1 1803 50 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 2 4401 19 MODULATION OF NEURONAL PLASTICITY FOLLOWING CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE WITH THE MOOD STABILIZER VALPROIC ACID. RATIONALE: COMBINATORY THERAPY IS WIDELY USED IN PSYCHIATRY OWING TO THE POSSIBILITY THAT DRUGS WITH DIFFERENT MECHANISMS OF ACTION MAY SYNERGIZE TO IMPROVE FUNCTIONS DETERIORATED IN SCHIZOPHRENIA, BIPOLAR DISORDERS, AND MAJOR DEPRESSION. WHILE COMBINATORY STRATEGIES RELY ON RECEPTOR AND SYNAPTIC MECHANISMS, IT SHOULD ALSO BE CONSIDERED THAT TWO DRUGS MAY ALSO "INTERACT" ON THE LONG-TERM TO DETERMINE MORE ROBUST CHANGES IN NEURONAL PLASTICITY, WHICH REPRESENTS A DOWNSTREAM TARGET IMPORTANT FOR FUNCTIONAL RECOVERY. OBJECTIVE: THE AIM OF THE STUDY IS TO INVESTIGATE NEUROADAPTIVE CHANGES SET IN MOTION BY CHRONIC CONCOMITANT ADMINISTRATION OF THE NOVEL ANTIPSYCHOTIC LURASIDONE AND THE MOOD STABILIZER VALPROATE. METHODS: ANIMALS WERE CHRONICALLY TREATED WITH LURASIDONE, VALPROATE, OR THE COMBINATION OF THE TWO DRUGS AND KILLED 24 H AFTER THE LAST INJECTION TO EVALUATE ALTERATIONS OF DIFFERENT MEASURES OF NEURONAL PLASTICITY SUCH AS THE NEUROTROPHIN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), THE IMMEDIATE EARLY GENE ACTIVITY-REGULATED CYTOSKELETAL ASSOCIATED PROTEIN, AND THE EPIGENETIC REGULATORS HDAC 1, 2, AND 5 IN DORSAL AND VENTRAL HIPPOCAMPUS. RESULTS: THE RESULTS SUGGEST THAT COADMINISTRATION OF LURASIDONE AND VALPROATE PRODUCES, WHEN COMPARED TO THE SINGLE DRUGS, A LARGER INCREASE IN THE EXPRESSION OF BDNF IN THE VENTRAL HIPPOCAMPUS, THROUGH THE REGULATION OF SPECIFIC NEUROTROPHIN TRANSCRIPTS. WE ALSO FOUND THAT THE HISTONE DEACETYLASES WERE REGULATED BY THE DRUG COMBINATION, SUGGESTING THAT SOME OF THE TRANSCRIPTIONAL CHANGES MAY BE SUSTAINED BY EPIGENETIC MECHANISMS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE BENEFICIAL EFFECTS ASSOCIATED WITH COMBINATORY TREATMENT BETWEEN A SECOND-GENERATION ANTIPSYCHOTIC AND A MOOD STABILIZER COULD RESULT FROM THE ABILITY TO MODULATE NEUROPLASTIC MOLECULES, WHOSE EXPRESSION AND FUNCTION IS DETERIORATED IN DIFFERENT PSYCHIATRIC CONDITIONS. 2013 3 593 18 BET PROTEIN INHIBITION REGULATES CYTOKINE PRODUCTION AND PROMOTES NEUROPROTECTION AFTER SPINAL CORD INJURY. BACKGROUND: SPINAL CORD INJURY (SCI) USUALLY CAUSES A DEVASTATING LIFELONG DISABILITY FOR PATIENTS. AFTER A TRAUMATIC LESION, DISRUPTION OF THE BLOOD-SPINAL CORD BARRIER INDUCES THE INFILTRATION OF MACROPHAGES INTO THE LESION SITE AND THE ACTIVATION OF RESIDENT GLIAL CELLS, WHICH RELEASE CYTOKINES AND CHEMOKINES. THESE EVENTS RESULT IN A PERSISTENT INFLAMMATION, WHICH HAS BOTH DETRIMENTAL AND BENEFICIAL EFFECTS, BUT EVENTUALLY LIMITS FUNCTIONAL RECOVERY AND CONTRIBUTES TO THE APPEARANCE OF NEUROPATHIC PAIN. