1 1850 112 ELECTROACUPUNCTURE AMELIORATES DEPRESSION-LIKE BEHAVIORS COMORBID TO CHRONIC NEUROPATHIC PAIN VIA TET1-MEDIATED RESTORATION OF ADULT NEUROGENESIS. ALTHOUGH ELECTROACUPUNCTURE (EA) STIMULATION IS A WIDELY USED THERAPY FOR CHRONIC PAIN AND COMORBID PSYCHIATRIC DISORDERS, ITS LONG-TERM EFFECTS ON CHRONIC NEUROPATHIC PAIN-INDUCED DEPRESSION AND THE UNDERLYING MECHANISMS REMAIN ELUSIVE. IN THE PRESENT STUDY, WE FOUND THAT EA STIMULATION WAS ABLE TO RESTORE ADULT NEUROGENESIS IN THE VENTRAL DENTATE GYRUS (DG), BY BOTH INCREASING NEURONAL DIFFERENTIATION AND RESTORING THE NORMAL MORPHOLOGY OF NEWBORN DENDRITES, IN MICE WITH SPARED NERVE INJURY SURGERY. BY ABLATING THE NESTIN+ NEURAL STEM CELLS (NSCS) VIA DIPHTHERIA TOXIN FRAGMENT A EXPRESSION, WE FURTHER PROVED THAT NEUROGENESIS IN THE VENTRAL DG WAS CRUCIAL TO THE LONG-TERM, BUT NOT THE IMMEDIATE ANTIDEPRESSANT EFFECT OF EA, NOR WAS IT ASSOCIATED WITH NOCICEPTION. FURTHERMORE, WE FOUND THAT THE RESTORATION OF NEUROGENESIS WAS DEPENDENT ON TET1-MEDIATED EPIGENETIC MODIFICATION UPON EA TREATMENT. TET1 COULD BIND TO THE PROMOTER OF THE PROX1 GENE, THUS CATALYZING ITS DEMETHYLATION AND FACILITATING ITS EXPRESSION, WHICH FINALLY CONTRIBUTED TO THE RESTORATION OF NEUROGENESIS AND AMELIORATION OF DEPRESSION-LIKE BEHAVIORS INDUCED BY CHRONIC NEUROPATHIC PAIN. THUS, WE CONCLUDE THAT EA STIMULATION RESTORES INHIBITED TET1 EXPRESSION IN HIPPOCAMPAL NSCS OF MICE WITH CHRONIC NEUROPATHIC PAIN, AND INCREASED TET1 EXPRESSION AMELIORATES HYPERMETHYLATION OF PROX1 AND RESTORES NORMAL ADULT NEUROGENESIS IN THE VENTRAL DG, WHICH CONTRIBUTES TO THE LONG-TERM ANTIDEPRESSANT EFFECT OF EA. 2023 2 3969 32 LONG-LASTING DEPRESSION-LIKE BEHAVIOR AND EPIGENETIC CHANGES OF BDNF GENE EXPRESSION INDUCED BY PERINATAL EXPOSURE TO METHYLMERCURY. SUBSTANTIAL EVIDENCE INDICATES THAT PREDISPOSITION TO DISEASES CAN BE ACQUIRED DURING EARLY STAGES OF DEVELOPMENT AND INTERACTIONS BETWEEN ENVIRONMENTAL AND GENETIC FACTORS MAY BE IMPLICATED IN THE ONSET OF MANY PATHOLOGICAL CONDITIONS. DATA COLLECTED OVER SEVERAL DECADES HAVE SHOWN THAT CHEMICALS ARE AMONG THE RELEVANT FACTORS THAT CAN ENDANGER CNS. WE PREVIOUSLY SHOWED THAT PERINATAL EXPOSURE TO METHYLMERCURY (MEHG) CAUSES PERSISTENT CHANGES IN LEARNING AND MOTIVATIONAL BEHAVIOR IN MICE. IN THIS STUDY, WE REPORT THAT THE DEPRESSION-LIKE BEHAVIOR IN MEHG-EXPOSED MALE MICE IS REVERSED BY CHRONIC TREATMENT WITH THE ANTIDEPRESSANT FLUOXETINE. BEHAVIORAL ALTERATIONS ARE ASSOCIATED WITH A DECREASE IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPAL DENTATE GYRUS AND FLUOXETINE TREATMENT RESTORES BDNF MRNA EXPRESSION. WE ALSO SHOW THAT MEHG-EXPOSURE INDUCES LONG-LASTING REPRESSIVE STATE OF THE CHROMATIN STRUCTURE AT THE BDNF PROMOTER REGION, IN PARTICULAR DNA HYPERMETHYLATION, AN INCREASE IN HISTONE H3-K27 TRI-METHYLATION AND A DECREASE IN H3 ACETYLATION AT THE PROMOTER IV. WHILE FLUOXETINE TREATMENT DOES NOT ALTER HYPERMETHYLATION OF H3-K27, IT SIGNIFICANTLY UP-REGULATES H3 ACETYLATION AT THE BDNF PROMOTER IV IN MEHG-EXPOSED MICE. OUR STUDY SHOWS THAT DEVELOPMENTAL EXPOSURE TO LOW LEVELS OF MEHG PREDISPOSES MICE TO DEPRESSION AND INDUCES EPIGENETIC SUPPRESSION OF BDNF GENE EXPRESSION IN THE HIPPOCAMPUS. 2008 3 345 34 ALTERED BRAIN EXPRESSION OF DNA METHYLATION AND HYDROXYMETHYLATION EPIGENETIC ENZYMES IN A RAT MODEL OF NEUROPATHIC PAIN. THE ROLE OF EPIGENETICS IN CHRONIC PAIN AT THE SUPRASPINAL LEVEL IS YET TO BE FULLY CHARACTERIZED. DNA HISTONE METHYLATION IS CRUCIALLY REGULATED BY DE NOVO METHYLTRANSFERASES (DNMT1-3) AND TEN-ELEVEN TRANSLOCATION DIOXYGENASES (TET1-3). EVIDENCE HAS SHOWN THAT METHYLATION MARKERS ARE ALTERED IN DIFFERENT CNS REGIONS RELATED TO NOCICEPTION, NAMELY THE DORSAL ROOT GANGLIA, THE SPINAL CORD, AND DIFFERENT BRAIN AREAS. DECREASED GLOBAL METHYLATION WAS FOUND IN THE DRG, THE PREFRONTAL CORTEX, AND THE AMYGDALA, WHICH WAS ASSOCIATED WITH DECREASED DNMT1/3A EXPRESSION. IN CONTRAST, INCREASED METHYLATION LEVELS AND MRNA LEVELS OF TET1 AND TET3 WERE LINKED TO AUGMENTED PAIN HYPERSENSITIVITY AND ALLODYNIA IN INFLAMMATORY AND NEUROPATHIC PAIN MODELS. SINCE EPIGENETIC MECHANISMS