1 994 124 CHRONIC STRESS INDUCES SEX-SPECIFIC ALTERATIONS IN METHYLATION AND EXPRESSION OF CORTICOTROPIN-RELEASING FACTOR GENE IN THE RAT. BACKGROUND: ALTHOUGH THE HIGHER PREVALENCE OF DEPRESSION IN WOMEN THAN IN MEN IS WELL KNOWN, THE NEURONAL BASIS OF THIS SEX DIFFERENCE IS LARGELY ELUSIVE. METHODS: MALE AND FEMALE RATS WERE EXPOSED TO CHRONIC VARIABLE MILD STRESS (CVMS) AFTER WHICH IMMEDIATE EARLY GENE PRODUCTS, CORTICOTROPIN-RELEASING FACTOR (CRF) MRNA AND PEPTIDE, VARIOUS EPIGENETIC-ASSOCIATED ENZYMES AND DNA METHYLATION OF THE CRF GENE WERE DETERMINED IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS (PVN), OVAL (BSTOV) AND FUSIFORM (BSTFU) PARTS OF THE BED NUCLEUS OF THE STRIA TERMINALIS, AND CENTRAL AMYGDALA (CEA). RESULTS: CVMS INDUCED SITE-SPECIFIC CHANGES IN CRF GENE METHYLATION IN ALL BRAIN CENTERS STUDIED IN FEMALE RATS AND IN THE MALE BST AND CEA, WHEREAS THE HISTONE ACETYLTRANSFERASE, CREB-BINDING PROTEIN WAS INCREASED IN THE FEMALE BST AND THE HISTONE-DEACETYLASE-5 DECREASED IN THE MALE CEA. THESE CHANGES WERE ACCOMPANIED BY AN INCREASED AMOUNT OF C-FOS IN THE PVN, BSTFU AND CEA IN MALES, AND OF FOSB IN THE PVN OF BOTH SEXES AND IN THE MALE BSTOV AND BSTFU. IN THE PVN, CVMS INCREASED CRF MRNA IN MALES AND CRF PEPTIDE DECREASED IN FEMALES. CONCLUSIONS: THE DATA CONFIRM OUR HYPOTHESIS THAT CHRONIC STRESS AFFECTS GENE EXPRESSION AND CRF TRANSCRIPTIONAL, TRANSLATIONAL AND SECRETORY ACTIVITIES IN THE PVN, BSTOV, BSTFU AND CEA, IN A BRAIN CENTER-SPECIFIC AND SEX-SPECIFIC MANNER. BRAIN REGION-SPECIFIC AND SEX-SPECIFIC CHANGES IN EPIGENETIC ACTIVITY AND NEURONAL ACTIVATION MAY PLAY, TOO, AN IMPORTANT ROLE IN THE SEX SPECIFICITY OF THE STRESS RESPONSE AND THE SUSCEPTIBILITY TO DEPRESSION. 2011 2 3325 35 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 3 6551 40 TRANSGENERATIONAL BLUNTING OF MORPHINE-INDUCED CORTICOSTERONE SECRETION IS ASSOCIATED WITH DYSREGULATED GENE EXPRESSION IN MALE OFFSPRING. A NUMBER OF PARENTAL EXPERIENCES, EVEN WHEN OCCURRING PRIOR TO CONCEPTION, HAVE BEEN SHOWN TO INDUCE TRANSGENERATIONAL EFFECTS BEYOND THE FIRST GENERATION. IN THE CASE OF EXPOSURE TO DRUGS OF ABUSE, STUDIES IN RODENTS SUGGEST THAT OFFSPRING DEMONSTRATE SIGNIFICANT DIFFERENCES IN HOW THEY RESPOND TO THE DRUG TO WHICH THEIR PARENT WAS EXPOSED. WE HAVE PREVIOUSLY OBSERVED SIGNIFICANT ALTERATIONS IN MORPHINE ANALGESIA, CONDITIONED PLACE PREFERENCE AND