY IN NAC BY USE OF VIRAL-MEDIATED GENE TRANSFER AND OBSERVED AN INCREASE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS WHEN MICE WERE ASSESSED IN THE OPEN-FIELD, ELEVATED-PLUS-MAZE, AND FORCED SWIM TESTS. USING A CRE-INDUCIBLE VIRAL VECTOR SYSTEM TO OVEREXPRESS SIRT1 SELECTIVELY IN DOPAMINE D1 OR D2 SUBPOPULATIONS OF MEDIUM SPINY NEURONS (MSNS) IN THE NAC, WE FOUND THAT SIRT1 PROMOTES DEPRESSIVE-LIKE BEHAVIORS ONLY WHEN OVEREXPRESSED IN D1 MSNS, WITH NO EFFECT SEEN IN D2 MSNS. CONVERSELY, SELECTIVE ABLATION OF SIRT1 IN THE NAC USING VIRAL-CRE IN FLOXED SIRT1 MICE RESULTED IN DECREASED DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. TOGETHER, THESE RESULTS DEMONSTRATE THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN THE NAC IN REGULATING MOOD-RELATED BEHAVIORAL ABNORMALITIES AND IDENTIFIES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT MAJOR DEPRESSIVE DISORDERS. SIGNIFICANCE STATEMENT: IN THIS STUDY, WE DEMONSTRATE A PIVOTAL ROLE FOR SIRT1 IN ANXIETY- AND DEPRESSION-LIKE BEHAVIORS IN THE NUCLEUS ACCUMBENS (NAC), A KEY BRAIN REWARD REGION. WE SHOW THAT STRESS STABLY INDUCES SIRT1 EXPRESSION IN THIS BRAIN REGION AND THAT ALTERING SIRT1 ACTIVITY USING A PHARMACOLOGICAL OR GENETIC APPROACH REGULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIORS. THESE RESULTS SUGGEST THAT SIRT1 PLAYS AN ESSENTIAL ROLE IN REGULATING MOOD-RELATED BEHAVIORS AND INTRODUCES A NOVEL SIGNALING PATHWAY FOR THE DEVELOPMENT OF INNOVATIVE ANTIDEPRESSANTS TO TREAT DEPRESSION AND OTHER STRESS-RELATED DISORDERS. A RECENT GROUNDBREAKING PUBLICATION BY THE CONVERGE CONSORTIUM (2015) IDENTIFIED A REPRODUCIBLE ASSOCIATION OF THE SIRT1 LOCUS WITH MAJOR DEPRESSION IN HUMANS. THEREFORE, OUR RESULTS ARE TIMELY AND HAVE SIGNIFICANT TRANSLATIONAL RELEVANCE. 2016 20 4069 29 MATERNAL CHRONIC FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET THROUGH METHYLATION ALTERATION OF BDNF AND GRIN2B IN OFFSPRING HIPPOCAMPUS. SCOPE: MATERNAL CONSUMPTION OF A HIGH-FAT DIET (HFD) DURING PREGNANCY INCREASES THE RISK OF BEHAVIORAL PROBLEMS. FOLATE PLAYS AN IMPORTANT ROLE IN NEUROPLASTICITY AND THE PRESERVATION OF NEURONAL INTEGRITY. THIS STUDY AIMS AT DETERMINING THE INFLUENCE OF DIETS SUPPLEMENTED WITH FOLATE ON OFFSPRING BEHAVIOR, AND THE MECHANISMS INVOLVED. METHODS AND RESULTS: FEMALE MICE WERE FED A CONTROL DIET, AN HFD, CONTROL DIET SUPPLEMENTED WITH FOLATE, OR AN HFD SUPPLEMENTED WITH FOLATE FOR 5 WEEKS BEFORE MATING. OPEN FIELD TASK AND ELEVATED PLUS MAZE ARE USED TO EVALUATE THE OFFSPRING BEHAVIORS. RESULTS SHOWED THAT OFFSPRING COGNITIVE PERFORMANCE AND ANXIETY-RELATED BEHAVIORS, INCLUDING THOSE RELATED TO OPEN FIELD EXPLORATION AND ELEVATED PLUS MAZE, WERE SIGNIFICANTLY IMPROVED WHEN DAMS WERE TREATED WITH FOLATE IN PREGNANCY. MOREOVER, THE MATERNAL FOLATE SUPPLEMENT DECREASED BDNF AND GRIN2B METHYLATION AND UPREGULATED THEIR EXPRESSIONS IN THE BRAIN OF OFFSPRING, WHICH WERE ASSOCIATED WITH DECREASING THE EXPRESSION OF DNA METHYLTRANSFERASES COMPARED WITH THOSE DAMS WERE TREATED ONLY HFD IN PREGNANCY. CONCLUSION: MATERNAL FOLATE SUPPLEMENTATION AMELIORATES BEHAVIOR DISORDERS INDUCED BY PRENATAL HIGH-FAT DIET. THE BENEFICIAL EFFECTS WERE ASSOCIATED WITH METHYLATION AND EXPRESSION ALTERATION OF BDNF AND GRIN2B GENES. 2017