1 6108 163 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS. 2019 2 3312 53 HIPPOCAMPAL AND BEHAVIORAL DYSFUNCTIONS IN A MOUSE MODEL OF ENVIRONMENTAL STRESS: NORMALIZATION BY AGOMELATINE. STRESS-INDUCED ALTERATIONS IN NEURONAL PLASTICITY AND IN HIPPOCAMPAL FUNCTIONS HAVE BEEN SUGGESTED TO BE INVOLVED IN THE DEVELOPMENT OF MOOD DISORDERS. IN THIS CONTEXT, WE INVESTIGATED IN THE HIPPOCAMPUS THE ACTIVATION OF INTRACELLULAR SIGNALING CASCADES, THE EXPRESSION OF EPIGENETIC MARKERS AND PLASTICITY-RELATED GENES IN A MOUSE MODEL OF STRESS-INDUCED HYPERACTIVITY AND OF MIXED AFFECTIVE DISORDERS. WE ALSO DETERMINED WHETHER THE ANTIDEPRESSANT DRUG AGOMELATINE, A MT1/MT2 MELATONERGIC RECEPTOR AGONIST/5-HT2C RECEPTOR ANTAGONIST, COULD PREVENT SOME NEUROBIOLOGICAL AND BEHAVIORAL ALTERATIONS PRODUCED BY STRESS. C57BL/6J MICE, EXPOSED FOR 3 WEEKS TO DAILY UNPREDICTABLE SOCIO-ENVIRONMENTAL STRESSORS OF MILD INTENSITY, WERE TREATED DURING THE WHOLE PROCEDURE WITH AGOMELATINE (50 MG KG(-1) PER DAY, INTRAPERITONEAL). STRESSED MICE DISPLAYED ROBUST INCREASES IN EMOTIONAL AROUSAL, VIGILANCE AND MOTOR ACTIVITY, TOGETHER WITH A REWARD DEFICIT AND A REDUCTION IN ANXIETY-LIKE BEHAVIOR. NEUROBIOLOGICAL INVESTIGATIONS SHOWED AN INCREASED PHOSPHORYLATION OF INTRACELLULAR SIGNALING PROTEINS, INCLUDING ATF1, CREB AND P38, IN THE HIPPOCAMPUS OF STRESSED MICE. DECREASED HIPPOCAMPAL LEVEL OF THE REPRESSIVE EPIGENETIC MARKS HDAC2 AND H3K9ME2, AS WELL AS INCREASED LEVEL OF THE PERMISSIVE MARK H3K9/14AC SUGGESTED THAT CHRONIC MILD STRESS WAS ASSOCIATED WITH INCREASED GENE TRANSCRIPTION, AND CLEAR-CUT EVIDENCE WAS FURTHER INDICATED BY CHANGES IN NEUROPLASTICITY-RELATED GENES, INCLUDING ARC, BCL2, BDNF, GDNF, IGF1 AND NEUROD1. TOGETHER WITH OTHER FINDINGS, THE PRESENT DATA SUGGEST THAT CHRONIC ULTRA-MILD STRESS CAN MODEL THE HYPERACTIVITY OR PSYCHOMOTOR AGITATION, AS WELL AS THE MIXED AFFECTIVE BEHAVIORS OFTEN OBSERVED DURING THE MANIC STATE OF BIPOLAR DISORDER PATIENTS. INTERESTINGLY, AGOMELATINE COULD NORMALIZE BOTH THE BEHAVIORAL AND THE MOLECULAR ALTERATIONS INDUCED BY STRESS, PROVIDING FURTHER INSIGHTS INTO THE MECHANISM OF ACTION OF THIS NEW GENERATION ANTIDEPRESSANT DRUG. 2014 3 910 34 CHRONIC EXPOSURE TO ETHANOL OF MALE MICE BEFORE MATING PRODUCES ATTENTION DEFICIT HYPERACTIVITY DISORDER-LIKE PHENOTYPE ALONG WITH EPIGENETIC DYSREGULATION OF DOPAMINE TRANSPORTER EXPRESSION IN MOUSE OFFSPRING. PRECONCEPTION EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE MAY AFFECT NEUROBEHAVIORAL AND DEVELOPMENTAL FEATURES OF OFFSPRING. THIS STUDY INVESTIGATES THE EFFECTS OF PATERNAL EXPOSURE TO ETOH BEFORE CONCEPTION ON THE HYPERACTIVITY, INATTENTION, AND IMPULSIVITY BEHAVIOR OF MALE OFFSPRING IN MICE. SIRE MICE WERE TREATED WITH ETOH IN A CONCENTRATION RANGE APPROXIMATING HUMAN BINGE DRINKING (0-4 G/KG/DAY ETOH) FOR 7 WEEKS AND MATED WITH UNTREATED FEMALES MICE TO PRODUCE OFFSPRING. ETOH EXPOSURE TO SIRE MICE INDUCED ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD)-LIKE HYPERACTIVE, INATTENTIVE, AND IMPULSIVE BEHAVIORS IN OFFSPRING. AS A MECHANISTIC LINK, BOTH PROTEIN AND MRNA EXPRESSION OF DOPAMINE TRANSPORTER (DAT), A KEY DETERMINANT OF ADHD-LIKE PHENOTYPES IN EXPERIMENTAL ANIMALS AND HUMANS, WERE SIGNIFICANTLY DECREASED BY PATERNAL ETOH EXPOSURE IN CEREBRAL CORTEX AND STRIATUM OF OFFSPRING MICE ALONG WITH INCREASED METHYLATION OF A CPG REGION OF THE DAT GENE PROMOTER. THE INCREASE IN METHYLATION OF DAT GENE PROMOTER WAS ALSO OBSERVED IN THE SPERM OF SIRE MICE, SUGGESTING GERMLINE CHANGES IN THE EPIGENETIC METHYLATION SIGNATURE OF DAT GENE BY ETOH EXPOSURE. IN ADDITION, THE EXPRESSION OF TWO KEY REGULATORS OF METHYLATION-DEPENDENT EPIGENETIC REGULATION OF FUNCTIONAL GENE EXPRESSION, NAMELY, MECP2 AND DNMT1, WAS MARKEDLY DECREASED IN OFFSPRING CORTEX AND STRIATUM SIRED BY ETOH-EXPOSED MICE. THESE RESULTS SUGGEST THAT PRECONCEPTIONAL EXPOSURE TO ETOH THROUGH THE PATERNAL ROUTE INDUCES BEHAVIORAL CHANGES IN OFFSPRING, POSSIBLY VIA EPIGENETIC CHANGES IN GENE EXPRESSION, WHICH IS ESSENTIAL FOR THE REGULATION OF ADHD-LIKE BEHAVIORS. 2014 4 1761 44 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS. 2013 5 1829 50 EFFECTS OF INHIBITING ASTROCYTES AND BET/BRD4 CHROMATIN READER ON SPATIAL MEMORY AND SYNAPTIC PROTEINS IN RATS WITH ALZHEIMER'S DISEASE. COMMUNICATION BETWEEN ASTROCYTES AND NEURONS HAS A PROFOUND EFFECT ON THE PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE (AD). ASTROCYTES REGULATE HOMEOSTASIS AND INCREASE SYNAPTIC PLASTICITY IN PHYSIOLOGICAL SITUATIONS, HOWEVER, THEY BECOME ACTIVATED DURING THE PROGRESSION OF AD. WHETHER OR NOT THESE REACTIONS ARE SUPPORTIVE OR DETRIMENTAL FOR THE CENTRAL NERVOUS SYSTEM HAVE NOT BEEN UNDERSTOOD YET. CONSIDERING EPIGENETIC REGULATION OF NEUROINFLAMMATORY GENES BY CHROMATIN READERS, PARTICULARLY BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY, HERE WE EXAMINED THE EFFECT OF CHRONIC CO-INHIBITION OF ASTROCYTES METABOLISM (WITH FLUOROCITRATE) AND ALSO BRD4 (WITH JQ1) ON COGNITION DEFICIT AT EARLY STAGES OF AD. FORTY ADULT MALE WISTAR RATS UNDERWENT STEREOTAXIC CANNULATION FOR INDUCING AD BY INTRAHIPPOCAMPAL INJECTION OF ABETA(1-42) (4 MUG/8 MUL/RAT). THEN ANIMALS WERE DIVIDED INTO FIVE GROUPS OF SALINE+DMSO, ABETA + SALINE+DMSO, ABETA + JQ1, ABETA + FC (FLUOROCITRATE), AND ABETA + JQ1 + FC AND RECEIVED THE RELATED TREATMENTS. TWO WEEKS LATER, SPATIAL MEMORY WAS RECORDED BY MORRIS WATER MAZE (MWM), AND THE LEVELS OF PHOSPHORYLATED CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CREB), POSTSYNAPTIC DENSITY 95 (PSD95), SYNAPTOPHYSIN (SYP), AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE MEASURED IN THE HIPPOCAMPUS BY WESTERN BLOTTING AND RT-QPCR. ADMINISTRATION OF JQ1 SIGNIFICANTLY IMPROVED BOTH ACQUISITION AND RETRIEVAL OF SPATIAL MEMORY, WHICH WERE EVIDENT BY DECREASED ESCAPE LATENCY AND INCREASED TOTAL TIME SPENT (TTS) IN TARGET