SELF-ADMINISTRATION IN THE OFFSPRING OF FEMALES EXPOSED TO MORPHINE DURING ADOLESCENT DEVELOPMENT. IN ADDITION TO EFFECTS ON PAIN PERCEPTION AND REWARD, MORPHINE ALSO MODULATES THE HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS. THE PURPOSE OF THE CURRENT STUDY WAS TO DETERMINE WHETHER FEMALE ADOLESCENT MORPHINE EXPOSURE RESULTS IN TRANSGENERATIONAL EFFECTS ON REGULATION OF THE HPA AXIS BY MORPHINE IN FUTURE GENERATIONS. ADOLESCENT MORPHINE WAS ADMINISTERED TO FEMALE SPRAGUE DAWLEY RATS USING A 10 DAY, ESCALATING DOSE REGIMEN OF MORPHINE (5-25 MG/KG; FROM 30 TO 39 DAYS OF AGE). CONTROL ANIMALS RECEIVED SALINE. BOTH SALINE AND MORPHINE EXPOSED FEMALES (SAL-F0 AND MOR-F0, RESPECTIVELY) WERE MATED WITH DRUG NAIVE MALES BEGINNING AT LEAST 3 WEEKS AFTER THE FINAL INJECTION. PLASMA CORTICOSTERONE LEVELS WERE MEASURED IN MALE AND FEMALE OFFSPRING (F1) DURING ADULTHOOD FOLLOWING 0, 0.1, OR 10 MG/KG MORPHINE. IN ADDITION, EXPRESSION OF CORTICOTROPIN RELEASING HORMONE (CRH) AND MU OPIOID RECEPTOR (OPRM1) IN THE PARAVENTRICULAR NUCLEUS (PVN) WERE MEASURED USING QUANTITATIVE PCR. MOR-F1 MALES, BUT NOT FEMALES, HAD BLUNTED MORPHINE-INDUCED CORTICOSTERONE SECRETION. THIS EFFECT WAS SPECIFIC TO OFFSPRING FROM FEMALES EXPOSED TO MORPHINE DURING ADOLESCENCE AS THOSE EXPOSED DURING ADULTHOOD PRODUCED OFFSPRING IN WHICH THE EFFECT WAS ABSENT. IN ADDITION, MOR-F1 MALES HAD SIGNIFICANTLY LOWER LEVELS OF PVN CRH FOLLOWING SALINE. THESE EFFECTS WERE NOT DRIVEN BY PVN OPRM1 IN THE F1 MALES AS THERE WERE NO DIFFERENCES BASED ON MATERNAL ADOLESCENT EXPOSURE. TO DETERMINE THE PERSISTENCE OF THE BLUNTED MORPHINE-INDUCED CORTICOSTERONE EFFECT, SAL-F2 AND MOR-F2 MALES WERE EXAMINED. BLUNTED MORPHINE-INDUCED CORTICOSTERONE SECRETION EXTENDED INTO THE MOR-F2 GENERATION, AS WELL AS EFFECTS ON CRH. IN ADDITION, THERE WAS ADDITIONAL DYSREGULATION OFOPRM1 EXPRESSION IN THE PVN IN MOR-F2 COMPARED WITH SAL-F2 MALES. THESE FINDINGS SUGGEST THAT SEX-SPECIFIC ALTERATIONS IN OPIOID-MEDIATED REGULATION OF THE HPA AXIS ARE TRANSGENERATIONALLY TRANSMITTED FOR AT LEAST TWO GENERATIONS FOLLOWING FEMALE ADOLESCENT MORPHINE EXPOSURE. THESE EFFECTS MAY PLAY A ROLE IN THE PREVIOUSLY OBSERVED CHANGES IN MORPHINE ANALGESIA AND REWARD-RELATED BEHAVIORS OBSERVED IN THIS PHENOTYPE. IN ADDITION, ALTERATIONS IN HPA FUNCTIONING SUCH AS THESE MAY PLAY A BROAD ROLE IN TRANSGENERATIONAL EPIGENETIC TRANSMISSION. 