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE THE EXPRESSION OF INFLAMMATORY GENES BY INTERACTING WITH ACETYLATED LYSINE RESIDUES. WHILE BET INHIBITORS ARE A PROMISING THERAPEUTIC STRATEGY FOR CANCER, LITTLE IS KNOWN ABOUT THEIR IMPLICATION AFTER SCI. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY ROLE OF BET INHIBITORS IN THIS PATHOLOGIC CONDITION. METHODS: WE EVALUATED THE EFFECTIVENESS OF THE BET INHIBITOR JQ1 TO MODIFY MACROPHAGE REACTIVITY IN VITRO AND TO MODULATE INFLAMMATION IN A SCI MICE MODEL. WE ANALYZED THE EFFECTS OF BET INHIBITION IN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PRODUCTION IN VITRO AND IN VIVO. WE DETERMINED THE EFFECTIVENESS OF BET INHIBITION IN TISSUE SPARING, INFLAMMATION, NEURONAL PROTECTION, AND BEHAVIORAL OUTCOME AFTER SCI. RESULTS: WE HAVE FOUND THAT THE BET INHIBITOR JQ1 REDUCED THE LEVELS OF PRO-INFLAMMATORY MEDIATORS AND INCREASED THE EXPRESSION OF ANTI-INFLAMMATORY CYTOKINES. A PROLONGED TREATMENT WITH JQ1 ALSO DECREASED REACTIVITY OF MICROGLIA/MACROPHAGES, ENHANCED NEUROPROTECTION AND FUNCTIONAL RECOVERY, AND ACUTELY REDUCED NEUROPATHIC PAIN AFTER SCI. CONCLUSIONS: BET PROTEIN INHIBITION IS AN EFFECTIVE TREATMENT TO REGULATE CYTOKINE PRODUCTION AND PROMOTE NEUROPROTECTION AFTER SCI. THESE NOVEL RESULTS DEMONSTRATE FOR THE FIRST TIME THAT TARGETING BET PROTEINS IS AN ENCOURAGING APPROACH FOR SCI REPAIR AND A POTENTIAL STRATEGY TO TREAT OTHER INFLAMMATORY PATHOLOGIES. 2019 4 3587 16 IMPACT OF TLR4 ON BEHAVIORAL AND COGNITIVE DYSFUNCTIONS ASSOCIATED WITH ALCOHOL-INDUCED NEUROINFLAMMATORY DAMAGE. TOLL-LIKE RECEPTORS (TLRS) PLAY AN IMPORTANT ROLE IN THE INNATE IMMUNE RESPONSE, AND EMERGING EVIDENCE INDICATES THEIR ROLE IN BRAIN INJURY AND NEURODEGENERATION. OUR RECENT RESULTS HAVE DEMONSTRATED THAT ETHANOL IS CAPABLE OF ACTIVATING GLIAL TLR4 RECEPTORS AND THAT THE ELIMINATION OF THESE RECEPTORS IN MICE PROTECTS AGAINST ETHANOL-INDUCED GLIAL ACTIVATION, INDUCTION OF INFLAMMATORY MEDIATORS AND APOPTOSIS. THIS STUDY WAS DESIGNED TO ASSESS WHETHER ETHANOL-INDUCED INFLAMMATORY DAMAGE CAUSES BEHAVIORAL AND COGNITIVE CONSEQUENCES, AND IF BEHAVIORAL ALTERATIONS ARE DEPENDENT OF TLR4 FUNCTIONS. HERE WE SHOW IN MICE DRINKING ALCOHOL FOR 5MONTHS, FOLLOWED BY A 15-DAY WITHDRAWAL PERIOD, THAT ACTIVATION OF THE