MAY BE RESPONSIBLE FOR THE REGULATION AND COORDINATION OF VARIOUS TRANSCRIPTIONAL MODIFICATIONS DESCRIBED IN CHRONIC PAIN STATES, WITH THIS STUDY, WE AIMED TO EVALUATE THE FUNCTIONAL ROLE OF TET1-3 AND DNMT1/3A GENES IN NEUROPATHIC PAIN IN SEVERAL BRAIN AREAS. IN A SPARED NERVE INJURY RAT MODEL OF NEUROPATHIC PAIN, 21 DAYS AFTER SURGERY, WE FOUND INCREASED TET1 EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX AND DECREASED EXPRESSION IN THE CAUDATE-PUTAMEN AND THE AMYGDALA; TET2 WAS UPREGULATED IN THE MEDIAL THALAMUS; TET3 MRNA LEVELS WERE REDUCED IN THE MEDIAL PREFRONTAL CORTEX AND THE CAUDATE-PUTAMEN; AND DNMT1 WAS DOWNREGULATED IN THE CAUDATE-PUTAMEN AND THE MEDIAL THALAMUS. NO STATISTICALLY SIGNIFICANT CHANGES IN EXPRESSION WERE OBSERVED WITH DNMT3A. OUR RESULTS SUGGEST A COMPLEX FUNCTIONAL ROLE FOR THESE GENES IN DIFFERENT BRAIN AREAS IN THE CONTEXT OF NEUROPATHIC PAIN. THE NOTION OF DNA METHYLATION AND HYDROXYMETHYLATION BEING CELL-TYPE SPECIFIC AND NOT TISSUE SPECIFIC, AS WELL AS THE POSSIBILITY OF CHRONOLOGICALLY DIFFERENTIAL GENE EXPRESSION AFTER THE ESTABLISHMENT OF NEUROPATHIC OR INFLAMMATORY PAIN MODELS, OUGHT TO BE ADDRESSED IN FUTURE STUDIES. 2023 4 4299 24 MICRORNA-15B CONTRIBUTES TO DEPRESSION-LIKE BEHAVIOR IN MICE BY AFFECTING SYNAPTIC PROTEIN LEVELS AND FUNCTION IN THE NUCLEUS ACCUMBENS. MAJOR DEPRESSION IS A PREVALENT AFFECTIVE DISORDER CHARACTERIZED BY RECURRENT LOW MOOD. IT PRESUMABLY RESULTS FROM STRESS-INDUCED DETERIORATIONS OF MOLECULAR NETWORKS AND SYNAPTIC FUNCTIONS IN BRAIN REWARD CIRCUITS OF GENETICALLY-SUSCEPTIBLE INDIVIDUALS THROUGH EPIGENETIC PROCESSES. EPIGENETIC REGULATOR MICRORNA-15B INHIBITS NEURONAL PROGENITOR PROLIFERATION AND IS UP-REGULATED IN THE MEDIAL PREFRONTAL CORTEX OF MICE THAT DEMONSTRATE DEPRESSION-LIKE BEHAVIOR, INDICATING THE CONTRIBUTION OF MICRORNA-15 TO MAJOR DEPRESSION. USING A MOUSE MODEL OF MAJOR DEPRESSION INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS), HERE WE EXAMINED THE EFFECTS OF MICRORNA-15B ON SYNAPSES AND SYNAPTIC PROTEINS IN THE NUCLEUS ACCUMBENS OF THESE MICE. THE APPLICATION OF A MICRORNA-15B ANTAGOMIR INTO THE NUCLEUS ACCUMBENS SIGNIFICANTLY REDUCED THE INCIDENCE OF CUMS-INDUCED DEPRESSION AND REVERSED THE ATTENUATIONS OF EXCITATORY SYNAPSE AND SYNTAXIN-BINDING PROTEIN 3 (STXBP3A)/VESICLE-ASSOCIATED PROTEIN 1 (VAMP1) EXPRESSION. IN CONTRAST, THE INJECTION OF A MICRORNA-15B ANALOG INTO THE NUCLEUS ACCUMBENS INDUCED DEPRESSION-LIKE BEHAVIOR AS WELL AS ATTENUATED EXCITATORY SYNAPSES AND STXBP3A/VAMP1 EXPRESSION SIMILAR TO THE DOWN-REGULATION OF THESE PROCESSES INDUCED BY THE CUMS. WE CONCLUDE THAT MICRORNA-15B-5P MAY PLAY A CRITICAL ROLE IN CHRONIC STRESS-INDUCED DEPRESSION BY DECREASING SYNAPTIC PROTEINS, INNERVATIONS, AND ACTIVITIES IN THE NUCLEUS ACCUMBENS. WE PROPOSE THAT THE TREATMENT OF ANTI-MICRORNA-15B-5P MAY CONVERT STRESS-INDUCED DEPRESSION INTO RESILIENCE. 2020 5 5820 38 STRESS DYNAMICALLY REGULATES BEHAVIOR AND GLUTAMATERGIC GENE EXPRESSION IN HIPPOCAMPUS BY OPENING A WINDOW OF EPIGENETIC PLASTICITY. EXCITATORY AMINO ACIDS PLAY A KEY ROLE IN BOTH ADAPTIVE AND DELETERIOUS EFFECTS OF STRESSORS ON THE BRAIN, AND DYSREGULATED GLUTAMATE HOMEOSTASIS HAS BEEN ASSOCIATED WITH PSYCHIATRIC AND NEUROLOGICAL DISORDERS. HERE, WE ELUCIDATE MECHANISMS OF EPIGENETIC PLASTICITY IN THE HIPPOCAMPUS IN THE INTERACTIONS BETWEEN A HISTORY OF CHRONIC STRESS AND FAMILIAR AND NOVEL ACUTE STRESSORS THAT ALTER EXPRESSION OF ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. WE DEMONSTRATE THAT ACUTE RESTRAINT AND ACUTE FORCED SWIM STRESSORS INDUCE DIFFERENTIAL EFFECTS ON THESE BEHAVIORS IN NAIVE MICE AND IN MICE WITH A HISTORY OF CHRONIC-RESTRAINT STRESS (CRS). THEY REVEAL A KEY ROLE FOR EPIGENETIC UP- AND DOWN-REGULATION OF THE PUTATIVE PRESYNAPTIC TYPE 2 METABOTROPIC GLUTAMATE (MGLU2) RECEPTORS AND THE POSTSYNAPTIC NR1/NMDA RECEPTORS IN THE HIPPOCAMPUS AND PARTICULARLY IN THE DENTATE GYRUS (DG), A REGION OF ACTIVE NEUROGENESIS AND A TARGET OF ANTIDEPRESSANT TREATMENT. WE SHOW CHANGES IN DG LONG-TERM POTENTIATION (LTP) THAT PARALLEL BEHAVIORAL RESPONSES, WITH HABITUATION TO THE SAME ACUTE RESTRAINT STRESSOR AND SENSITIZATION TO A NOVEL FORCED-SWIM STRESSOR. IN WT MICE AFTER CRS AND IN UNSTRESSED MICE WITH A BDNF LOSS-OF-FUNCTION ALLELE (BDNF VAL66MET), WE SHOW THAT THE EPIGENETIC ACTIVATOR OF HISTONE ACETYLATION, P300, PLAYS A PIVOTAL ROLE IN THE DYNAMIC UP- AND DOWN-REGULATION OF MGLU2 IN HIPPOCAMPUS VIA HISTONE-3-LYSINE-27-ACETYLATION (H3K27AC) WHEN ACUTE STRESSORS ARE APPLIED. THESE HIPPOCAMPAL RESPONSES REVEAL A WINDOW OF EPIGENETIC PLASTICITY THAT MAY BE USEFUL FOR TREATMENT OF DISORDERS IN WHICH GLUTAMATERGIC TRANSMISSION IS DYSREGULATED. 