2018 4 989 33 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS. 2019 5 5339 33 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 6 5205 29 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 7 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 8 1903 38 ENHANCED NEUROINFLAMMATION MEDIATED BY DNA METHYLATION OF THE GLUCOCORTICOID RECEPTOR TRIGGERS COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS SUBJECTED TO MATERNAL SEPARATION DURING THE NEONATAL PERIOD. BACKGROUND: MOUNTING EVIDENCE INDICATES THAT CHILDREN WHO EXPERIENCE ABUSE AND NEGLECT ARE PRONE TO CHRONIC DISEASES AND PREMATURE MORTALITY LATER IN LIFE. ONE MECHANISTIC HYPOTHESIS FOR THIS PHENOMENON IS THAT EARLY LIFE ADVERSITY ALTERS THE EXPRESSION OR FUNCTIONING OF THE GLUCOCORTICOID RECEPTOR (GR) THROUGHOUT THE COURSE OF LIFE AND THEREBY INCREASES SENSITIVITY TO INFLAMMATORY STIMULATION. AN EXAGGERATED PRO-INFLAMMATORY RESPONSE IS GENERALLY CONSIDERED TO BE A KEY CAUSE OF POSTOPERATIVE COGNITIVE DYSFUNCTION (POCD). THE AIM OF THIS STUDY WAS TO EXAMINE THE EFFECTS OF EARLY LIFE ADVERSITY ON COGNITIVE FUNCTION AND NEUROINFLAMMATION AFTER SEVOFLURANE ANESTHESIA IN ADULT RATS AND TO DETERMINE WHETHER SUCH EFFECTS ARE ASSOCIATED WITH THE EPIGENETIC REGULATION OF GR. METHODS: WISTAR RAT PUPS WERE REPEATEDLY SUBJECTED TO INFANT MATERNAL SEPARATION (EARLY LIFE STRESS) FROM POSTNATAL DAYS 2-21. IN ADULTHOOD, THEIR BEHAVIOR AND THE SIGNALING OF HIPPOCAMPAL PRO-INFLAMMATORY FACTORS AND NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) AFTER SEVOFLURANE ANESTHESIA WERE EVALUATED. WE ALSO EXAMINED THE EFFECTS OF MATERNAL SEPARATION (MS) ON THE EXPRESSION OF GR AND THE DNA METHYLATION STATUS OF THE PROMOTER REGION OF EXON 1(7) OF GR AND WHETHER BEHAVIORAL CHANGES AND NEUROINFLAMMATION AFTER ANESTHESIA WERE REVERSIBLE WHEN THE EXPRESSION OF GR WAS INCREASED BY ALTERING DNA METHYLATION. RESULTS: MS INDUCED COGNITIVE DECLINE AFTER SEVOFLURANE INHALATION IN THE MORRIS WATER MAZE AND CONTEXT FEAR CONDITIONING TESTS AND ENHANCED THE RELEASE OF CYTOKINES AND THE ACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING INDUCED BY SEVOFLURANE IN THE HIPPOCAMPUS OF ADULT RATS. BLOCKING NF-KAPPAB SIGNALING BY PYRROLIDINE DITHIOCARBAMATE (PDTC) INHIBITED THE RELEASE OF CYTOKINES. MS ALSO REDUCED THE EXPRESSION OF GR AND UPREGULATED THE METHYLATION LEVELS OF THE PROMOTER REGION OF GR EXON 1(7), AND SUCH