ASTROGLIAL AND MICROGLIAL CELLS IN FRONTAL CORTEX AND STRIATUM IS MAINTAINED AND THAT THESE EVENTS ARE ASSOCIATED WITH COGNITIVE AND ANXIETY-RELATED BEHAVIORAL IMPAIRMENTS IN WILD-TYPE (WT) MICE, AS DEMONSTRATED BY TESTING THE ANIMALS WITH OBJECT MEMORY RECOGNITION, CONDITIONED TASTE AVERSION AND DARK AND LIGHT BOX ANXIETY TASKS. MICE LACKING TLR4 RECEPTORS ARE PROTECTED AGAINST ETHANOL-INDUCED INFLAMMATORY DAMAGE, AND BEHAVIORAL ASSOCIATED EFFECTS. WE FURTHER ASSESS THE POSSIBILITY OF THE EPIGENETIC MODIFICATIONS PARTICIPATING IN SHORT- OR LONG-TERM BEHAVIORAL EFFECTS ASSOCIATED WITH NEUROINFLAMMATORY DAMAGE. WE SHOW THAT CHRONIC ALCOHOL TREATMENT DECREASES H4 HISTONE ACETYLATION AND HISTONE ACETYLTRANSFERASES ACTIVITY IN FRONTAL CORTEX, STRIATUM AND HIPPOCAMPUS OF WT MICE. ALTERATIONS IN CHROMATIN STRUCTURE WERE NOT OBSERVED IN TLR4(-/-) MICE. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF THE ROLE THAT TLR4 FUNCTIONS PLAY IN THE BEHAVIORAL CONSEQUENCES OF ALCOHOL-INDUCED INFLAMMATORY DAMAGE AND SUGGEST THAT THE EPIGENETIC MODIFICATIONS MEDIATED BY TLR4 COULD CONTRIBUTE TO SHORT- OR LONG-TERM ALCOHOL-INDUCED BEHAVIORAL OR COGNITIVE DYSFUNCTIONS. 2011 5 4860 16 OREXIN SIGNALING MEDIATES THE ANTIDEPRESSANT-LIKE EFFECT OF CALORIE RESTRICTION. DURING PERIODS OF REDUCED FOOD AVAILABILITY, ANIMALS MUST RESPOND WITH BEHAVIORAL ADAPTATIONS THAT PROMOTE SURVIVAL. DESPITE THE FACT THAT MANY PSYCHIATRIC SYNDROMES INCLUDE DISORDERED EATING PATTERNS AS A COMPONENT OF THE ILLNESS, LITTLE IS KNOWN ABOUT THE NEUROBIOLOGY UNDERLYING BEHAVIORAL CHANGES INDUCED BY SHORT-TERM CALORIE RESTRICTION. PRESENTLY, WE DEMONSTRATE THAT 10 D OF CALORIE RESTRICTION, CORRESPONDING TO A 20-25% WEIGHT LOSS, CAUSES A MARKED ANTIDEPRESSANT-LIKE RESPONSE IN TWO RODENT MODELS OF DEPRESSION AND THAT THIS RESPONSE IS DEPENDENT ON THE HYPOTHALAMIC NEUROPEPTIDE OREXIN (HYPOCRETIN). WILD-TYPE MICE, BUT NOT MICE LACKING OREXIN, SHOW LONGER LATENCY TO IMMOBILITY AND LESS TOTAL IMMOBILITY IN THE FORCED SWIM TEST AFTER CALORIE RESTRICTION. IN THE SOCIAL DEFEAT MODEL OF CHRONIC STRESS, CALORIE RESTRICTION REVERSES THE BEHAVIORAL DEFICITS SEEN IN WILD-TYPE MICE BUT NOT IN OREXIN KNOCK-OUT MICE. ADDITIONALLY, CHRONIC SOCIAL DEFEAT STRESS INDUCES A PROLONGED REDUCTION IN THE EXPRESSION OF PREPRO-OREXIN MRNA VIA EPIGENETIC MODIFICATION OF THE OREXIN GENE PROMOTER, WHEREAS CALORIE RESTRICTION ENHANCES THE ACTIVATION OF OREXIN CELLS AFTER SOCIAL DEFEAT. TOGETHER, THESE DATA INDICATE THAT OREXIN PLAYS AN ESSENTIAL ROLE IN MEDIATING REDUCED DEPRESSION-LIKE SYMPTOMS INDUCED BY CALORIE RESTRICTION. 