QUADRANT, AND SIGNIFICANT RISE IN P-CREB, PSD95, AND SYNAPTOPHYSIN COMPARED WITH ABETA + SALINE+DMSO GROUP. IN CONTRAST, BOTH GROUPS RECEIVING FC DEMONSTRATED MEMORY DECLINE, AND REDUCTION IN P-CREB, PSD95 AND SYNAPTOPHYSIN IN PARALLEL WITH INCREASE IN TNF-ALPHA. OUR DATA INDICATE THAT CHRONIC INHIBITION OF BRD4 SIGNIFICANTLY RESTORES MEMORY IMPAIRED BY AMYLOID BETA PARTLY VIA CREB SIGNALING AND UPREGULATING SYNAPTIC PROTEINS OF PSD95 AND SYNAPTOPHYSIN. HOWEVER, INHIBITION OF ASTROCYTES NULLIFIES THE MEMORY-BOOSTING EFFECTS OF JQ1 AND REDUCES CREB/PSD95/SYNAPTOPHYSIN LEVELS IN HIPPOCAMPUS. 2022 6 869 39 CHRONIC AGOMELATINE TREATMENT CORRECTS BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES INDUCED BY PRENATAL STRESS IN RATS. RATIONALE AND OBJECTIVES: THE RAT MODEL OF PRENATAL RESTRAINT STRESS (PRS) REPLICATES FACTORS THAT ARE IMPLICATED IN THE ETIOLOGY OF ANXIOUS/DEPRESSIVE DISORDERS. WE USED THIS MODEL TO TEST THE THERAPEUTIC EFFICACY OF AGOMELATINE, A NOVEL ANTIDEPRESSANT THAT BEHAVES AS A MIXED MT1/MT2 MELATONIN RECEPTOR AGONIST/5-HT(2C) SEROTONIN RECEPTOR ANTAGONIST. RESULTS: ADULT PRS RATS SHOWED BEHAVIORAL, CELLULAR, AND BIOCHEMICAL ABNORMALITIES THAT WERE CONSISTENT WITH AN ANXIOUS/DEPRESSIVE PHENOTYPE. THESE INCLUDED AN INCREASED IMMOBILITY IN THE FORCED SWIM TEST, AN ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE, REDUCED HIPPOCAMPAL LEVELS OF PHOSPHORYLATED CAMP-RESPONSIVE ELEMENT BINDING PROTEIN (P-CREB), REDUCED HIPPOCAMPAL LEVELS OF MGLU2/3 AND MGLU5 METABOTROPIC GLUTAMATE RECEPTORS, AND REDUCED NEUROGENESIS IN THE VENTRAL HIPPOCAMPUS, THE SPECIFIC PORTION OF THE HIPPOCAMPUS THAT ENCODES MEMORIES RELATED TO STRESS AND EMOTIONS. ALL OF THESE CHANGES WERE REVERSED BY A 3- OR 6-WEEK TREATMENT WITH AGOMELATINE (40-50 MG/KG, I.P., ONCE A DAY). REMARKABLY, AGOMELATINE HAD NO EFFECT IN AGE-MATCHED CONTROL RATS, THEREBY BEHAVING AS A "DISEASE-DEPENDENT" DRUG. CONCLUSIONS: THESE DATA INDICATE THAT AGOMELATINE DID NOT ACT ON INDIVIDUAL SYMPTOMS BUT CORRECTED ALL ASPECTS OF THE PATHOLOGICAL EPIGENETIC PROGRAMMING TRIGGERED BY PRS. OUR FINDINGS STRONGLY SUPPORT THE ANTIDEPRESSANT ACTIVITY OF AGOMELATINE AND SUGGEST THAT THE DRUG IMPACTS MECHANISMS THAT LIE AT THE CORE OF ANXIOUS/DEPRESSIVE DISORDERS. 2011 7 747 28 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE. 2021 8 3177 56 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021 9 3977 51 LONG-TERM EFFECT OF POST-TRAUMATIC STRESS IN ADOLESCENCE ON DENDRITE DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN MALE RAT HIPPOCAMPUS AND PREFRONTAL CORTEX. EXPOSURE TO A HARSH ENVIRONMENT IN EARLY LIFE INCREASES IN THE RISK OF POST-TRAUMATIC STRESS DISORDER (PTSD) OF AN INDIVIDUAL. BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) PLAYS AN IMPORTANT ROLE IN NEURODEVELOPMENT IN DEVELOPMENTAL STAGES. BOTH CHRONIC AND TRAUMATIC STRESSES INDUCE A DECREASE IN THE LEVEL OF BDNF AND REDUCE NEURAL PLASTICITY, WHICH