2015 6 1808 36 EFFECTS OF ADOLESCENT SOCIAL STRESS AND ANTIDEPRESSANT TREATMENT ON COGNITIVE INFLEXIBILITY AND BDNF EPIGENETIC MODIFICATIONS IN THE MPFC OF ADULT MICE. ADOLESCENT SOCIAL STRESS (ASS) CAN INCREASE SUSCEPTIBILITY TO DEPRESSION IN ADULTHOOD. HOWEVER, THE UNDERLYING PSYCHOLOGICAL AND NEURAL MECHANISMS REMAIN UNCLEAR. CORTICALLY MEDIATED COGNITIVE DYSFUNCTIONS ARE INCREASINGLY RECOGNIZED AS AN INDEPENDENT AND IMPORTANT RISK FACTOR OF DEPRESSION. USING SOCIAL DEFEAT STRESS, A CLASSICAL ANIMAL MODEL OF DEPRESSION, OUR PREVIOUS STUDIES FOUND THAT MICE SUBJECTED TO THIS FORM OF STRESS DURING EARLY ADOLESCENCE DISPLAYED COGNITIVE INFLEXIBILITY (CI) IN ADULTHOOD. THIS CHANGE WAS ACCOMPANIED BY A DOWN-REGULATION OF BDNF GENE EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX (MPFC); THIS GENE ENCODES A KEY MOLECULE INVOLVED IN DEPRESSION AND ANTIDEPRESSANT ACTION. IN THE PRESENT PAPER, WE IDENTIFIED EPIGENETIC MODIFICATION OF BDNF AS A POSSIBLE MECHANISM UNDERLYING THE BEHAVIORAL AND MOLECULAR CHANGES. ASS INDUCED A SET OF DEPRESSIVE PHENOTYPES, INCLUDING INCREASED SOCIAL AVOIDANCE AND CI, AS WELL AS REDUCED LEVELS OF TOTAL BDNF AND ISOFORM IV BUT NOT ISOFORM I OR VI TRANSCRIPTS IN THE MPFC. IN PARALLEL WITH CHANGES IN BDNF GENE EXPRESSION, PREVIOUSLY STRESSED ADULT MICE SHOWED INCREASED LEVELS OF DIMETHYLATION OF HISTONE H3 AT LYSINE K9 (H3K9ME2) IMMEDIATELY DOWNSTREAM OF THE BDNF IV PROMOTER. ON THE OTHER HAND, NO DIFFERENCES WERE FOUND IN TRIMETHYLATION OF HISTONE H3 AT LYSINE K4 (H3K4ME3) OR IN ACETYLATION OF HISTONE H3 AT LYSINE K9 (H3K9AC) OR AT K4 (H3K4AC) IN THE BDNF IV PROMOTER. LIKEWISE, NO ALTERATIONS WERE FOUND IN DNA METHYLATION OF THE BDNF IV PROMOTER. ADDITIONALLY, TREATMENT WITH THE CHRONIC ANTIDEPRESSANT TRANYLCYPROMINE REVERSED BDNF EPIGENETIC CHANGES AND RELATED GENE TRANSCRIPTION WHILE ALSO REVERSING CI, BUT NOT SOCIAL AVOIDANCE, IN PREVIOUSLY STRESSED ADULT MICE. THESE RESULTS SUGGEST THAT EPIGENETIC CHANGES TO THE BDNF GENE IN THE MPFC AFTER ADOLESCENT SOCIAL ADVERSITY MAY BE INVOLVED IN THE REGULATION OF COGNITIVE DYSFUNCTION IN DEPRESSION AND ANTIDEPRESSANT ACTION IN ADULTHOOD. 2018 7 1803 18 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 8 1907 43 ENRICHED ENVIRONMENT PRIORS TO TET1 HIPPOCAMPAL ADMINISTRATION FOR REGULATING PSYCHIATRIC BEHAVIORS VIA GLIAL REACTIVITY IN CHRONIC CEREBRAL HYPOPERFUSION MODELS. BACKGROUND: CHRONIC CEREBRAL HYPOPERFUSION (CCH) HAS BEEN GRADUALLY REGARDED AS A COMMON ETIOLOGIC MECHANISM FOR COGNITIVE AND PSYCHIATRIC DISTURBANCES. TEN-ELEVEN TRANSLOCATION METHYLCYTOSINE DIOXYGENASE 1 (TET1) PLAYED AN IMPORTANT ROLE IN ADULT HIPPOCAMPAL NEUROGENESIS (AHN), NEURONAL CIRCUITS FORMATION, COGNITION AND PSYCHIATRIC DISORDERS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON COGNITION AND DEPRESSION VIA EFFECTIVELY REGULATING AHN AND GLIAL REACTIVITY. THIS STUDY AIMED TO ASSESS WHICH STRATEGY WAS FEASIBLE TO IMPROVE COGNITION AND PSYCHIATRIC DISTURBANCES BY COMPARING THE TET1 HIPPOCAMPAL MICROINJECTION AND EE IN CCH MODELS AND TO INVESTIGATE THE POSSIBLE MECHANISMS. METHOD: CCH RATS WERE ESTABLISHED VIA PERMANENT BILATERAL COMMON CAROTID ARTERY OCCLUSION (2-VO). RATS WERE STEREOTAXICALLY INJECTED WITH THE HUMAN CATALYTIC DOMAIN OF TET1 (HTET1) TO OVEREXPRESS THE HTET1 IN THE HIPPOCAMPUS 10 DAYS BEFORE 2-VO. 3 DAYS AFTER 2-VO, RATS WERE SUBJECTED TO STANDARD ENVIRONMENT OR EE WITH FREE ACCESS TO FOOD AND WATER. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION BEFORE SACRIFICE. EPIGENETIC MOLECULES, ADULT NEUROGENESIS, SYNAPTIC PROTEINS EXPRESSION, AND GLIAL ACTIVATION WERE ANALYZED USING IMMUNOFLUORESCENT STAINING, QRT-PCR AND WESTERN BLOT. RESULTS: IN THE PRESENT STUDY, WE FOUND BOTH EE AND GENETICAL TREATMENT WITH OVEREXPRESSING HTET1 WERE SUFFICIENT FOR STIMULATING AHN. HOWEVER, PROMOTING ANH COULD NOT DEAL WITH THE COGNITIVE DYSFUNCTION AND DEPRESSIVE-LIKE BEHAVIORS IN CCH RATS. NOTABLY, A HEALTHY LOCAL BRAIN ENVIRONMENT WITH ELEVATED BDNF AND ASTROCYTES WAS CONDUCIVE TO IMPROVING COGNITIVE DYSFUNCTION. MEANWHILE, ASTROCYTES WERE INVOLVED IN THE COGNITIVE REGULATING PROCESS OF NEURONS, PRESYNAPTIC FUNCTION AND MICROGLIA. IN GENERAL, WE HELD THAT DEPRESSIVE DISTURBANCES WERE DETERMINED BY BDNF LEVELS, NEURONAL AND PRESYNAPTIC FUNCTION, AS WELL AS GLIAL ACTIVATION CONTAINING ASTROCYTES AND MICROGLIA. TO FURTHER SUPPORT THIS POINT, WE INVESTIGATED SEVERE DEPRESSIVE SYMPTOMS THAT WERE STRONGLY CORRELATED WITH THE ACTIVATION OF ASTROGLIA AND MICROGLIA. IMPORTANTLY, CAUSAL MEDIATION ANALYSIS SHOWED SIGNIFICANT MEDIATION BY THE PRESENCE OF REACTIVE GLIAL CELLS IN THE RELATION BETWEEN NEURAL PLASTICITY AND DEPRESSIVE SYMPTOMS. FINALLY, WE SHOWED EE PERFORMED BETTER THAN HTET1 TREATMENT FOR COGNITIVE DEFICITS AND DEPRESSION. EE WITH LESS GLIAL REACTIVITY WAS MUCH MORE RESISTANT TO DEPRESSION, WHILE HTET1 WITH MORE GLIAL ACTIVATION WAS MORE VULNERABLE TO DEPRESSIVE DISORDERS. CONCLUSIONS: EE WAS LIKELY TO BE SUPERIOR TO TET1 HIPPOCAMPAL ADMINISTRATION FOR COGNITION AND PSYCHIATRIC BEHAVIORS IN CCH RATS. FURTHERMORE, A HEALTHY LOCAL BRAIN ENVIRONMENT WITH ELEVATED BDNF AND ASTROCYTES WAS CONDUCIVE TO IMPROVING COGNITIVE DYSFUNCTION. MORE GLIAL ACTIVATION, AND MORE VULNERABLE TO DEPRESSIVE DISORDERS. THESE RESULTS WERE IMPORTANT FOR OUR UNDERSTANDING OF DISEASE MECHANISMS AND PROVIDED VALUABLE TOOLS FOR THE OVERALL MANAGEMENT OF CCH PATIENTS. 2022 9 2705 29 EXERCISE AND LOW-LEVEL GABA(A) RECEPTOR INHIBITION MODULATE LOCOMOTOR ACTIVITY AND THE EXPRESSION OF BDNF ACCOMPANIED BY CHANGES IN EPIGENETIC REGULATION IN THE HIPPOCAMPUS. AEROBIC EXERCISE IS KNOWN TO INCREASE EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) IN THE HIPPOCAMPUS AND TO IMPROVE COGNITIVE FUNCTION. THE INHIBITION OF GABAERGIC SYNAPSES ENHANCES HIPPOCAMPAL PLASTICITY AS WELL AS LEARNING AND MEMORY. THE OBJECTIVE OF THE PRESENT STUDY WAS TO EXAMINE THE INTERACTIVE EFFECT OF LOW-LEVEL GABA(A) RECEPTOR INHIBITION AND EXERCISE ON BEHAVIOR TESTS (COGNITIVE FUNCTION AND LOCOMOTOR ACTIVITY), EXPRESSION OF BDNF AND EPIGENETIC REGULATIONS INCLUDING THE ACTIVITY LEVELS OF HISTONE ACETYLTRANSFERASES (HATS) AND HISTONE DEACETYLASES (HDACS) IN THE HIPPOCAMPUS. ICR MICE WERE DIVIDED INTO TWO GROUPS: THOSE WHO DID NOT PARTICIPATE IN EXERCISE AND THOSE WHO PARTICIPATED IN EXERCISE. EACH GROUP WAS SUBDIVIDED INTO TWO OTHER GROUPS: THE ONE WHO RECEIVED VEHICLE AND THE ONE WHO RECEIVED GABA(A) RECEPTOR ANTAGONIST, BICUCULLIN. WE ADMINISTERED SALINE OR BICUCULLINE INTRAPERITONEALLY TO THE MICE AT A NON-EPILEPTIC DOSE OF 0.25 MG/KG, WHEREAS THE MICE WERE EXERCISED ON A TREADMILL FOR APPROXIMATELY 1 H A DAY, 5 DAYS A WEEK FOR 4 WEEKS. NOVEL-OBJECT RECOGNITION TEST AND LOCOMOTOR ACTIVITY WERE ASSESSED AT A REST DAY APPROXIMATELY 4 DAYS BEFORE THE EUTHANASIA. THE MICE WERE EUTHANIZED 4 H AFTER THE LAST EXERCISE SESSION. AEROBIC EXERCISE FOR 4 WEEKS INCREASED MRNA AND PROTEIN EXPRESSION OF BDNF IN THE HIPPOCAMPUS, ACCOMPANIED BY ENHANCED HAT ACTIVITY. ALTERNATIVELY, BICUCULLINE ADMINISTRATION INCREASED HDAC ACTIVITY IN THE HIPPOCAMPUS. FURTHERMORE, EXERCISE IN THE PRESENCE OF BICUCULLINE ADMINISTRATION INCREASED LOCOMOTOR ACTIVITY, INDICATING THAT EXERCISE COMBINED WITH LOW-LEVEL GABA(A) RECEPTOR INHIBITION POTENTIATED THE ACTIVITY OF THE MICE. ALTOGETHER, THE PRESENT STUDY SUGGESTED THAT EXERCISE BENEFICIALLY CONTRIBUTES TO NEUROPROTECTION IN THE HIPPOCAMPUS ACCOMPANIED BY THE UP-REGULATION OF BDNF EXPRESSION AND EPIGENETIC REGULATION, WHEREAS THE CHRONIC INHIBITION OF GABA(A) RECEPTOR POTENTIATES EXERCISE-INDUCED BEHAVIORAL ACTIVITY. 2018 10 5007 32 PERIPHERAL NERVE INJURY IS ASSOCIATED WITH CHRONIC, REVERSIBLE CHANGES IN GLOBAL DNA METHYLATION IN THE MOUSE PREFRONTAL CORTEX. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ARE ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS INCLUDING LOW BACK PAIN AND FIBROMYALGIA. THE MAGNITUDE OF THESE CHANGES CORRELATES WITH THE DURATION AND/OR THE INTENSITY OF CHRONIC PAIN. MOST STUDIES REPORT CHANGES IN COMMON AREAS INVOLVED IN PAIN MODULATION, INCLUDING THE PREFRONTAL CORTEX (PFC), AND PAIN-RELATED PATHOLOGICAL CHANGES IN THE PFC CAN BE REVERSED WITH EFFECTIVE TREATMENT. WHILE THE MECHANISMS UNDERLYING THESE CHANGES ARE UNKNOWN, THEY MUST BE DYNAMICALLY REGULATED. EPIGENETIC MODULATION OF GENE EXPRESSION IN RESPONSE TO EXPERIENCE AND ENVIRONMENT IS REVERSIBLE AND DYNAMIC. EPIGENETIC MODULATION BY DNA METHYLATION IS ASSOCIATED WITH ABNORMAL BEHAVIOR AND PATHOLOGICAL GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM. DNA METHYLATION MIGHT ALSO BE INVOLVED IN MEDIATING THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN IN THE BRAIN. WE THEREFORE TESTED A) WHETHER ALTERATIONS IN DNA METHYLATION ARE FOUND IN THE BRAIN LONG AFTER CHRONIC NEUROPATHIC PAIN IS INDUCED IN THE PERIPHERY USING THE SPARED NERVE INJURY MODAL AND B) WHETHER THESE INJURY-ASSOCIATED CHANGES ARE REVERSIBLE BY INTERVENTIONS THAT REVERSE THE PATHOLOGIES ASSOCIATED WITH CHRONIC PAIN. SIX MONTHS FOLLOWING PERIPHERAL NERVE INJURY, ABNORMAL SENSORY THRESHOLDS AND INCREASED ANXIETY WERE ACCOMPANIED BY DECREASED GLOBAL METHYLATION IN THE PFC AND THE AMYGDALA BUT NOT IN THE VISUAL CORTEX OR THE THALAMUS. ENVIRONMENTAL ENRICHMENT ATTENUATED NERVE INJURY-INDUCED HYPERSENSITIVITY AND REVERSED THE CHANGES IN GLOBAL PFC METHYLATION. FURTHERMORE, GLOBAL PFC METHYLATION CORRELATED WITH MECHANICAL AND THERMAL SENSITIVITY IN NEUROPATHIC MICE. IN SUMMARY, INDUCTION OF CHRONIC PAIN BY PERIPHERAL NERVE INJURY IS ASSOCIATED WITH EPIGENETIC CHANGES IN THE BRAIN. THESE CHANGES ARE DETECTED LONG AFTER THE ORIGINAL INJURY, AT A LONG DISTANCE FROM THE SITE OF INJURY AND ARE REVERSIBLE WITH ENVIRONMENTAL MANIPULATION. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION THAT ARE ASSOCIATED WITH CHRONIC PAIN CONDITIONS MAY THEREFORE BE MEDIATED BY EPIGENETIC MECHANISMS. 2013 11 2740 25 EXPOSURE TO EARLY LIFE STRESS RESULTS IN EPIGENETIC CHANGES IN NEUROTROPHIC FACTOR GENE EXPRESSION IN A PARKINSONIAN RAT MODEL. EARLY LIFE ADVERSITY INCREASES THE RISK OF MENTAL DISORDERS LATER IN LIFE. CHRONIC EARLY LIFE STRESS MAY ALTER NEUROTROPHIC FACTOR GENE EXPRESSION INCLUDING THOSE FOR BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND GLIAL CELL DERIVED NEUROTROPHIC FACTOR (GDNF) THAT ARE IMPORTANT IN NEURONAL GROWTH, SURVIVAL, AND MAINTENANCE. MATERNAL SEPARATION WAS USED IN THIS STUDY TO MODEL EARLY LIFE STRESS. FOLLOWING UNILATERAL INJECTION OF A MILD DOSE OF 6-HYDROXYDOPAMINE (6-OHDA), WE MEASURED CORTICOSTERONE (CORT) IN THE BLOOD AND STRIATUM OF STRESSED AND NONSTRESSED RATS; WE ALSO MEASURED DNA METHYLATION AND BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM USING REAL TIME PCR. IN THE PRESENCE OF STRESS, WE FOUND THAT THERE WAS INCREASED CORTICOSTERONE CONCENTRATION IN BOTH BLOOD AND STRIATAL TISSUE. FURTHER TO THIS, WE FOUND HIGHER DNA METHYLATION AND DECREASED NEUROTROPHIC FACTOR GENE EXPRESSION. 6-OHDA LESION INCREASED NEUROTROPHIC FACTOR GENE EXPRESSION IN BOTH STRESSED AND NONSTRESSED RATS BUT THIS INCREASE WAS HIGHER IN THE NONSTRESSED RATS. OUR RESULTS SUGGEST THAT EXPOSURE TO EARLY POSTNATAL STRESS INCREASES CORTICOSTERONE CONCENTRATION WHICH LEADS TO INCREASED DNA METHYLATION. THIS EFFECT RESULTS IN DECREASED BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM LEADING TO DECREASED PROTECTION AGAINST SUBSEQUENT INSULTS LATER IN LIFE. 2016 12 4173 29 MELATONIN INDUCES HISTONE HYPERACETYLATION IN THE RAT BRAIN. WE HAVE REPORTED THAT MELATONIN INDUCES HISTONE HYPERACETYLATION IN MOUSE NEURAL STEM CELLS, SUGGESTING AN EPIGENETIC ROLE FOR THIS PLEIOTROPIC HORMONE. TO SUPPORT SUCH A ROLE, IT IS NECESSARY TO DEMONSTRATE THAT MELATONIN PRODUCES SIMILAR EFFECTS IN VIVO. HISTONE ACETYLATION, FOLLOWING CHRONIC TREATMENT WITH MELATONIN (4MUG/ML IN DRINKING WATER FOR 17 DAYS), WAS EXAMINED BY