1 4629 141 NEUROEPIGENETIC CHANGES IN DNA METHYLATION AFFECTING DIABETES-INDUCED COGNITIVE IMPAIRMENT. CHRONIC DIABETIC CONDITIONS HAVE BEEN ASSOCIATED WITH CERTAIN CEREBRAL COMPLICATIONS, THAT INCLUDE NEUROBEHAVIORAL DYSFUNCTIONAL PATTERNS AND MORPHOLOGICAL ALTERATIONS OF NEURONS, ESPECIALLY THE HIPPOCAMPUS. NEUROANATOMICAL STUDIES DONE BY THE AUTHORS HAVE SHOWN DECREASED TOTAL DENDRITIC LENGTH, INTERSECTIONS, DENDRITIC LENGTH PER BRANCH ORDER AND NODES IN THE CA1 HIPPOCAMPAL REGION OF THE DIABETIC BRAIN AS COMPARED TO ITS NORMAL CONTROL GROUP, INDICATING REDUCED DENDRITIC ARBORIZATION OF THE HIPPOCAMPAL CA1 NEURONS. EPIGENETIC ALTERATIONS IN THE BRAIN ARE WELL KNOWN TO AFFECT AGE-ASSOCIATED DISORDERS, HOWEVER ITS ASSOCIATION WITH THE EVOLVING DIABETES-INDUCED DAMAGE IN THE BRAIN IS STILL NOT FULLY UNDERSTOOD. DNA HYPERMETHYLATION WITHIN THE NEURONS, TEND TO SILENT THE GENE EXPRESSION OF SEVERAL REGULATORY PROTEINS. THE FINDINGS IN THE STUDY HAVE SHOWN AN INCREASE IN GLOBAL DNA METHYLATION IN PALMITIC ACID-INDUCED LIPOTOXIC NEURO-2A CELLS AS WELL AS WITHIN THE DIABETIC MICE BRAIN. INHIBITING DNA METHYLATION, RESTORED THE LEVELS OF HSF1 AND CERTAIN HSPS, SUGGESTING PLAUSIBLE EFFECT OF DNMTS IN MAINTAINING THE PROTEOSTASIS AND SYNAPTIC FIDELITY. NEUROINFLAMMATION, AS EXHIBITED BY THE ASTROCYTE ACTIVATION (GFAP), WERE FURTHER SIGNIFICANTLY DECREASED IN THE 5-AZADEOXYCYTIDINE GROUP (DNMT INHIBITOR). THIS WAS FURTHER EVIDENCED BY DECREASE IN PROINFLAMMATORY CYTOKINES TNF?, IL-6, AND MEDIATORS INOS AND PHOSPHO-NFKB. OUR RESULTS SUGGEST THAT CHANGES IN DNA METHYLATION ADVOCATE EPIGENETIC DYSREGULATION AND ITS INVOLVEMENT IN DISRUPTING THE SYNAPTIC EXACTITUDE IN THE HIPPOCAMPUS OF DIABETIC MICE MODEL, PROVIDING AN INSIGHT INTO THE PATHOPHYSIOLOGY OF DIABETES-INDUCED NEUROEPIGENETIC CHANGES. 2023 2 4628 54 NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX OF TYPE 2 DIABETIC MICE THROUGH DNA HYPERMETHYLATION. BACKGROUND: DNA METHYLATION CHANGES HAVE KNOWN TO DOWNREGULATE SEVERAL REGULATORY PROTEINS EPIGENETICALLY DURING VARIOUS NEURODEGENERATIVE DISORDERS. OUR STUDY AIMS TO UNDERSTAND THE EFFECT OF THIS GLOBAL DNA METHYLATION ON THE CEREBRAL COMPLICATIONS OF TYPE 2 DIABETES MICE, AND ITS NOTABLE EFFECT ON MAINTAINING THE SYNAPTIC FIDELITY. METHODS AND RESULTS: CHRONIC HIGH FAT DIET AND STREPTOZOTOCIN-INDUCED DIABETIC MICE WERE STUDIED FOR THE NEUROBEHAVIORAL AND NEUROANATOMIC PARAMETERS PERTAINING TO PREFRONTAL CORTEX, SUBSEQUENTLY ELUCIDATING THE ASSOCIATED CHANGES IN DNA METHYLATION WITHIN THESE DIABETIC BRAINS. FURTHER, THE IMPACT OF THIS EPIGENETIC DYSREGULATION ON HSF1, BDNF AND PSD95 WERE STUDIED BY ASSESSING THE BINDING AFFINITY AND LEVEL OF % METHYLATION WITHIN THE PROMOTER SITE OF THEIR RESPECTIVE GENES. OUR STUDY SUGGEST