IS LINKED TO THE PATHOGENESIS OF PTSD. ALSO, STUDIES HAVE SHOWN THAT STRESS ALTERS THE EPIGENETIC MARKER H3K9ME2, WHICH CAN BIND TO THE PROMOTER REGION OF THE BDNF GENE AND REDUCE BDNF PROTEIN LEVEL. HOWEVER, THE LONG-TERM EFFECTS OF TRAUMATIC STRESS DURING ADOLESCENCE ON H3K9ME2, BDNF EXPRESSION AND DENDRITE DEVELOPMENT ARE NOT WELL-KNOWN. THE PRESENT STUDY ESTABLISHED A MODEL OF PTSD IN ADOLESCENT RATS USING AN INESCAPABLE FOOT SHOCK (IFS) PROCEDURE. ANXIETY-LIKE BEHAVIORS, SOCIAL INTERACTION BEHAVIOR AND MEMORY FUNCTION WERE ASSESSED BY THE OPEN FIELD TEST, ELEVATED PLUS MAZE TEST, THREE-CHAMBER SOCIABILITY TEST AND MORRIS WATER MAZE TEST. IN ADDITION, NEURONAL DEVELOPMENT AND H3K9ME2/BDNF EXPRESSION IN HIPPOCAMPUS (HIP) AND PREFRONTAL CORTEX (PFC) WERE EVALUATED BY GOLGI STAINING, WESTERN BLOTTING, QRT-PCR ANALYSIS AND CHIP-QPCR ANALYSIS. ADDITIONALLY, THE UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (EHMT2) WAS USED FOR INTERVENTION. THE RESULTS SHOWED THAT THE IFS PROCEDURE INDUCED THE PTSD-LIKE BEHAVIORS IN RATS, RESULTED IN FEWER DENDRITE BRANCHES AND SHORTER DENDRITE LENGTH IN CA1 OF HIP AND PFC, INCREASED H3K9ME2 LEVEL AND DECREASED BDNF EXPRESSION IN HIP AND PFC. ALSO, ALTHOUGH ALL THE CHANGES CAN PERSIST TO ADULTHOOD, UNC0642 ADMINISTRATION RELIEVED MOST OF ALTERATIONS. OUR STUDY SUGGESTS THAT TRAUMATIC STRESS IN ADOLESCENCE LEADS TO IMMEDIATE AND LONG-TERM MENTAL DISORDERS, NEURONAL MORPHOLOGICAL CHANGES, LOWER BDNF LEVEL AND INCREASED H3K9ME2 LEVEL IN THE HIP AND PFC, INDICATING THAT H3K9ME2/BDNF DYSFUNCTION PLAYS A KEY ROLE IN PATHOGENESIS OF PTSD. 2020 10 4069 44 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 11 5752 44 SOCIAL ISOLATION AND SOCIAL SUPPORT AT ADULTHOOD AFFECT EPIGENETIC MECHANISMS, BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS AND BEHAVIOR OF CHRONICALLY STRESSED RATS. EPIGENETIC MODULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROVIDES ONE POSSIBLE EXPLANATION FOR THE DYSFUNCTIONS INDUCED BY STRESS, SUCH AS PSYCHIATRIC DISORDERS AND COGNITIVE DECLINE. INTERESTINGLY, SOCIAL SUPPORT CAN BE PROTECTIVE AGAINST SOME OF THESE EFFECTS, BUT THE MECHANISMS OF SOCIAL BUFFERING ARE POORLY UNDERSTOOD. CONVERSELY, EARLY ISOLATION EXACERBATES THE RESPONSES TO STRESSORS, ALTHOUGH ITS EFFECTS IN ADULTHOOD REMAIN UNCLEAR. THIS STUDY INVESTIGATED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL BUFFERING ON HIPPOCAMPAL EPIGENETIC MECHANISMS, BDNF LEVELS AND BEHAVIORAL RESPONSES OF CHRONICALLY STRESSED YOUNG ADULT RATS. MALE WISTAR RATS (3 MONTHS) WERE ASSIGNED TO ACCOMPANIED (PAIRED) OR ISOLATED HOUSING. AFTER ONE-MONTH HALF OF EACH GROUP WAS SUBMITTED TO A CHRONIC UNPREDICTABLE STRESS (CUS) PROTOCOL FOR 18 DAYS. AMONG ACCOMPANIED ANIMALS, ONLY ONE WAS EXPOSED TO STRESS. BEHAVIORAL ANALYSIS ENCOMPASSED THE OPEN FIELD, PLUS MAZE AND INHIBITORY AVOIDANCE TASKS. HIPPOCAMPAL H3K9 AND H4K12 ACETYLATION, HDAC5 EXPRESSION AND BDNF LEVELS WERE