EFFECTS WERE REVERSED BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA) IN ADULT RATS. MOREOVER, TSA TREATMENT IN ADULT MS RATS INHIBITED THE OVERACTIVATION OF ASTROCYTE INTRACELLULAR NF-KAPPAB SIGNALING AND THE RELEASE OF CYTOKINES AND ALLEVIATED COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA. CONCLUSIONS: EARLY LIFE STRESS INDUCES COGNITIVE DYSFUNCTION AFTER SEVOFLURANE ANESTHESIA, PERHAPS DUE TO THE ABERRANT METHYLATION OF THE GR GENE PROMOTER, WHICH REDUCES THE EXPRESSION OF THE GR GENE AND FACILITATES EXAGGERATED INFLAMMATORY RESPONSES. 2017 9 5065 30 PHOTOPERIOD-INDUCED NEUROTRANSMITTER PLASTICITY DECLINES WITH AGING: AN EPIGENETIC REGULATION? NEUROPLASTICITY HAS CLASSICALLY BEEN UNDERSTOOD TO ARISE THROUGH CHANGES IN SYNAPTIC STRENGTH OR SYNAPTIC CONNECTIVITY. A NEWLY DISCOVERED FORM OF NEUROPLASTICITY, NEUROTRANSMITTER SWITCHING, INVOLVES CHANGES IN NEUROTRANSMITTER IDENTITY. CHRONIC EXPOSURE TO DIFFERENT PHOTOPERIODS ALTERS THE NUMBER OF DOPAMINE (TYROSINE HYDROXYLASE, TH+) AND SOMATOSTATIN (SST+) NEURONS IN THE PARAVENTRICULAR NUCLEUS (PAVN) OF THE HYPOTHALAMUS OF ADULT RATS AND RESULTS IN DISCRETE BEHAVIORAL CHANGES. HERE, WE INVESTIGATE WHETHER PHOTOPERIOD-INDUCED NEUROTRANSMITTER SWITCHING PERSISTS DURING AGING AND WHETHER EPIGENETIC MECHANISMS OF HISTONE ACETYLATION AND DNA METHYLATION MAY CONTRIBUTE TO THIS NEUROTRANSMITTER PLASTICITY. WE SHOW THAT THIS PLASTICITY IN RATS IS ROBUST AT 1 AND AT 3 MONTHS BUT REDUCED IN TH+ NEURONS AT 12 MONTHS AND COMPLETELY ABOLISHED IN BOTH TH+ AND SST+ NEURONS BY 18 MONTHS. DE NOVO EXPRESSION OF DNMT3A CATALYZING DNA METHYLATION AND ANTI-ACETYLH3 ASSESSING HISTONE 3 ACETYLATION WERE OBSERVED FOLLOWING SHORT-DAY PHOTOPERIOD EXPOSURE IN BOTH TH+ AND SST+ NEURONS AT 1 AND 3 MONTHS WHILE AN OVERALL INCREASE IN DNMT3A IN SST+ NEURONS PARALLELED NEUROPLASTICITY REDUCTION AT 12 AND 18 MONTHS. HISTONE ACETYLATION INCREASED IN TH+ NEURONS AND DECREASED IN SST+ NEURONS FOLLOWING SHORT-DAY EXPOSURE AT 3 MONTHS WHILE THE TOTAL NUMBER OF ANTI-ACETYLH3+ PAVN NEURONS REMAINED CONSTANT. RECIPROCAL HISTONE ACETYLATION IN TH+ AND SST+ NEURONS INDICATES THE IMPORTANCE OF STUDYING EPIGENETIC REGULATION AT THE CIRCUIT LEVEL FOR IDENTIFIED CELL PHENOTYPES. THE FINDINGS MAY BE USEFUL FOR DEVELOPING APPROACHES FOR NONINVASIVE TREATMENT OF DISORDERS CHARACTERIZED BY NEUROTRANSMITTER DYSFUNCTION. 