INCREASED DNMT ABERRATIONS WITHIN THE PREFRONTAL CORTEX, WITH INCREASED MECP2 LEVELS, CONFIRMING DNA HYPERMETHYLATION. THIS WAS IN ACCORDANCE WITH THE ALTERED NEUROBEHAVIORAL CHANGES. FURTHER, THE HYPERMETHYLATION WAS FOUND TO PARTICIPATE IN GENE SILENCING OF HSF1, BDNF AND PSD95 PROTEINS, RESPONSIBLE FOR MAINTAINING THE SYNAPTIC FIDELITY. CONCLUSION: OVERALL, OUR STUDY CONCLUDES THE PLAUSIBLE INVOLVEMENT OF NEUROEPIGENETIC ALTERATIONS IN THE PREFRONTAL CORTEX (PFC) OF THE TYPE 2 DIABETES MICE, SPECIFICALLY DNA HYPERMETHYLATION. PFC PLAYS A CENTRAL ROLE IN MODULATING COGNITIVE AND OTHER EXECUTIVE FUNCTIONS THROUGH ITS CONNECTION WITH SEVERAL BRAIN REGIONS, AND THUS THERAPEUTIC STRATEGIES TARGETING EPIGENETIC MODULATIONS IN IT, CAN PAVE A WAY IN CONTROLLING SEVERAL NEUROLOGICAL ALTERATIONS IN THE BRAIN. 2022 3 948 26 CHRONIC METABOLIC DERANGEMENT-INDUCED COGNITIVE DEFICITS AND NEUROTOXICITY ARE ASSOCIATED WITH REST INACTIVATION. CHRONIC METABOLIC ALTERATIONS MAY REPRESENT A RISK FACTOR FOR THE DEVELOPMENT OF COGNITIVE IMPAIRMENT, DEMENTIA, OR NEURODEGENERATIVE DISEASES. HYPERGLYCEMIA AND OBESITY ARE KNOWN TO IMPRINT EPIGENETIC MARKERS THAT COMPROMISE THE PROPER EXPRESSION OF CELL SURVIVAL GENES. HERE, WE SHOWED THAT CHRONIC HYPERGLYCEMIA (60 DAYS) INDUCED BY A SINGLE INTRAPERITONEAL INJECTION OF STREPTOZOTOCIN COMPROMISED COGNITION BY REDUCING HIPPOCAMPAL ERK SIGNALING AND BY INDUCING NEUROTOXICITY IN RATS. THE MECHANISMS APPEAR TO BE LINKED TO REDUCED ACTIVE DNA DEMETHYLATION AND DIMINISHED EXPRESSION OF THE NEUROPROTECTIVE TRANSCRIPTION FACTOR REST. THE IMPACT OF THE RELATIONSHIP BETWEEN ADIPOSITY AND DNA HYPERMETHYLATION ON REST EXPRESSION WAS ALSO DEMONSTRATED IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN OBESE CHILDREN WITH REDUCED LEVELS OF BLOOD ASCORBATE. THE REVERSIBLE NATURE OF EPIGENETIC MODIFICATIONS AND THE COGNITIVE IMPAIRMENT REPORTED IN OBESE CHILDREN, ADOLESCENTS, AND ADULTS SUGGEST THAT THE CORRECTION OF THE ANTHROPOMETRY AND THE PERIPHERAL METABOLIC ALTERATIONS WOULD PROTECT BRAIN HOMEOSTASIS AND REDUCE THE RISK OF DEVELOPING NEURODEGENERATIVE DISEASES. 2019 4 5007 29 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 5 6174 41 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 6 377 35 AN EPIGENETIC HYPOTHESIS FOR THE GENOMIC MEMORY OF PAIN. CHRONIC PAIN IS ACCOMPANIED WITH LONG-TERM SENSORY, AFFECTIVE AND COGNITIVE DISTURBANCES. WHAT ARE THE MECHANISMS THAT MEDIATE THE LONG-TERM CONSEQUENCES OF PAINFUL EXPERIENCES AND EMBED THEM IN THE GENOME? WE HYPOTHESIZE THAT ALTERATIONS IN DNA METHYLATION, AN ENZYMATIC COVALENT MODIFICATION OF CYTOSINE BASES IN DNA, SERVE AS A "GENOMIC" MEMORY OF PAIN IN THE ADULT CORTEX. DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR LONG-TERM REGULATION