EVALUATED. ISOLATED HOUSING INCREASED HDAC5 EXPRESSION, DECREASED H3K9 AND H4K12 ACETYLATION, REDUCED BDNF LEVELS, AND IMPAIRED LONG-TERM MEMORY. STRESS AFFECTED WEIGHT GAIN, INDUCED ANXIETY-LIKE BEHAVIOR AND DECREASED ACK9H3 LEVELS. INTERACTIONS BETWEEN HOUSING CONDITIONS AND SOCIAL STRESS WERE SEEN ONLY FOR HDAC5 EXPRESSION, WHICH SHOWED A FURTHER INCREASE IN THE ISOLATED + CUS GROUP BUT REMAINED CONSTANT IN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION AT ADULTHOOD INDUCED EPIGENETIC ALTERATIONS AND EXACERBATED THE EFFECTS OF CHRONIC STRESS ON HDAC5. NOTWITHSTANDING, SOCIAL SUPPORT COUNTERACTED THE ADVERSE EFFECTS OF STRESS ON HDAC5 EXPRESSION. 2019 12 3973 36 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 13 683 38 BRAIN PLASTICITY AND COGNITIVE FUNCTIONS AFTER ETHANOL CONSUMPTION IN C57BL/6J MICE. ACUTE OR CHRONIC ADMINISTRATIONS OF HIGH DOSES OF ETHANOL IN MICE ARE KNOWN TO PRODUCE SEVERE COGNITIVE DEFICITS LINKED TO HIPPOCAMPAL DAMAGE. HOWEVER, WE RECENTLY REPORTED THAT CHRONIC AND MODERATE ETHANOL INTAKE IN C57BL/6J MICE INDUCED CHROMATIN REMODELING WITHIN THE BDNF PROMOTERS, LEADING TO BOTH ENHANCED BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND HIPPOCAMPAL NEUROGENESIS UNDER FREE-CHOICE PROTOCOL. WE PERFORMED HERE A SERIES OF CELLULAR AND BEHAVIORAL STUDIES TO ANALYZE THE CONSEQUENCES OF THESE MODIFICATIONS. WE SHOWED THAT A 3-WEEK CHRONIC FREE-CHOICE ETHANOL CONSUMPTION IN C57BL/6J MICE LED TO A DECREASE IN DNA METHYLATION OF THE BDNF GENE WITHIN THE CA1 AND CA3 SUBFIELDS OF THE HIPPOCAMPUS, AND UPREGULATED HIPPOCAMPAL BDNF SIGNALING PATHWAYS MEDIATED BY ERK, AKT AND CREB. HOWEVER, THIS ACTIVATION DID NOT AFFECT LONG-TERM POTENTIATION IN THE CA1. CONVERSELY, ETHANOL INTAKE IMPAIRED LEARNING AND MEMORY CAPACITIES ANALYZED IN THE CONTEXTUAL FEAR CONDITIONING TEST AND THE NOVEL OBJECT RECOGNITION TASK. IN ADDITION, ETHANOL INCREASED BEHAVIORAL PERSEVERATION IN THE BARNES MAZE TEST BUT DID NOT ALTER THE MOUSE OVERALL SPATIAL CAPACITIES. THESE DATA SUGGESTED THAT IN CONDITIONS OF CHRONIC AND MODERATE ETHANOL INTAKE, THE CHROMATIN REMODELING LEADING TO BDNF SIGNALING UPREGULATION IS PROBABLY AN ADAPTIVE PROCESS, ENGAGED VIA EPIGENETIC REGULATIONS, TO COUNTERACT THE COGNITIVE DEFICITS INDUCED BY ETHANOL. 2015 14 2827 39 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS. 2011 15 5019 36 PERSISTENT INFLAMMATORY PAIN IS LINKED WITH ANXIETY-LIKE BEHAVIORS, INCREASED BLOOD CORTICOSTERONE, AND REDUCED GLOBAL DNA METHYLATION IN THE RAT AMYGDALA. CHRONIC PAIN INCREASES THE RISK OF DEVELOPING ANXIETY, WITH LIMBIC AREAS BEING LIKELY NEUROLOGICAL SUBSTRATES. DESPITE HIGH CLINICAL RELEVANCE, LITTLE IS KNOWN ABOUT THE PRECISE BEHAVIORAL, HORMONAL, AND BRAIN NEUROPLASTIC CORRELATES OF ANXIETY IN THE CONTEXT OF PERSISTENT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT DECREASED NOCICEPTIVE THRESHOLDS IN CHRONIC PAIN MODELS ARE PARALLELED BY ANXIETY-LIKE BEHAVIOR