2008 6 2353 16 EPIGENETIC REGULATION OF OPIOID-INDUCED HYPERALGESIA, DEPENDENCE, AND TOLERANCE IN MICE. REPEATED ADMINISTRATION OF OPIOIDS SUCH AS MORPHINE INDUCES PERSISTENT BEHAVIORAL CHANGES INCLUDING OPIOID-INDUCED HYPERALGESIA (OIH), TOLERANCE, AND PHYSICAL DEPENDENCE. IN THE CURRENT WORK WE EXPLORED HOW THE BALANCE OF HISTONE ACETYLTRANSFERASE (HAT) VERSUS HISTONE DEACETYLASE (HDAC) MIGHT REGULATE THESE MORPHINE-INDUCED CHANGES. NOCICEPTIVE THRESHOLDS, ANALGESIA, AND PHYSICAL DEPENDENCE WERE ASSESSED DURING AND FOR A PERIOD OF SEVERAL WEEKS AFTER MORPHINE EXPOSURE. TO PROBE THE ROLES OF HISTONE ACETYLATION, THE HAT INHIBITOR CURCUMIN OR A SELECTIVE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) WAS ADMINISTERED DAILY TO GROUPS OF ANIMALS. HISTONE ACETYLATION IN SPINAL CORD WAS ASSESSED BY WESTERN BLOT AND IMMUNOHISTOCHEMISTRY. CONCURRENT ADMINISTRATION OF CURCUMIN WITH MORPHINE FOR 4 DAYS SIGNIFICANTLY REDUCED DEVELOPMENT OF OPIOID-INDUCED MECHANICAL ALLODYNIA, THERMAL HYPERALGESIA, TOLERANCE, AND PHYSICAL DEPENDENCE. CONVERSELY, THE HDAC INHIBITOR SAHA ENHANCED THESE RESPONSES. INTERESTINGLY, SAHA TREATMENT AFTER THE TERMINATION OF OPIOID ADMINISTRATION SUSTAINED THESE BEHAVIORAL CHANGES FOR AT LEAST 4 WEEKS. HISTONE H3 ACETYLATION IN THE DORSAL HORN OF THE SPINAL CORD WAS INCREASED AFTER CHRONIC MORPHINE TREATMENT, BUT H4 ACETYLATION WAS UNCHANGED. MOREOVER, WE OBSERVED A DECREASE IN HDAC ACTIVITY IN THE SPINAL CORDS OF MORPHINE-TREATED MICE WHILE OVERALL HAT ACTIVITY WAS UNCHANGED, SUGGESTING A SHIFT TOWARD A STATE OF ENHANCED HISTONE ACETYLATION. PERSPECTIVE: THE CURRENT STUDY INDICATES THAT EPIGENETIC MECHANISMS PLAY A CRUCIAL ROLE IN OPIOID-INDUCED LONG-LASTING NEUROPLASTICITY. THESE RESULTS PROVIDE NEW SIGHT INTO UNDERSTANDING THE MECHANISMS OF OPIOID-INDUCED NEUROPLASTICITY AND SUGGEST NEW STRATEGIES TO LIMIT OPIOID ABUSE POTENTIAL AND INCREASE THE VALUE OF THESE DRUGS AS ANALGESICS. 2013 7 6527 15 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 8 5019 21 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 9 2214 19 EPIGENETIC MODIFICATIONS ASSOCIATED TO NEUROINFLAMMATION AND NEUROPATHIC PAIN AFTER NEURAL TRAUMA. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC ALTERATIONS LIE BEHIND THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN. NEUROPATHIC PAIN IS USUALLY A CHRONIC CONDITION CAUSED BY A LESION, OR PATHOLOGICAL CHANGE, WITHIN THE NERVOUS SYSTEM. NEUROPATHIC PAIN APPEARS FREQUENTLY AFTER NERVE AND SPINAL CORD INJURIES OR DISEASES, PRODUCING A DEBILITATION OF THE PATIENT AND A DECREASE OF THE QUALITY OF LIFE. AT THE CELLULAR LEVEL, NEUROPATHIC PAIN IS THE RESULT OF NEURONAL PLASTICITY SHAPED BY AN INCREASE IN THE SENSITIVITY AND EXCITABILITY OF SENSORY NEURONS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM. ONE OF THE MECHANISMS THOUGHT TO CONTRIBUTE TO HYPEREXCITABILITY AND THEREFORE TO THE ONTOGENY OF NEUROPATHIC PAIN IS THE ALTERED EXPRESSION, TRAFFICKING, AND FUNCTIONING OF RECEPTORS AND ION CHANNELS EXPRESSED BY PRIMARY SENSORY NEURONS. BESIDES, NEURONAL AND GLIAL CELLS, SUCH AS MICROGLIA AND ASTROCYTES, TOGETHER WITH BLOOD BORNE MACROPHAGES, PLAY A CRITICAL ROLE IN THE INDUCTION AND MAINTENANCE OF NEUROPATHIC PAIN BY RELEASING POWERFUL NEUROMODULATORS SUCH AS PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, WHICH ENHANCE NEURONAL EXCITABILITY. ALTERED GENE EXPRESSION OF NEURONAL RECEPTORS, ION CHANNELS, AND PRO-INFLAMMATORY CYTOKINES AND CHEMOKINES, HAVE BEEN ASSOCIATED TO EPIGENETIC ADAPTATIONS OF THE INJURED TISSUE. WITHIN THIS REVIEW, WE DISCUSS THE INVOLVEMENT OF THESE EPIGENETIC CHANGES, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, NON-CODING RNAS, AND ALTERATION OF CHROMATIN MODIFIERS, THAT HAVE BEEN SHOWN TO TRIGGER MODIFICATION OF NOCICEPTION AFTER NEURAL LESIONS. IN PARTICULAR, THE FUNCTION ON THESE PROCESSES OF EZH2, JMJD3, MECP2, SEVERAL HISTONE DEACETYLASES (HDACS) AND HISTONE ACETYL TRANSFERASES (HATS), G9A, DNMT, REST AND DIVERSE NON-CODING RNAS, ARE DESCRIBED. DESPITE THE EFFORT ON DEVELOPING NEW THERAPIES, CURRENT TREATMENTS HAVE ONLY PRODUCED LIMITED RELIEF OF THIS PAIN IN A PORTION OF PATIENTS. THUS, THE PRESENT REVIEW AIMS TO CONTRIBUTE TO FIND NOVEL TARGETS FOR CHRONIC NEUROPATHIC PAIN TREATMENT. 2018 10 5624 10 SELECTIVE BOOSTING OF TRANSCRIPTIONAL AND BEHAVIORAL RESPONSES TO DRUGS OF ABUSE BY HISTONE DEACETYLASE INHIBITION. HISTONE ACETYLATION AND OTHER MODIFICATIONS OF THE CHROMATIN ARE IMPORTANT REGULATORS OF GENE EXPRESSION AND, CONSEQUENTLY, MAY CONTRIBUTE TO DRUG-INDUCED BEHAVIORS AND NEUROPLASTICITY. EARLIER STUDIES HAVE SHOWN THAT A REDUCTION IN HISTONE DEACETYLASE (HDAC) ACTIVITY RESULTS IN THE ENHANCEMENT OF SOME PSYCHOSTIMULANT-INDUCED BEHAVIORS. IN THIS STUDY, WE EXTEND THOSE SEMINAL FINDINGS BY SHOWING THAT THE ADMINISTRATION OF THE HDAC INHIBITOR SODIUM BUTYRATE ENHANCES MORPHINE-INDUCED LOCOMOTOR SENSITIZATION AND CONDITIONED PLACE PREFERENCE. IN CONTRAST, THIS COMPOUND HAS NO EFFECTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE. SIMILAR