OF GENE EXPRESSION. NEURONAL PLASTICITY AT THE NEUROANATOMICAL, FUNCTIONAL, MORPHOLOGICAL, PHYSIOLOGICAL AND MOLECULAR LEVELS HAS BEEN DEMONSTRATED THROUGHOUT THE NEUROAXIS IN RESPONSE TO PERSISTENT PAIN, INCLUDING IN THE ADULT PREFRONTAL CORTEX (PFC). WE HAVE PREVIOUSLY REPORTED WIDESPREAD CHANGES IN GENE EXPRESSION AND DNA METHYLATION IN THE PFC MANY MONTHS FOLLOWING PERIPHERAL NERVE INJURY. IN SUPPORT OF THIS HYPOTHESIS, WE SHOW HERE THAT UP-REGULATION OF A GENE INVOLVED WITH SYNAPTIC FUNCTION, SYNAPTOTAGMIN II (SYT2), IN THE PFC IN A CHRONIC PAIN MODEL IS ASSOCIATED WITH LONG-TERM CHANGES IN DNA METHYLATION. THE CHALLENGES OF UNDERSTANDING THE CONTRIBUTIONS OF EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION WITHIN THE PFC TO PAIN CHRONICITY AND THEIR THERAPEUTIC IMPLICATIONS ARE DISCUSSED. 2015 7 5710 27 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 8 4604 32 NEGATIVE EVIDENCE FOR A FUNCTIONAL ROLE OF NEURONAL DNMT3A IN PERSISTENT PAIN. TRADITIONALLY, NEUROSCIENCE HAS HAD TO RELY ON MIXED TISSUE ANALYSIS TO EXAMINE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN THE CONTEXT OF NERVOUS SYSTEM FUNCTION OR PATHOLOGY. HOWEVER, PARTICULARLY WHEN STUDYING CHRONIC PAIN CONDITIONS, THIS APPROACH CAN BE FLAWED, SINCE IT NEGLECTS TO TAKE INTO ACCOUNT THE SHIFTING CONTRIBUTION OF DIFFERENT CELL TYPES ACROSS EXPERIMENTAL CONDITIONS. HERE, WE DEMONSTRATE THIS USING THE EXAMPLE OF DNA METHYLTRANSFERASES (DNMTS) - A GROUP OF EPIGENETIC MODIFIERS CONSISTING OF DNMT1, DNMT3A, AND DNMT3B IN MAMMALIAN CELLS. WE USED SENSORY NEURON-SPECIFIC KNOCKOUT MICE FOR DNMT3A/3B AS WELL AS PHARMACOLOGICAL BLOCKADE OF DNMT1 TO STUDY THEIR ROLE IN NOCICEPTION. IN CONTRAST TO PREVIOUS ANALYSES ON WHOLE TISSUE, WE FIND THAT DNMT3A AND 3B PROTEIN IS NOT EXPRESSED IN ADULT DRG NEURONS, THAT NONE OF THE DNA METHYLTRANSFERASES ARE REGULATED WITH INJURY AND THAT INTERFERING WITH THEIR FUNCTION HAS NO EFFECT ON NOCICEPTION. OUR RESULTS THEREFORE CURRENTLY DO NOT SUPPORT A ROLE FOR NEURONAL DNA METHYLTRANSFERASES IN PAIN PROCESSING IN ADULT ANIMALS. 2018 9 3587 41 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 10 5818 32 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 11 5645 33 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 12 4093 31 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 13 6527 38 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 14 1614 39 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 15 6427 31 THE TRANSITION FROM ACUTE TO CHRONIC PAIN: DYNAMIC EPIGENETIC REPROGRAMMING OF THE MOUSE PREFRONTAL CORTEX UP TO 1 YEAR AFTER NERVE INJURY. CHRONIC PAIN IS ASSOCIATED WITH PERSISTENT STRUCTURAL AND FUNCTIONAL CHANGES THROUGHOUT THE NEUROAXIS, INCLUDING IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPORTANT IN THE INTEGRATION OF SENSORY, COGNITIVE, AND EMOTIONAL INFORMATION AND IN CONDITIONED PAIN MODULATION. WE PREVIOUSLY REPORTED WIDESPREAD EPIGENETIC REPROGRAMMING IN THE PFC MANY MONTHS AFTER NERVE INJURY IN RODENTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, CAN DRIVE CHANGES IN GENE EXPRESSION WITHOUT MODIFYING DNA SEQUENCES. TO DATE, LITTLE IS KNOWN ABOUT EPIGENETIC DYSREGULATION AT THE ONSET OF ACUTE PAIN OR HOW IT PROGRESSES AS PAIN TRANSITIONS FROM ACUTE TO CHRONIC. WE HYPOTHESIZE THAT ACUTE PAIN AFTER INJURY RESULTS IN RAPID AND PERSISTENT EPIGENETIC REMODELLING IN THE PFC THAT EVOLVES AS PAIN BECOMES CHRONIC. WE FURTHER PROPOSE THAT UNDERSTANDING EPIGENETIC REMODELLING WILL PROVIDE INSIGHTS INTO THE MECHANISMS DRIVING PAIN-RELATED CHANGES IN THE BRAIN. EPIGENOME-WIDE ANALYSIS WAS PERFORMED IN THE MOUSE PFC 1 DAY, 2 WEEKS, 6 MONTHS, AND 1 YEAR AFTER PERIPHERAL INJURY USING THE SPARED NERVE INJURY IN MICE. SPARED NERVE INJURY RESULTED IN RAPID AND PERSISTENT CHANGES IN DNA METHYLATION, WITH ROBUST DIFFERENTIAL METHYLATION OBSERVED BETWEEN SPARED NERVE INJURY AND SHAM-OPERATED CONTROL MICE AT ALL TIME POINTS. HUNDREDS OF DIFFERENTIALLY METHYLATED GENES WERE IDENTIFIED, INCLUDING MANY WITH KNOWN FUNCTION IN PAIN. PATHWAY ANALYSIS REVEALED ENRICHMENT IN GENES RELATED TO STIMULUS RESPONSE AT EARLY TIME POINTS, IMMUNE FUNCTION AT LATER TIME POINTS, AND ACTIN AND CYTOSKELETAL REGULATION THROUGHOUT THE TIME COURSE. THESE RESULTS EMPHASIZE THE IMPORTANCE OF CONSIDERING PAIN CHRONICITY IN BOTH PAIN RESEARCH AND IN TREATMENT OPTIMIZATION. 2020 16 1790 26 EFFECT OF CHRONIC MILD STRESS ON HIPPOCAMPAL TRANSCRIPTOME IN MICE SELECTED FOR HIGH AND LOW STRESS-INDUCED ANALGESIA AND DISPLAYING DIFFERENT EMOTIONAL BEHAVIORS. THERE IS INCREASING EVIDENCE THAT MOOD DISORDERS MAY DERIVE FROM THE IMPACT OF ENVIRONMENTAL PRESSURE ON GENETICALLY SUSCEPTIBLE INDIVIDUALS. STRESS-INDUCED HIPPOCAMPAL PLASTICITY HAS BEEN IMPLICATED IN DEPRESSION. WE STUDIED HIPPOCAMPAL TRANSCRIPTOMES IN STRAINS OF MICE THAT DISPLAY HIGH (HA) AND LOW (LA) SWIM STRESS-INDUCED ANALGESIA AND THAT DIFFER IN EMOTIONAL BEHAVIORS AND RESPONSES TO DIFFERENT CLASSES OF ANTIDEPRESSANTS. CHRONIC MILD STRESS (CMS) AFFECTED EXPRESSION OF A NUMBER OF GENES COMMON FOR BOTH STRAINS. CMS ALSO PRODUCED STRAIN SPECIFIC CHANGES IN EXPRESSION SUGGESTING THAT HIPPOCAMPAL RESPONSES TO STRESS DEPEND ON GENOTYPE. CONSIDERABLY LARGER NUMBER OF GENES, BIOLOGICAL PROCESSES, MOLECULAR FUNCTIONS, BIOCHEMICAL PATHWAYS, AND GENE NETWORKS WERE AFFECTED BY CMS IN LA THAN IN HA MICE. THE RESULTS SUGGEST THAT POTENTIAL DRUG TARGETS AGAINST DETRIMENTAL EFFECTS OF STRESS INCLUDE GLUTAMATE TRANSPORTERS, AND CHOLINERGIC, CHOLECYSTOKININ (CCK), GLUCOCORTICOIDS, AND THYROID HORMONES RECEPTORS. FURTHERMORE, SOME BIOLOGICAL PROCESSES EVOKED BY STRESS AND DIFFERENT BETWEEN THE STRAINS, SUCH AS APOPTOSIS, NEUROGENESIS AND CHROMATIN MODIFICATIONS, MAY BE RESPONSIBLE FOR THE LONG-TERM, IRREVERSIBLE EFFECTS OF STRESS AND SUGGEST A ROLE FOR EPIGENETIC REGULATION OF MOOD RELATED STRESS RESPONSES. 