IN RATS, BUT THERE ARE CONFLICTING IDEAS REGARDING ITS EFFECTS ON THE STRESS RESPONSE AND CIRCULATING CORTICOSTERONE LEVELS. EVEN LESS IS KNOWN ABOUT THE MOLECULAR MECHANISMS THROUGH WHICH THE BRAIN ENCODES PAIN-RELATED ANXIETY. THIS STUDY EXAMINES HOW PERSISTENT INFLAMMATORY PAIN IN A RAT MODEL WOULD IMPACT ANXIETY-LIKE BEHAVIORS AND CORTICOSTERONE RELEASE, AND WHETHER THESE CHANGES WOULD BE REFLECTED IN LEVELS OF GLOBAL DNA METHYLATION IN BRAIN AREAS INVOLVED IN STRESS REGULATION. COMPLETE FREUND'S ADJUVANT (CFA) OR SALINE WAS ADMINISTERED IN THE RIGHT HINDPAW OF ADULT MALE WISTAR RATS. BEHAVIORAL TESTING INCLUDED THE MEASUREMENT OF NOCICEPTIVE THRESHOLDS (DIGITAL ANESTHESIOMETER), MOTOR FUNCTION (OPEN FIELD TEST), AND ANXIETY-LIKE BEHAVIORS (ELEVATED PLUS MAZE AND THE DARK-LIGHT BOX TEST). CORTICOSTERONE WAS MEASURED VIA RADIOIMMUNOASSAY. GLOBAL DNA METHYLATION (ENZYME IMMUNOASSAY) AS WELL AS DNMT3A LEVELS (WESTERN BLOTTING) WERE QUANTIFIED IN THE AMYGDALA, PREFRONTAL CORTEX, AND VENTRAL HIPPOCAMPUS. CFA ADMINISTRATION RESULTED IN PERSISTENT REDUCTION IN NOCICEPTIVE THRESHOLD IN THE ABSENCE OF LOCOMOTOR ABNORMALITIES. INCREASED ANXIETY-LIKE BEHAVIORS WERE OBSERVED IN THE ELEVATED PLUS MAZE AND WERE ACCOMPANIED BY INCREASED BLOOD CORTICOSTERONE LEVELS 10 DAYS AFTER PAIN INDUCTION. GLOBAL DNA METHYLATION WAS DECREASED IN THE AMYGDALA, WITH NO CHANGES IN DNMT3A ABUNDANCE IN ANY OF THE REGIONS EXAMINED. PERSISTENT INFLAMMATORY PAIN PROMOTES ANXIETY -LIKE BEHAVIORS, HPA AXIS ACTIVATION, AND EPIGENETIC REGULATION THROUGH DNA METHYLATION IN THE AMYGDALA. THESE FINDINGS DESCRIBE A MOLECULAR MECHANISM THAT LINKS PAIN AND STRESS IN A WELL-CHARACTERIZED RODENT MODEL. 2022 16 3978 40 LONG-TERM EFFECTS OF PRENATAL SEVERE HYPOXIA ON CENTRAL AND PERIPHERAL COMPONENTS OF THE GLUCOCORTICOID SYSTEM IN RATS. INTRODUCTION: PRENATAL HYPOXIA IS A RISK FACTOR FOR THE DEVELOPMENT OF NUMEROUS NEUROLOGICAL DISORDERS. IT IS KNOWN THAT THE MATERNAL STRESS RESPONSE TO HYPOXIA DETERMINES THE EPIGENETIC IMPAIRMENT OF THE PERINATAL EXPRESSION OF GLUCOCORTICOID RECEPTORS (GR) IN THE HIPPOCAMPUS OF THE PROGENY, BUT SO FAR NO DETAILED STUDY OF HOW THIS AFFECTS THE FUNCTIONAL STATE OF THE GLUCOCORTICOID SYSTEM DURING FURTHER ONTOGENESIS HAS BEEN PERFORMED. OBJECTIVE: THE GOAL OF THE PRESENT STUDY WAS TO EXAMINE THE LONG-TERM EFFECTS OF THE PRENATAL HYPOXIA ON THE FUNCTIONING OF THE GLUCOCORTICOID SYSTEM THROUGHOUT LIFE. METHODS: PRENATAL SEVERE HYPOBARIC HYPOXIA (PSH) WAS INDUCED IN THE CRITICAL PERIOD OF EMBRYONIC HIPPOCAMPAL FORMATION ON DAYS 14-16 OF GESTATION IN A HYPOBARIC CHAMBER (180 TORR, 5% OXYGEN, 3 H). THE ACTIVITY OF CENTRAL (HIPPOCAMPUS) AND PERIPHERAL (LIVER) COMPONENTS OF THE GLUCOCORTICOID SYSTEM WAS ASSESSED IN 1-DAY-OLD (NEWBORN), 2-WEEK-OLD (JUVENILE), 3-MONTH-OLD (ADULT), AND 18-MONTH-OLD (AGED) MALE RATS. RESULTS: THE PSH RESULTED IN CONTINUOUSLY ELEVATED BASELINE CORTICOSTERONE BLOOD LEVELS IN