2020 10 905 24 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 11 5152 32 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 12 6602 26 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 13 195 24 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 14 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 15 3328 38 HISTONE DEACETYLASE 5 MODULATES THE EFFECTS OF SOCIAL ADVERSITY IN EARLY LIFE ON COCAINE-INDUCED BEHAVIOR. PSYCHOSTIMULANTS INDUCE STABLE CHANGES IN NEURAL PLASTICITY AND BEHAVIOR IN A TRANSCRIPTION-DEPENDENT MANNER. FURTHER, STABLE CELLULAR CHANGES REQUIRE TRANSCRIPTION THAT IS REGULATED BY EPIGENETIC MECHANISMS THAT ALTER CHROMATIN STRUCTURE, SUCH AS HISTONE ACETYLATION. THIS MECHANISM IS TYPICALLY CATALYZED BY ENZYMES WITH HISTONE ACETYLTRANSFERASE OR HISTONE DEACETYLASE (HDAC) ACTIVITY. CLASS IIA HDACS ARE NOTABLE FOR THEIR HIGH EXPRESSION IN IMPORTANT REGIONS OF THE BRAIN REWARD CIRCUITRY AND THEIR NEURAL ACTIVITY-DEPENDENT SHUTTLING IN AND OUT OF THE CELL NUCLEUS. IN PARTICULAR, HDAC5 HAS AN IMPORTANT MODULATORY FUNCTION IN COCAINE-INDUCED BEHAVIORS AND SOCIAL DEFEAT STRESS-INDUCED EFFECTS. ALTHOUGH A MUTATION IN HDAC5 HAS BEEN SHOWN TO CAUSE HYPERSENSITIVE RESPONSES TO CHRONIC COCAINE USE WHETHER THIS RESPONSE WORSENS DURING CHRONIC EARLY LIFE STRESS HAS NOT BEEN EXAMINED YET. IN THIS STUDY, WE EXPOSED MOUSE PUPS TO TWO DIFFERENT EARLY LIFE STRESS PARADIGMS (SOCIAL ISOLATION, ESI, AND SOCIAL THREAT, EST) TO DETERMINE WHETHER THE HETEROZYGOUS NULL MUTATION IN HDAC5 (HDAC5+/-) MODERATED THE EFFECTS OF EXPOSURE TO STRESS IN EARLY LIFE ON ADULT COCAINE-INDUCED CONDITIONED PLACE PREFERENCE (CPP). NOTABLY, HDAC5+/- MICE THAT HAD BEEN EXPOSED TO ESI WERE MORE SUSCEPTIBLE TO DEVELOPING COCAINE-INDUCED CPP AND MORE RESISTANT TO EXTINGUISHING THIS BEHAVIOR. THE SAME EFFECT WAS NOT OBSERVED FOR HDAC5+/- MICE EXPERIENCING EST, SUGGESTING THAT ONLY ESI INDUCES BEHAVIORAL CHANGES BY ACTING PRECISELY THROUGH HDAC5-RELATED BIOLOGICAL PATHWAYS. FINALLY, AN ANALYSIS OF C-FOS EXPRESSION PERFORMED TO DISCOVER THE NEUROBIOLOGICAL SUBSTRATES THAT MEDIATED THIS PHENOTYPE, IDENTIFIED THE DORSOLATERAL STRIATUM AS AN IMPORTANT STRUCTURE THAT MEDIATES THE INTERACTION BETWEEN HDAC5 MUTATION AND ESI. OUR DATA DEMONSTRATE THAT DECREASED HDAC5 FUNCTION IS ABLE TO EXACERBATE THE LONG-TERM BEHAVIORAL EFFECTS OF ADVERSE REARING ENVIRONMENT IN MOUSE. 