2011 17 2119 29 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 18 4642 36 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 19 6400 30 THE ROLES OF CLASS I HISTONE DEACETYLASES (HDACS) IN MEMORY, LEARNING, AND EXECUTIVE COGNITIVE FUNCTIONS: A REVIEW. COORDINATED CHANGES IN GENE EXPRESSION ARE CRITICAL FOR SYNAPTIC PLASTICITY SUPPORTING LEARNING, MEMORY, AND OPTIMAL COGNITIVE TASK PERFORMANCE. THESE GENE EXPRESSION CHANGES ARE NOT ONLY MEDIATED BY SIGNALING PATHWAYS THAT ACTIVATE TRANSCRIPTION FACTORS, BUT ALSO BY CHROMATIN MODIFICATIONS THAT INFLUENCE THE ACCESSIBILITY OF THE TRANSCRIPTIONAL MACHINERY TO SPECIFIC GENOMIC REGIONS. DURING THE PAST DECADE, EVIDENCE ACCUMULATED THAT ALTERATIONS IN CHROMATIN-BASED EPIGENETIC REGULATION OF GENE EXPRESSION ARE LINKED TO COGNITIVE DYSFUNCTIONS IN THE AGEING OR NEURODEGENERATING BRAIN AS WELL AS TO COGNITIVE DYSFUNCTIONS RESULTING FROM CHRONIC STRESS EXPOSURE. THIS REVIEW SUMMARIZES THE RESULTS OF STUDIES THAT UNRAVELED A ROLE OF HISTONE MODIFYING ENZYMES AND HISTONE MODIFICATIONS IN NORMAL AND IMPAIRED LEARNING AND MEMORY, AND IN THE DISRUPTION OF EXECUTIVE COGNITIVE TASK PERFORMANCE. IT EMPHASIZES THE DIFFERENT ROLES OF SPECIFIC CLASS I HISTONE DEACETYLASES (HDACS) IN COGNITIVE PROCESSES GOVERNED BY THE HIPPOCAMPUS AND PREFRONTAL CORTEX AND DISCUSSES THE POTENTIAL THERAPEUTIC IMPLICATIONS OF TARGETING THEM TO HOLD THE PROGRESSION OF DISEASE-RELATED COGNITIVE DYSFUNCTIONS. 2017 20 2598 27 EPIGENETICS OF THE DEPRESSED BRAIN: ROLE OF HISTONE ACETYLATION AND METHYLATION. MAJOR DEPRESSIVE DISORDER IS A CHRONIC, REMITTING SYNDROME INVOLVING WIDELY DISTRIBUTED CIRCUITS IN THE BRAIN. STABLE ALTERATIONS IN GENE EXPRESSION THAT CONTRIBUTE TO STRUCTURAL AND FUNCTIONAL CHANGES IN MULTIPLE BRAIN REGIONS ARE IMPLICATED IN THE HETEROGENEITY AND PATHOGENESIS OF THE ILLNESS. EPIGENETIC EVENTS THAT ALTER CHROMATIN STRUCTURE TO REGULATE PROGRAMS OF GENE EXPRESSION HAVE BEEN ASSOCIATED WITH DEPRESSION-RELATED BEHAVIOR, ANTIDEPRESSANT ACTION, AND RESISTANCE TO DEPRESSION OR 'RESILIENCE' IN ANIMAL MODELS, WITH INCREASING EVIDENCE FOR SIMILAR MECHANISMS OCCURRING IN POSTMORTEM BRAINS OF DEPRESSED HUMANS. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETIC CONTRIBUTIONS TO DEPRESSION, IN PARTICULAR THE ROLE OF HISTONE ACETYLATION AND METHYLATION, WHICH ARE REVEALING NOVEL MECHANISTIC INSIGHT INTO THE SYNDROME THAT MAY AID IN THE DEVELOPMENT OF NOVEL TARGETS FOR DEPRESSION TREATMENT. 2013