EFFECTS WERE OBSERVED FOR COCAINE AND ETHANOL-INDUCED BEHAVIORS. THESE BEHAVIORAL CHANGES WERE ACCOMPANIED BY A SELECTIVE BOOSTING OF A COMPONENT OF THE TRANSCRIPTIONAL PROGRAM ACTIVATED BY CHRONIC MORPHINE ADMINISTRATION THAT INCLUDED CIRCADIAN CLOCK GENES AND OTHER GENES RELEVANT TO ADDICTIVE BEHAVIOR. OUR RESULTS SUPPORT A SPECIFIC FUNCTION FOR HISTONE ACETYLATION AND THE EPIGENETIC MODULATION OF TRANSCRIPTION AT A REDUCED NUMBER OF BIOLOGICALLY RELEVANT LOCI ON NON-HOMEOSTATIC, LONG-LASTING, DRUG-INDUCED BEHAVIORAL PLASTICITY. 2009 11 2827 16 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 12 6175 17 THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA) ALLEVIATES DEPRESSION-LIKE BEHAVIOR AND NORMALIZES EPIGENETIC CHANGES IN THE HIPPOCAMPUS DURING ETHANOL WITHDRAWAL. WITHDRAWAL FROM CHRONIC ALCOHOL DRINKING CAN CAUSE DEPRESSION, LEADING TO AN INABILITY TO FUNCTION IN DAILY LIFE AND AN INCREASED RISK FOR RELAPSE TO HARMFUL DRINKING. UNDERSTANDING THE CAUSES OF ALCOHOL WITHDRAWAL-RELATED DEPRESSION MAY LEAD TO NEW THERAPEUTIC TARGETS FOR TREATMENT. EPIGENETIC FACTORS HAVE RECENTLY EMERGED AS IMPORTANT CONTRIBUTORS TO BOTH DEPRESSION AND ALCOHOL USE DISORDER (AUD). SPECIFICALLY, ACETYLATION OF THE N-TERMINAL TAILS OF HISTONE PROTEINS THAT PACKAGE DNA INTO NUCLEOSOMES IS ALTERED IN STRESS-INDUCED MODELS OF DEPRESSION AND DURING ALCOHOL WITHDRAWAL. THE GOAL OF THIS STUDY WAS TO EXAMINE DEPRESSION-LIKE BEHAVIOR DURING ALCOHOL WITHDRAWAL AND ASSOCIATED CHANGES IN HISTONE ACETYLATION AND EXPRESSION OF HISTONE DEACETYLASE 2 (HDAC2) IN THE HIPPOCAMPUS, A BRAIN REGION CRITICAL FOR MOOD REGULATION AND DEPRESSION. MALE SPRAGUE-DAWLEY RATS WERE TREATED WITH THE LIEBER-DECARLI ETHANOL LIQUID DIET FOR 15 DAYS AND THEN UNDERWENT WITHDRAWAL. RATS WERE TREATED WITH THE HDAC INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), DURING WITHDRAWAL AND WERE TESTED FOR DEPRESSION-LIKE BEHAVIOR. IN A SEPARATE GROUP OF RATS, THE HIPPOCAMPUS WAS ANALYZED FOR MRNA AND PROTEIN EXPRESSION OF HDAC2 AND LEVELS OF HISTONE H3 LYSINE 9 ACETYLATION (H3K9AC) DURING CHRONIC ETHANOL EXPOSURE AND WITHDRAWAL. RATS UNDERGOING ETHANOL WITHDRAWAL EXHIBITED DEPRESSION-LIKE BEHAVIOR AND HAD INCREASED HDAC2 AND DECREASED H3K9AC LEVELS IN SPECIFIC STRUCTURES OF THE HIPPOCAMPUS. TREATMENT WITH SAHA DURING WITHDRAWAL AMELIORATED DEPRESSION-LIKE BEHAVIOR AND NORMALIZED CHANGES IN HIPPOCAMPAL HDAC2 AND H3K9AC LEVELS. THESE RESULTS DEMONSTRATE THAT ETHANOL WITHDRAWAL CAUSES AN ALTERED EPIGENETIC STATE IN THE HIPPOCAMPUS. TREATMENT WITH AN HDAC INHIBITOR CAN CORRECT THIS STATE AND ALLEVIATE DEPRESSION-LIKE SYMPTOMS DEVELOPED DURING WITHDRAWAL. TARGETING HISTONE ACETYLATION MAY BE A NOVEL STRATEGY TO REDUCE ETHANOL WITHDRAWAL-INDUCED DEPRESSION. 