WESTERN BLOTTING IN SELECTED RAT BRAIN REGIONS. MELATONIN INDUCED SIGNIFICANT INCREASES IN HISTONE H3 AND HISTONE H4 ACETYLATION IN THE HIPPOCAMPUS. HISTONE H4 WAS ALSO HYPERACETYLATED IN THE STRIATUM, BUT THERE WERE NO SIGNIFICANT CHANGES IN HISTONE H3 ACETYLATION IN THIS BRAIN REGION. NO SIGNIFICANT CHANGES IN THE ACETYLATION OF EITHER HISTONE H3 OR H4 WERE OBSERVED IN THE MIDBRAIN AND CEREBELLUM. AN EXAMINATION OF KINASE ACTIVATION, WHICH MAY BE RELATED TO THESE CHANGES, REVEALED THAT MELATONIN TREATMENT INCREASED THE LEVELS OF PHOSPHO-ERK (EXTRACELLULAR SIGNAL-REGULATED KINASE) IN THE HIPPOCAMPUS AND STRIATUM, BUT PHOSPHO-AKT (PROTEIN KINASE B) LEVELS WERE UNCHANGED. THESE FINDINGS SUGGEST THAT CHROMATIN REMODELING AND ASSOCIATED CHANGES IN THE EPIGENETIC REGULATION OF GENE EXPRESSION UNDERLIE THE MULTIPLE PHYSIOLOGICAL EFFECTS OF MELATONIN. 2013 13 6804 42 [EPIGENETIC REGULATION IN DEPRESSION]. RECENT RESEARCH HAS RAISED THE NOTION THAT EPIGENETIC MECHANISMS (E.G., DNA METHYLATION AND HISTONE MODIFICATIONS), WHICH EXERT LASTING CONTROL OVER GENE EXPRESSION WITHOUT ALTERING THE GENETIC CODE, COULD MEDIATE STABLE CHANGES IN BRAIN FUNCTION. HOWEVER, THE ROLE OF ENVIRONMENTAL FACTORS ALONG WITH GENETIC FACTORS IN THE EPIGENETIC REGULATION OF THE PATHOGENESIS OF DEPRESSION IS LARGELY UNKNOWN. TWO GENETICALLY DISTINCT MICE STRAINS, BALB/C (BALB) AND C57BL/6 (B6), EXHIBIT DIFFERENT BEHAVIORAL RESPONSES TO CHRONIC STRESS. WITH CHRONIC STRESS, BALB MICE SHOWED DEPRESSIVE-LIKE BEHAVIORS, BUT NOT B6 MICE, AND GLIAL CELL-DERIVED NEUROTROPHIC FACTOR (GDNF) EXPRESSION LEVEL WAS DECREASED IN THE VENTRAL STRIATUM OF BALB MICE BUT INCREASED IN B6 MICE. IN BALB MICE, DEPRESSIVE-LIKE BEHAVIORS AND DECREASED GDNF EXPRESSION WERE RECOVERED BY CHRONIC ANTIDEPRESSANT TREATMENT. THEREFORE, WE USED THESE TWO MICE STRAINS TO INVESTIGATE HOW THE EPIGENETIC STATUS OF THE GDNF GENE IN THE VENTRAL STRIATUM MODULATES STRESS VULNERABILITY. BOTH MICE STRAINS SHOWED INCREASED DNA METHYLATION LEVELS AND MECP2 RECRUITMENT IN THE GDNF PROMOTER REGION. HOWEVER, HISTONE H3 ACETYLATION LEVEL WAS DECREASED IN BALB MICE, BUT INCREASED IN B6 MICE. FURTHERMORE, BALB MICE SHOWED INCREASED HISTONE DEACETYLASE2 (HDAC2) EXPRESSION LEVEL AND RE-CHIP ASSAY REVEALED HDAC2-MECP2 COMPLEX IN BALB MICE. OUR RESULTS INDICATE THE CRUCIAL ROLE OF HISTONE MODIFICATION BY HDAC2 AND MECP2 COMPLEX FOR THE CONTROL OF GDNF EXPRESSION AND SUBSEQUENT BEHAVIORAL RESPONSES TO CHRONIC STRESS, IN OTHER WORDS, THE SUSCEPTIBILITY TO STRESS. IN ADDITION, WE INVESTIGATED THE EFFECT OF ANTIDEPRESSANTS ON THE EPIGENETIC REGULATION OF GDNF EXPRESSION. WE FOUND A REDUCED LEVEL OF HDAC4 RECRUITMENT AT THE GDNF PROMOTER REGION WITH ANTIDEPRESSANTS. THUS, OUR DATA SUGGEST THAT ANTIDEPRESSANTS INCREASE TRANSCRIPTIONAL ACTIVITY OF THE GDNF GENE THROUGH THE MODULATION OF HISTONE ACETYLATION BY HDAC4. FINALLY, WE EXAMINED THE EXPRESSIONS OF GDNF AND EPIGENETIC-RELATED MOLECULES MRNAS WITH MAJOR DEPRESSIVE AND BIPOLAR DISORDER PATIENTS BY USING QUANTITATIVE REAL-TIME PCR. WE FOUND THE ABERRANT EXPRESSION OF GDNF AND EPIGENETIC-RELATED GENES INCLUDING HDAC2 AND HDAC4 IN MOOD DISORDER PATIENTS. THUS, OUR DATA PROVIDE NOVEL INSIGHTS SUGGESTING THAT EPIGENETIC MECHANISMS OF GDNF EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OR PATHOPHYSIOLOGY OF DEPRESSION. 2012 14 5759 33 SODIUM BUTYRATE ABOLISHES LIPOPOLYSACCHARIDE-INDUCED DEPRESSION-LIKE BEHAVIORS AND HIPPOCAMPAL MICROGLIAL ACTIVATION IN MICE. PATIENTS WITH MAJOR DEPRESSIVE DISORDER HAVE ELEVATED PERIPHERAL INFLAMMATION; THE DEGREE OF THIS INCREASE CORRELATES WITH THE SEVERITY OF THE DISORDER. CHRONIC PSYCHOLOGICAL STRESS INCREASES PRO-INFLAMMATORY CYTOKINES AND PROMOTES MICROGLIAL ACTIVATION, LEADING TO STRESS VULNERABILITY. EPIGENETICS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION, ARE ALSO RELATED TO THE PATHOPHYSIOLOGY OF MAJOR DEPRESSIVE DISORDER. SODIUM BUTYRATE (SB), A HISTONE DEACETYLASE INHIBITOR, EXERTS AN ANTIDEPRESSANT EFFECT BY ALTERING GENE EXPRESSION IN THE HIPPOCAMPUS. IN THIS STUDY, WE INVESTIGATED WHETHER LIPOPOLYSACCHARIDE (LPS)-INDUCED DEPRESSIVE-LIKE