THE ADULT AND AGED RATS. THE CHRONIC ELEVATION OF THE CORTICOSTERONE LEVELS WAS ACCOMPANIED BY A PROGRESSIVE DEFICIT OF THE GR EXPRESSION IN THE LIVER, INCREASED HEPATIC GLYCOGEN CONTENT, DYSREGULATED GLUCOSE-6-PHOSPHATASE ACTIVITY, AND EVENTUALLY HYPOGLYCEMIA. ELEVATED CORTICOSTERONE APPEARS TO RESULT FROM THE IMPAIRMENT OF THE MECHANISMS OF GLUCOCORTICOID NEGATIVE FEEDBACK SINCE A SUBSTANTIAL DECREASE IN BOTH THE TOTAL NUMBER OF GR AND THEIR NUCLEAR LOCALIZATION WAS OBSERVED ALREADY IN THE HIPPOCAMPUS OF NEWBORN RAT PUPS AND PERSISTED THROUGHOUT LIFE. CORRESPONDING STABLE HIPPOCAMPAL DOWNREGULATION OF GR-DEPENDENT GENES WAS OBSERVED AS WELL. SUPPRESSION OF THE MATERNAL GLUCOCORTICOID STRESS RESPONSE TO HYPOXIA BY METYRAPONE INJECTION TO PREGNANT RATS PRIOR TO EACH HYPOXIC CHALLENGE CONSIDERABLY REDUCED CORTICOSTERONE OVER-RESPONSE TO HYPOXIA AND PREVENTED REDUCED HIPPOCAMPAL GR. CONCLUSIONS: OUR FINDINGS DEMONSTRATE THAT IN PROGENY A DEFICIT OF HIPPOCAMPAL GR RESULTING FROM MATERNAL GLUCOCORTICOID RESPONSE TO HYPOXIA REMAINS STABLE THROUGHOUT LIFE AND IS ACCOMPANIED BY SEVERE DISTURBANCES OF BASELINE GLUCOCORTICOID LEVELS AND ITS PERIPHERAL RECEPTION. NEGATIVE CONSEQUENCES OF PSH CAN BE PREVENTED BY INJECTION WITH AN INHIBITOR OF CORTICOSTERONE SYNTHESIS (METYRAPONE) TO PREGNANT FEMALES UNDERGOING HYPOXIA. 2020 17 1753 40 EARLY LIFE STRESS TRIGGERS SUSTAINED CHANGES IN HISTONE DEACETYLASE EXPRESSION AND HISTONE H4 MODIFICATIONS THAT ALTER RESPONSIVENESS TO ADOLESCENT ANTIDEPRESSANT TREATMENT. EARLY LIFE STRESS CAN ELICIT LONG-LASTING CHANGES IN GENE EXPRESSION AND BEHAVIOR. RECENT STUDIES ON RODENTS SUGGEST THAT THESE LASTING EFFECTS DEPEND ON THE GENETIC BACKGROUND. WHETHER EPIGENETIC FACTORS ALSO PLAY A ROLE REMAINS TO BE INVESTIGATED. HERE WE EXPOSED THE STRESS-SUSCEPTIBLE MOUSE STRAIN BALB/C AND THE MORE RESILIENT STRAIN C57BL/6 TO A POWERFUL EARLY LIFE STRESS PARADIGM, INFANT MATERNAL SEPARATION. IN BALB/C MICE, INFANT MATERNAL SEPARATION LED TO DECREASED EXPRESSION OF MRNA ENCODING THE HISTONE DEACETYLASES (HDACS) 1, 3, 7, 8, AND 10 IN THE FOREBRAIN NEOCORTEX IN ADULTHOOD, AN EFFECT ACCOMPANIED BY INCREASED EXPRESSION OF ACETYLATED HISTONE H4 PROTEINS, ESPECIALLY ACETYLATED H4K12 PROTEIN. THESE CHANGES IN HDAC EXPRESSION AND HISTONE MODIFICATIONS WERE NOT DETECTED IN C57BL/6 MICE EXPOSED TO EARLY LIFE STRESS. MOREOVER, A REVERSAL OF THE H4K12 HYPERACETYLATION DETECTED IN INFANT MATERNALLY SEPARATED BALB/C MICE (ACHIEVED WITH CHRONIC ADOLESCENT TREATMENT WITH A LOW DOSE OF THEOPHYLLINE THAT ONLY ACTIVATES HDACS) WORSENED THE ABNORMAL EMOTIONAL PHENOTYPE RESULTING FROM THIS EARLY LIFE STRESS EXPOSURE. IN CONTRAST, FLUOXETINE, A DRUG WITH POTENT ANTIDEPRESSANT EFFICACY IN INFANT MATERNALLY SEPARATED BALB/C MICE, POTENTIATED ALL HISTONE MODIFICATIONS TRIGGERED BY EARLY LIFE STRESS. MOREOVER, IN NON-STRESSED BALB/C MICE, CO-ADMINISTRATION OF AN HDAC INHIBITOR AND FLUOXETINE, BUT NOT FLUOXETINE ALONE, ELICITED ANTIDEPRESSANT EFFECTS AND ALSO TRIGGERED CHANGES IN HISTONE H4 EXPRESSION THAT WERE SIMILAR TO THOSE PROVOKED BY FLUOXETINE TREATMENT OF MICE EXPOSED TO EARLY LIFE STRESS. THESE RESULTS SUGGEST THAT BALB/C MICE DEVELOP EPIGENETIC MODIFICATIONS AFTER EARLY LIFE STRESS EXPOSURE THAT, IN TERMS OF THE EMOTIVE PHENOTYPE, ARE OF ADAPTIVE NATURE, AND THAT ENHANCE THE EFFICACY OF ANTIDEPRESSANT DRUGS. 