2017 16 2672 30 ETHANOL-INDUCED EPIGENETIC REGULATIONS AT THE BDNF GENE IN C57BL/6J MICE. HIGH ETHANOL INTAKE IS WELL KNOWN TO INDUCE BOTH ANXIOLYTIC AND ANXIOGENIC EFFECTS, IN CORRELATION WITH CHROMATIN REMODELING IN THE AMYGDALOID BRAIN REGION AND DEFICITS IN CELL PROLIFERATION AND SURVIVAL IN THE HIPPOCAMPUS OF RODENTS. WHETHER ONLY MODERATE BUT CHRONIC ETHANOL INTAKE IN C57BL/6J MICE COULD ALSO HAVE AN IMPACT ON CHROMATIN REMODELING AND NEUROPLASTICITY WAS ADDRESSED HERE. CHRONIC ETHANOL CONSUMPTION IN A FREE CHOICE PARADIGM WAS FOUND TO INDUCE MARKED CHANGES IN THE EXPRESSION OF GENES IMPLICATED IN NEURAL DEVELOPMENT AND HISTONE POST-TRANSLATIONAL MODIFICATIONS IN THE MOUSE HIPPOCAMPUS. TRANSCRIPTS ENCODING NEURAL BHLH ACTIVATORS AND THOSE FROM BDNF EXONS II, III AND VI WERE UPREGULATED, WHEREAS THOSE FROM BDNF EXON VIII AND HDACS WERE DOWNREGULATED BY ETHANOL COMPARED WITH WATER CONSUMPTION. THESE ETHANOL-INDUCED CHANGES WERE ASSOCIATED WITH ENRICHMENT IN BOTH ACETYLATED H3 AT BDNF PROMOTER PVI AND TRIMETHYLATED H3 AT PII AND PIII. CONVERSELY, ACETYLATED H3 AT PIII AND PVIII AND TRIMETHYLATED H3 AT PVIII WERE DECREASED IN ETHANOL-EXPOSED MICE. IN PARALLEL, HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND TRKB-MEDIATED NEUROGENESIS IN THE DENTATE GYRUS WERE SIGNIFICANTLY ENHANCED BY ETHANOL CONSUMPTION. THESE RESULTS SUGGEST THAT, IN C57BL/6J MICE, CHRONIC AND MODERATE ETHANOL INTAKE PRODUCES MARKED EPIGENETIC CHANGES UNDERLYING BDNF OVEREXPRESSION AND DOWNSTREAM HIPPOCAMPAL NEUROGENESIS. 2015 17 3093 25 GENOMIC AND EPIGENOMIC RESPONSES TO CHRONIC STRESS INVOLVE MIRNA-MEDIATED PROGRAMMING. STRESS REPRESENTS A CRITICAL INFLUENCE ON MOTOR SYSTEM FUNCTION AND HAS BEEN SHOWN TO IMPAIR MOVEMENT PERFORMANCE. WE HYPOTHESIZED THAT STRESS-INDUCED MOTOR IMPAIRMENTS ARE DUE TO BRAIN-SPECIFIC CHANGES IN MIRNA AND PROTEIN-ENCODING GENE EXPRESSION. HERE WE SHOW A CAUSAL LINK BETWEEN STRESS-INDUCED MOTOR IMPAIRMENT AND ASSOCIATED GENETIC AND EPIGENETIC RESPONSES IN RELEVANT CENTRAL MOTOR AREAS IN A RAT MODEL. EXPOSURE TO TWO WEEKS OF MILD RESTRAINT STRESS ALTERED THE EXPRESSION OF 39 GENES AND NINE MIRNAS IN THE CEREBELLUM. IN LINE WITH PERSISTENT BEHAVIOURAL IMPAIRMENTS, SOME CHANGES IN GENE AND MIRNA EXPRESSION WERE RESISTANT TO RECOVERY FROM STRESS. INTERESTINGLY, STRESS UP-REGULATED THE EXPRESSION OF ADIPOQ AND PROLACTIN RECEPTOR MRNAS IN THE CEREBELLUM. STRESS ALSO ALTERED THE EXPRESSION OF