BEHAVIORS IN MICE ARE AFFECTED BY THE REPEATED TREATMENT WITH SB. INTRAPERITONEAL INJECTION OF LPS (5 MG/KG) INDUCED CYTOKINES AND IONIZED CALCIUM-BINDING ADAPTOR MOLECULE 1(IBA1), A MARKER OF MICROGLIAL ACTIVATION, IN THE HIPPOCAMPUS. IT ALSO INCREASED THE IMMOBILITY TIME IN A FORCED SWIM TEST, WITHOUT CHANGING LOCOMOTION. REPEATED TREATMENT WITH SB REDUCED LPS-INDUCED ALTERATIONS. THESE FINDINGS SUGGESTED THAT EPIGENETIC REGULATION EXIST IN HIPPOCAMPAL MICROGLIAL ACTIVATION, AND IS INVOLVED IN DEPRESSIVE-LIKE BEHAVIORS ASSOCIATED WITH NEURO-INFLAMMATION. FURTHER, USING CDNA MICROARRAY ANALYSES, WE EXAMINED WHETHER LPS AND SB TREATMENT AFFECTED THE MICROGLIAL GENE PROFILES. OUR RESULTS INDICATED 64 OVERLAPPING GENES, BETWEEN LPS-INCREASED GENES AND SB-DECREASED GENES. AMONG THESE GENES, EF HAND CALCIUM BINDING DOMAIN 1 WAS A PARTICULARLY DISTINCT CANDIDATE GENE. ALTOGETHER, OUR FINDINGS INDICATED THAT MICROGLIAL ACTIVATION MEDIATED THROUGH EPIGENETIC REGULATION MAY BE INVOLVED IN DEPRESSIVE-LIKE BEHAVIORS. IN ADDITION, WE DEMONSTRATED THE EFFECT OF SB ON GENE INFORMATION IN HIPPOCAMPAL MICROGLIA UNDER NEUROINFLAMMATORY CONDITIONS. 2018 15 5019 28 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 5219 33 PREVIOUS HISTORY OF CHRONIC STRESS CHANGES THE TRANSCRIPTIONAL RESPONSE TO GLUCOCORTICOID CHALLENGE IN THE DENTATE GYRUS REGION OF THE MALE RAT HIPPOCAMPUS. CHRONIC STRESS IS A RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISEASES, SUCH AS DEPRESSION AND PSYCHOSIS. IN RESPONSE TO STRESS GLUCOCORTICOIDS (GCS) ARE SECRETED THAT BIND TO MINERALOCORTICOID AND GLUCOCORTICOID RECEPTORS, LIGAND-ACTIVATED TRANSCRIPTION FACTORS THAT REGULATE THE TRANSCRIPTION OF GENE NETWORKS IN THE BRAIN NECESSARY FOR COPING WITH STRESS, RECOVERY, AND ADAPTATION. CHRONIC STRESS PARTICULARLY AFFECTS THE DENTATE GYRUS (DG) SUBREGION OF THE HIPPOCAMPUS, CAUSING SEVERAL FUNCTIONAL AND MORPHOLOGICAL CHANGES WITH CONSEQUENCES FOR LEARNING AND MEMORY, WHICH ARE LIKELY ADAPTIVE BUT AT THE SAME TIME MAKE DG NEURONS MORE VULNERABLE TO SUBSEQUENT CHALLENGES. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE TRANSCRIPTIONAL RESPONSE OF DG NEURONS TO A GC CHALLENGE IN MALE RATS PREVIOUSLY EXPOSED TO CHRONIC RESTRAINT STRESS (CRS). AN INTRIGUING FINDING OF THE CURRENT STUDY WAS THAT HAVING A HISTORY OF CRS HAD PROFOUND CONSEQUENCES FOR THE SUBSEQUENT RESPONSE TO ACUTE GC CHALLENGE, DIFFERENTIALLY AFFECTING THE EXPRESSION OF SEVERAL HUNDREDS OF GENES IN THE DG COMPARED WITH CHALLENGED NONSTRESSED CONTROL ANIMALS. THIS ENDURING EFFECT OF PREVIOUS STRESS EXPOSURE SUGGESTS THAT EPIGENETIC PROCESSES MAY BE INVOLVED. IN LINE WITH THIS, CRS INDEED AFFECTED THE EXPRESSION OF SEVERAL GENES INVOLVED IN CHROMATIN STRUCTURE AND EPIGENETIC PROCESSES, INCLUDING ASF1, ASH1L, HIST1H3F, AND TP63. THE DATA PRESENTED HERE INDICATE THAT CRS ALTERS THE TRANSCRIPTIONAL RESPONSE TO A SUBSEQUENT GC INJECTION. WE PROPOSE THAT THIS ALTERED TRANSCRIPTIONAL POTENTIAL FORMS PART OF THE MOLECULAR MECHANISM UNDERLYING THE ENHANCED VULNERABILITY FOR STRESS-RELATED DISORDERS LIKE DEPRESSION CAUSED BY CHRONIC STRESS. 2013 17 1626 37 DNMT1 MEDIATES CHRONIC PAIN-RELATED DEPRESSION BY INHIBITING GABAERGIC NEURONAL ACTIVATION IN THE CENTRAL AMYGDALA. BACKGROUND: CHRONIC PAIN CAN INDUCE DEPRESSIVE EMOTION. DNA METHYLTRANSFERASES (DNMTS) HAVE BEEN SHOWN TO BE INVOLVED IN THE DEVELOPMENT OF CHRONIC PAIN AND DEPRESSION. HOWEVER, THE ROLE AND MECHANISM OF DNMTS IN CHRONIC PAIN-INDUCED DEPRESSION ARE NOT WELL UNDERSTOOD. METHODS: IN WELL-ESTABLISHED SPARED NERVE INJURY (SNI)-INDUCED CHRONIC PAIN-RELATED DEPRESSION MODELS, THE EXPRESSION OF DNMTS AND THE FUNCTIONAL ROLES AND UNDERLYING MECHANISMS OF DNMT1 IN CENTRAL AMYGDALA (CEA) GABAERGIC (GAMMA-AMINOBUTYRIC ACIDERGIC) NEURONS WERE INVESTIGATED USING MOLECULAR, PHARMACOLOGICAL, ELECTROPHYSIOLOGICAL, OPTOGENETIC, AND CHEMOGENETIC TECHNIQUES AND BEHAVIORAL TESTS. RESULTS: DNMT1, BUT NOT DNMT3A OR DNMT3B, WAS UPREGULATED IN THE CEA OF RATS WITH SNI-INDUCED CHRONIC PAIN-DEPRESSION. INHIBITION OF DNMT1 BY 5-AZA OR VIRAL KNOCKDOWN OF DNMT1 IN GABAERGIC NEURONS IN THE CEA EFFECTIVELY