2019 13 4642 17 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 14 4173 15 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 15 5818 19 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES. 2014 16 2473 14 EPIGENETIC TREATMENTS OF ADULT RATS PROMOTE RECOVERY FROM VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION. IN MAMMALS THE DEVELOPMENT OF THE VISUAL SYSTEM MAY BE ALTERED DURING A SENSITIVE PERIOD BY MODIFYING THE VISUAL INPUT TO ONE OR BOTH EYES. THESE PLASTIC PROCESSES ARE REDUCED AFTER THE END OF THE SENSITIVE PERIOD. IT HAS BEEN PROPOSED THAT REDUCED LEVELS OF PLASTICITY ARE AT THE BASIS OF THE LACK OF RECOVERY FROM EARLY VISUAL DEPRIVATION OBSERVED IN ADULT ANIMALS. A DEVELOPMENTAL DOWNREGULATION OF EXPERIENCE-DEPENDENT REGULATION OF HISTONE ACETYLATION HAS RECENTLY BEEN FOUND TO BE INVOLVED IN CLOSING THE SENSITIVE PERIOD. THEREFORE, WE TESTED WHETHER PHARMACOLOGICAL EPIGENETIC TREATMENTS INCREASING HISTONE ACETYLATION COULD BE USED TO REVERSE VISUAL ACUITY DEFICITS INDUCED BY LONG-TERM MONOCULAR DEPRIVATION INITIATED DURING THE SENSITIVE PERIOD. WE FOUND THAT CHRONIC INTRAPERITONEAL ADMINISTRATION OF VALPROIC ACID OR SODIUM BUTYRATE (TWO DIFFERENT HISTONE DEACETYLASES INHIBITORS) TO LONG-TERM MONOCULARLY DEPRIVED ADULT RATS COUPLED WITH REVERSE LID-SUTURING CAUSED A COMPLETE RECOVERY OF VISUAL ACUITY, TESTED ELECTROPHYSIOLOGICALLY AND BEHAVIORALLY. THUS, MANIPULATIONS OF THE EPIGENETIC MACHINERY CAN BE USED TO PROMOTE FUNCTIONAL RECOVERY FROM EARLY ALTERATIONS OF SENSORY INPUT IN THE ADULT CORTEX. 2010 17 2013 12 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 18 706 15 BUTYRATE AND DIETARY SOLUBLE FIBER IMPROVE NEUROINFLAMMATION ASSOCIATED WITH AGING IN MICE. AGING RESULTS IN CHRONIC SYSTEMIC INFLAMMATION THAT CAN ALTER NEUROINFLAMMATION OF THE BRAIN. SPECIFICALLY, MICROGLIA SHIFT TO A PRO-INFLAMMATORY PHENOTYPE PREDISPOSING THEM TO HYPERACTIVATION UPON STIMULATION BY PERIPHERAL IMMUNE SIGNALS. IT IS PROPOSED THAT CERTAIN NUTRIENTS CAN DELAY BRAIN AGING BY PREVENTING OR REVERSING MICROGLIAL HYPERACTIVATION. BUTYRATE, A SHORT-CHAIN FATTY ACID (SCFA) PRODUCED PRIMARILY BY BACTERIAL FERMENTATION OF FIBER IN THE COLON, HAS BEEN EXTENSIVELY STUDIED PHARMACOLOGICALLY AS A HISTONE DEACETYLASE INHIBITOR AND SERVES AS AN