2012 18 2013 39 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 19 5207 32 PRENATAL STRESS INDUCES SPATIAL MEMORY DEFICITS AND EPIGENETIC CHANGES IN THE HIPPOCAMPUS INDICATIVE OF HETEROCHROMATIN FORMATION AND REDUCED GENE EXPRESSION. STRESS DURING PREGNANCY HAS A WIDE VARIETY OF NEGATIVE EFFECTS IN BOTH HUMAN [1] AND ANIMAL OFFSPRING [2]. THESE EFFECTS ARE ESPECIALLY APPARENT IN VARIOUS FORMS OF LEARNING AND MEMORY SUCH AS OBJECT RECOGNITION [3] AND SPATIAL MEMORY [4]. THE COGNITIVE EFFECTS OF PRENATAL STRESS (PNS) MAY BE MEDIATED THROUGH EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION AND DNA METHYLATION [5]. AS SUCH, THE PRESENT STUDY INVESTIGATED THE EFFECTS OF CHRONIC UNPREDICTABLE PNS ON MEMORY AND EPIGENETIC MEASURES IN ADULT OFFSPRING. MICE THAT UNDERWENT PNS EXHIBITED IMPAIRED SPATIAL MEMORY IN THE MORRIS WATER MAZE, AS WELL AS SEX-SPECIFIC CHANGES IN LEVELS OF DNA METHYLTRANSFERASE (DNMT) 1 PROTEIN, AND ACETYLATED HISTONE H3 (ACH3) IN THE HIPPOCAMPUS, AND SERUM CORTICOSTERONE. MALE MICE EXPOSED TO PNS EXHIBITED DECREASED HIPPOCAMPAL ACH3, WHEREAS FEMALE PNS MICE DISPLAYED A FURTHER REDUCTION IN ACH3, AS WELL AS HEIGHTENED HIPPOCAMPAL DNMT1 PROTEIN LEVELS AND CORTICOSTERONE LEVELS. THESE DATA SUGGEST THAT PNS MAY EPIGENETICALLY REDUCE TRANSCRIPTION IN THE HIPPOCAMPUS, PARTICULARLY IN FEMALES IN WHOM THIS EFFECT MAY BE RELATED TO INCREASED BASELINE STRESS HORMONE LEVELS, AND WHICH MAY UNDERLIE THE SEXUAL DIMORPHISM IN RATES OF MENTAL ILLNESS IN HUMANS. 2015 20 3787 21 INTERGENERATIONAL METABOLIC SYNDROME AND NEURONAL NETWORK HYPEREXCITABILITY IN AUTISM. WE REVIEW EVIDENCE THAT SUGGESTS A ROLE FOR EXCESSIVE CONSUMPTION OF ENERGY-DENSE FOODS, PARTICULARLY FRUCTOSE, AND CONSEQUENT OBESITY AND INSULIN RESISTANCE (METABOLIC SYNDROME) IN THE RECENT INCREASE IN PREVALENCE OF AUTISM SPECTRUM DISORDERS (ASD). MATERNAL INSULIN RESISTANCE, OBESITY, AND DIABETES MAY PREDISPOSE OFFSPRING TO ASD BY MECHANISMS INVOLVING CHRONIC ACTIVATION OF ANABOLIC CELLULAR PATHWAYS AND A LACK OF METABOLIC SWITCHING TO KETOSIS RESULTING IN A DEFICIT IN GABAERGIC SIGNALING AND NEURONAL NETWORK HYPEREXCITABILITY. METABOLIC REPROGRAMMING BY EPIGENETIC DNA AND CHROMATIN MODIFICATIONS MAY CONTRIBUTE TO ALTERATIONS IN GENE EXPRESSION THAT RESULT IN ASD. THESE MECHANISTIC INSIGHTS SUGGEST THAT INTERVENTIONS THAT IMPROVE METABOLIC HEALTH SUCH AS INTERMITTENT FASTING AND EXERCISE MAY AMELIORATE DEVELOPMENTAL NEURONAL NETWORK ABNORMALITIES AND CONSEQUENT BEHAVIORAL MANIFESTATIONS IN ASD. 2019