AMELIORATED THE DEPRESSION-LIKE BEHAVIORS INDUCED BY CHRONIC PAIN. THE DNMT1 ACTION WAS ASSOCIATED WITH METHYLATION AT THE CPG-RICH GAD1 PROMOTER AND GAD67 DOWNREGULATION, LEADING TO A DECREASE OF GABAERGIC NEURONAL ACTIVITY. OPTOGENETIC ACTIVATION OF GABAERGIC NEURONS IN THE CEA IMPROVED SNI-INDUCED DEPRESSION-LIKE BEHAVIORS. MOREOVER, OPTOGENETIC OR CHEMOGENETIC INHIBITION OF GABAERGIC NEURONS IN THE CEA REVERSED DNMT1 KNOCKDOWN-INDUCED IMPROVEMENT OF DEPRESSION-LIKE BEHAVIORS IN SNI MICE. CONCLUSIONS: OUR FINDINGS SUGGEST THAT DNMT1 IS INVOLVED IN THE DEVELOPMENT OF CHRONIC PAIN-RELATED DEPRESSION BY EPIGENETIC REPRESSION OF GAD67, LEADING TO THE INHIBITION OF GABAERGIC NEURONAL ACTIVATION. THIS STUDY INDICATES THAT DNMT1 COULD BE A POTENTIAL TARGET FOR THE TREATMENT OF CHRONIC PAIN-RELATED DEPRESSION. 2023 18 1614 32 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES. 2021 19 5467 33 RESILIENT PHENOTYPE IN CHRONIC MILD STRESS PARADIGM IS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF MIR-18A-5P AND SEROTONIN 5-HT(1A) RECEPTOR IN DORSAL PART OF THE HIPPOCAMPUS. DISTURBED SEROTONERGIC SIGNALING IN THE HIPPOCAMPUS OBSERVED IN MANY INDIVIDUALS VULNERABLE TO STRESS HAS BEEN SUGGESTED AS ONE OF THE PRIMARY FACTORS CONTRIBUTING TO THE DEVELOPMENT OF DEPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PHYSIOLOGY OF THE BRAIN IN THE RESILIENT PHENOTYPE. RESILIENT SUBJECTS MAINTAIN A POSITIVE MOOD AND PSYCHOLOGICAL BALANCE DESPITE BEING UNDER THE STRESS INFLUENCE. IN OUR STUDY, WE GENERATED STRESS-VULNERABLE AND RESILIENT RATS BY USING A CHRONIC MILD STRESS (CMS) PARADIGM. USING DIFFERENT MOLECULAR APPROACHES, WE REVEALED THAT RESILIENT ANIMALS EXHIBITED A SIGNIFICANTLY DECREASED EXPRESSION LEVEL OF MIR-18A-5P AND, IN THE SAME TIME, AN ELEVATED LEVEL OF 5-HT1AR IN DORSAL, BUT NOT VENTRAL, PART OF THE HIPPOCAMPUS. DESCRIBED BIOCHEMICAL CHANGES WERE NOT OBSERVED IN ANIMALS BEHAVIORALLY VULNERABLE TO STRESS. FURTHER, IN VITRO ANALYSIS SHOWED THAT MIR-18A-5P MAY BE A NEGATIVE EPIGENETIC REGULATOR OF 5-HT1AR SINCE THE TREATMENT OF ADULT HIPPOCAMPAL NEURONS WITH MIR-18A-5P MIMIC SIGNIFICANTLY LOWERED THE EXPRESSION LEVEL OF MRNA ENCODING 5-HT1AR. MOREOVER, BIOINFORMATIC ANALYSIS OF POTENTIAL TARGET GENES EXPRESSED IN THE HIPPOCAMPUS AND BEING REGULATED BY MIR-18A-5P SHOWED THAT THIS MICRORNA MAY REGULATE BIOLOGICAL PROCESSES, SUCH AS AXONOGENESIS, WHICH ARE IMPORTANT IN THE FUNCTIONING OF THE HIPPOCAMPUS IN BOTH RATS AND HUMANS. ALL THESE MOLECULAR FEATURES MAY CONTRIBUTE TO SEROTONERGIC HOMEOSTATIC BALANCE AT THE LEVEL OF SEROTONIN TURNOVER OBSERVED IN HIPPOCAMPI OF RESILIENT BUT NOT STRESS-VULNERABLE RATS. DELINEATION OF FURTHER MOLECULAR AND BIOCHEMICAL MARKERS UNDERLYING RESILIENCE TO STRESS MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW ANTIDEPRESSANT STRATEGIES WHICH WILL RESTORE RESILIENT PHENOTYPE IN DEPRESSED PATIENTS. 2019 20 3194 29 HDAC INHIBITORS ATTENUATE THE DEVELOPMENT OF HYPERSENSITIVITY IN MODELS OF NEUROPATHIC PAIN. HISTONE DEACETYLASE INHIBITORS (HDACIS) INTERFERE WITH THE EPIGENETIC PROCESS OF HISTONE ACETYLATION AND ARE KNOWN TO HAVE ANALGESIC PROPERTIES IN MODELS OF CHRONIC INFLAMMATORY PAIN. THE AIM OF THIS STUDY WAS TO DETERMINE WHETHER THESE COMPOUNDS COULD ALSO AFFECT NEUROPATHIC PAIN. DIFFERENT CLASS I HDACIS WERE DELIVERED INTRATHECALLY INTO RAT SPINAL CORD IN MODELS OF TRAUMATIC NERVE INJURY AND ANTIRETROVIRAL DRUG-INDUCED PERIPHERAL NEUROPATHY (STAVUDINE, D4T). MECHANICAL AND THERMAL HYPERSENSITIVITY WAS ATTENUATED BY 40% TO 50% AS A RESULT OF HDACI TREATMENT, BUT ONLY IF STARTED BEFORE ANY INSULT. THE DRUGS GLOBALLY INCREASED HISTONE ACETYLATION IN THE SPINAL CORD, BUT APPEARED TO HAVE NO MEASURABLE EFFECTS IN RELEVANT DORSAL ROOT GANGLIA IN THIS TREATMENT PARADIGM, SUGGESTING THAT ANY POTENTIAL MECHANISM SHOULD BE SOUGHT IN THE CENTRAL NERVOUS SYSTEM. MICROARRAY ANALYSIS OF DORSAL CORD RNA REVEALED THE SIGNATURE OF THE SPECIFIC COMPOUND USED (MS-275) AND SUGGESTED THAT ITS MAIN EFFECT WAS MEDIATED THROUGH HDAC1. TAKEN TOGETHER, THESE DATA SUPPORT A ROLE FOR HISTONE ACETYLATION IN THE EMERGENCE OF NEUROPATHIC PAIN. 2013