ATTRACTIVE THERAPEUTIC CANDIDATE, AS BUTYRATE HAS ALSO BEEN SHOWN TO BE ANTI-INFLAMMATORY AND IMPROVE MEMORY IN ANIMAL MODELS. IN THIS STUDY, WE DEMONSTRATE THAT BUTYRATE CAN ATTENUATE PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MICROGLIA IN AGED MICE. IT IS STILL NOT FULLY UNDERSTOOD, HOWEVER, IF AN INCREASE IN BUTYRATE-PRODUCING BACTERIA IN THE GUT AS A CONSEQUENCE OF A DIET HIGH IN SOLUBLE FIBER COULD AFFECT MICROGLIAL ACTIVATION DURING AGING. ADULT AND AGED MICE WERE FED EITHER A 1% CELLULOSE (LOW FIBER) OR 5% INULIN (HIGH FIBER) DIET FOR 4 WEEKS. FINDINGS INDICATE THAT MICE FED INULIN HAD AN ALTERED GUT MICROBIOME AND INCREASED BUTYRATE, ACETATE, AND TOTAL SCFA PRODUCTION. IN ADDITION, HISTOLOGICAL SCORING OF THE DISTAL COLON DEMONSTRATED THAT AGED ANIMALS ON THE LOW FIBER DIET HAD INCREASED INFLAMMATORY INFILTRATE THAT WAS SIGNIFICANTLY REDUCED IN ANIMALS CONSUMING THE HIGH FIBER DIET. FURTHERMORE, GENE EXPRESSION OF INFLAMMATORY MARKERS, EPIGENETIC REGULATORS, AND THE MICROGLIAL SENSORY APPARATUS (I.E., THE SENSOME) WERE ALTERED BY BOTH DIET AND AGE, WITH AGED ANIMALS EXHIBITING A MORE ANTI-INFLAMMATORY MICROGLIAL PROFILE ON THE HIGH FIBER DIET. TAKEN TOGETHER, HIGH FIBER SUPPLEMENTATION IN AGING IS A NON-INVASIVE STRATEGY TO INCREASE BUTYRATE LEVELS, AND THESE DATA SUGGEST THAT AN INCREASE IN BUTYRATE THROUGH ADDED SOLUBLE FIBER SUCH AS INULIN COULD COUNTERBALANCE THE AGE-RELATED MICROBIOTA DYSBIOSIS, POTENTIALLY LEADING TO NEUROLOGICAL BENEFITS. 2018 19 1238 13 CURCUMIN BLOCKS CHRONIC MORPHINE ANALGESIC TOLERANCE AND BRAIN-DERIVED NEUROTROPHIC FACTOR UPREGULATION. THIS STUDY WAS CARRIED OUT BASED ON THE ASSUMPTION THAT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MAY COUNTERBALANCE THE ACTION OF MORPHINE IN THE BRAIN. MORPHINE ANALGESIC TOLERANCE AFTER DAILY ADMINISTRATIONS FOR SIX DAYS WAS BLOCKED BY INTRACEREBROVENTRICULAR INJECTION OF ANTI-BDNF IGG ON DAY 5, BUT NOT BY ADMINISTRATIONS ON DAYS 1-4. CHRONIC MORPHINE TREATMENT SIGNIFICANTLY INCREASED THE EXPRESSION OF EXON I AND IV BDNF TRANSCRIPTS, INDICATING DIFFERENTIAL REGULATION OF BDNF GENE EXPRESSION. DAILY ADMINISTRATION OF THE CREB-BINDING PROTEIN INHIBITOR CURCUMIN ABOLISHED THE UPREGULATION OF BDNF TRANSCRIPTION AND MORPHINE ANALGESIC TOLERANCE. THESE RESULTS SUGGEST THAT CURCUMIN MIGHT BE A PROMISING ADJUVANT TO REDUCE MORPHINE ANALGESIC TOLERANCE, AND THAT EPIGENETIC CONTROL COULD BE A NEW STRATEGY USEFUL FOR THE CONTROL OF THIS PROBLEM. 2009 20 5207 17 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