PRLR, MIR-186, AND MIR-709 IN HIPPOCAMPUS AND PREFRONTAL CORTEX. IN ADDITION, OUR FINDINGS DEMONSTRATE THAT MIR-186 TARGETS THE GENE EPS15. FURTHERMORE, WE FOUND AN AGE-DEPENDENT INCREASE IN EPHRINB3 AND GABAA4 RECEPTORS. THESE DATA SHOW THAT EVEN MILD STRESS RESULTS IN SUBSTANTIAL GENOMIC AND EPIGENOMIC CHANGES INVOLVING MIRNA EXPRESSION AND ASSOCIATED GENE TARGETS IN THE MOTOR SYSTEM. THESE FINDINGS SUGGEST A CENTRAL ROLE OF MIRNA-REGULATED GENE EXPRESSION IN THE STRESS RESPONSE AND IN ASSOCIATED NEUROLOGICAL FUNCTION. 2012 18 3590 30 IMPAIRED LATENT INHIBITION IN GDNF-DEFICIENT MICE EXPOSED TO CHRONIC STRESS. INCREASED REACTIVITY TO STRESS IS MALADAPTIVE AND LINKED TO ABNORMAL BEHAVIORS AND PSYCHOPATHOLOGY. CHRONIC UNPREDICTABLE STRESS (CUS) ALTERS CATECHOLAMINERGIC NEUROTRANSMISSION AND REMODELS NEURONAL CIRCUITS INVOLVED IN LEARNING, ATTENTION AND DECISION MAKING. GLIAL-DERIVED NEUROTROPHIC FACTOR (GDNF) IS ESSENTIAL FOR THE PHYSIOLOGY AND SURVIVAL OF DOPAMINERGIC NEURONS IN SUBSTANTIA NIGRA AND OF NORADRENERGIC NEURONS IN THE LOCUS COERULEUS. UP-REGULATION OF GDNF EXPRESSION DURING STRESS IS LINKED TO RESILIENCE; ON THE OTHER HAND, THE INABILITY TO UP-REGULATE GDNF IN RESPONSE TO STRESS, AS A RESULT OF EITHER GENETIC OR EPIGENETIC MODIFICATIONS, INDUCES BEHAVIORAL ALTERATIONS. FOR EXAMPLE, GDNF-DEFICIENT MICE EXPOSED TO CHRONIC STRESS EXHIBIT ALTERATIONS OF EXECUTIVE FUNCTION, SUCH AS INCREASED TEMPORAL DISCOUNTING. HERE WE INVESTIGATED THE EFFECTS OF CUS ON LATENT INHIBITION (LI), A MEASURE OF SELECTIVE ATTENTION AND LEARNING, IN GDNF-HETEROZYGOUS (HET) MICE AND THEIR WILD-TYPE (WT) LITTERMATE CONTROLS. NO DIFFERENCES IN LI WERE FOUND BETWEEN GDNF HET AND WT MICE UNDER BASELINE EXPERIMENTAL CONDITIONS. HOWEVER, FOLLOWING CUS, GDNF-DEFICIENT MICE FAILED TO EXPRESS LI. MOREOVER, STRESSED GDNF-HET MICE, BUT NOT THEIR WT CONTROLS, SHOWED DECREASED NEURONAL ACTIVATION (NUMBER OF C-FOS POSITIVE NEURONS) IN THE NUCLEUS ACCUMBENS SHELL AND INCREASED ACTIVATION IN THE NUCLEUS ACCUMBENS CORE, BOTH KEY REGIONS IN THE EXPRESSION OF LI. OUR RESULTS ADD LI TO THE LIST OF BEHAVIORS AFFECTED BY CHRONIC STRESS AND SUPPORT A ROLE FOR GDNF DEFICITS IN STRESS-INDUCED PATHOLOGICAL BEHAVIORS RELEVANT TO SCHIZOPHRENIA AND OTHER PSYCHIATRIC DISORDERS. 2017 19 2886 23 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 20 4499 36 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