1 1734 124 EAAT2 AS A RESEARCH TARGET IN BIPOLAR DISORDER AND UNIPOLAR DEPRESSION: A SYSTEMATIC REVIEW. GLUTAMATE IS IMPLICATED IN THE NEUROPATHOLOGY OF BOTH MAJOR DEPRESSIVE DISORDER AND BIPOLAR DISORDER. EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) IS THE MAJOR GLUTAMATE TRANSPORTER IN THE MAMMALIAN BRAIN, REMOVING GLUTAMATE FROM THE SYNAPTIC CLEFT AND TRANSPORTING IT INTO GLIA FOR RECYCLING. IT IS THEREBY THE PRINCIPAL REGULATOR OF EXTRACELLULAR GLUTAMATE LEVELS AND PREVENTS NEURONAL EXCITOTOXICITY. EAAT2 IS A PROMISING TARGET FOR ELUCIDATING THE MECHANISMS BY WHICH THE GLUTAMATE-GLUTAMINE CYCLE INTERACTS WITH NEURONAL SYSTEMS IN MOOD DISORDERS. FORTY EAAT2 STUDIES (PUBLISHED JANUARY 1992-JANUARY 2018) WERE IDENTIFIED VIA A SYSTEMATIC LITERATURE SEARCH. THE STUDIES DEMONSTRATED THAT CHRONIC STRESS/STEROIDS WERE MOST COMMONLY ASSOCIATED WITH DECREASED EAAT2. IN RODENTS, EAAT2 INHIBITION WORSENED DEPRESSIVE BEHAVIORS. HUMAN EAAT2 EXPRESSION USUALLY DECREASED IN DEPRESSION, WITH SOME REGIONAL BRAIN DIFFERENCES. FEWER DATA HAVE BEEN COLLECTED REGARDING THE ROLES AND REGULATION OF EAAT2 IN BIPOLAR DISORDER. FUTURE DIRECTIONS FOR RESEARCH INCLUDE CORRELATING EAAT2 AND GLUTAMATE LEVELS IN VIVO, ELUCIDATING GENETIC VARIABILITY AND EPIGENETIC REGULATION, CLARIFYING INTRACELLULAR PROTEIN AND PHARMACOLOGIC INTERACTIONS, AND EXAMINING EAAT2 IN DIFFERENT BIPOLAR MOOD STATES. AS PART OF A MACROMOLECULAR COMPLEX WITHIN GLIA, EAAT2 MAY CONTRIBUTE SIGNIFICANTLY TO INTRACELLULAR SIGNALING, ENERGY REGULATION, AND CELLULAR HOMEOSTASIS. AN ENHANCED UNDERSTANDING OF THIS SYSTEM IS NEEDED. 2020 2 533 38 ASTROCYTIC TRANSCRIPTION FACTOR REST UPREGULATES GLUTAMATE TRANSPORTER EAAT2, PROTECTING DOPAMINERGIC NEURONS FROM MANGANESE-INDUCED EXCITOTOXICITY. CHRONIC EXPOSURE TO HIGH LEVELS OF MANGANESE (MN) LEADS TO MANGANISM, A NEUROLOGICAL DISORDER WITH SIMILAR SYMPTOMS TO THOSE INHERENT TO PARKINSON'S DISEASE. HOWEVER, THE UNDERLYING MECHANISMS OF THIS PATHOLOGICAL CONDITION HAVE YET TO BE ESTABLISHED. SINCE THE HUMAN EXCITATORY AMINO ACID TRANSPORTER 2 (EAAT2) (GLUTAMATE TRANSPORTER 1 IN RODENTS) IS PREDOMINANTLY EXPRESSED IN ASTROCYTES AND ITS DYSREGULATION IS INVOLVED IN MN-INDUCED EXCITOTOXIC NEURONAL INJURY, CHARACTERIZATION OF THE MECHANISMS THAT MEDIATE THE MN-INDUCED IMPAIRMENT IN EAAT2 FUNCTION IS CRUCIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS AGAINST MN NEUROTOXICITY. REPRESSOR ELEMENT 1-SILENCING TRANSCRIPTION FACTOR (REST) EXERTS PROTECTIVE EFFECTS IN MANY NEURODEGENERATIVE DISEASES. BUT THE EFFECTS OF REST ON EAAT2 EXPRESSION AND ENSUING NEUROPROTECTION ARE UNKNOWN. GIVEN THAT THE EAAT2 PROMOTER CONTAINS REST BINDING SITES, THE PRESENT STUDY INVESTIGATED THE ROLE OF REST IN EAAT2 EXPRESSION AT THE TRANSCRIPTIONAL LEVEL IN ASTROCYTES AND MN-INDUCED NEUROTOXICITY IN AN ASTROCYTE-NEURON COCULTURE SYSTEM. THE RESULTS REVEAL THAT ASTROCYTIC REST POSITIVELY REGULATES EAAT2 EXPRESSION WITH THE RECRUITMENT OF AN EPIGENETIC MODIFIER, CAMP RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300, TO ITS CONSENSUS BINDING SITES IN THE EAAT2 PROMOTER. MOREOVER, ASTROCYTIC OVEREXPRESSION OF REST ATTENUATES MN-INDUCED REDUCTION IN EAAT2 EXPRESSION, LEADING TO ATTENUATION OF GLUTAMATE-INDUCED NEUROTOXICITY IN THE ASTROCYTE-NEURON COCULTURE SYSTEM. OUR FINDINGS DEMONSTRATE THAT ASTROCYTIC REST PLAYS A CRITICAL ROLE IN PROTECTION AGAINST MN-INDUCED NEUROTOXICITY BY ATTENUATING MN-INDUCED EAAT2 REPRESSION AND THE ENSUING EXCITOTOXIC DOPAMINERGIC NEURONAL INJURY. THIS INDICATES THAT ASTROCYTIC REST COULD BE A POTENTIAL MOLECULAR TARGET FOR THE TREATMENT OF MN TOXICITY AND OTHER NEUROLOGICAL DISORDERS ASSOCIATED WITH EAAT2 DYSREGULATION. 2021 3 6097 17 THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION IN THE BRAIN. STRESS LEADS TO DETRIMENTAL EFFECTS ON BRAIN FUNCTIONS AND RESULTS IN VARIOUS DISEASES. RECENT STUDIES HIGHLIGHT THE INVOLVEMENT OF GLUTAMATERGIC TRANSMISSION IN PATHOGENESIS OF DEPRESSIVE BEHAVIORS AND FEARS. ACUTE STRESS GENERATES DIFFERENT IMPACTS ON THE EXCITATORY TRANSMISSION COMPARED TO CHRONIC STRESS. DIFFERENT NEUROMODULATORS AND EPIGENETIC FACTORS ALSO PARTICIPATE IN THE ALTERATION OF SYNAPTIC TRANSMISSION AND THE REGULATION OF SYNAPTIC PLASTICITY. RESTORATION OF THE GLUTAMATERGIC TRANSMISSION IN STRESS-AFFECTED BRAIN AREAS THEREFORE PROVIDES NOVEL DIRECTIONS OF THERAPEUTIC INTERVENTIONS AGAINST STRESS. 2015 4 2092 25 EPIGENETIC EFFECT OF CHRONIC STRESS ON DOPAMINE SIGNALING AND DEPRESSION. BECAUSE OF THE COMPLEX CAUSAL FACTORS LEADING TO DEPRESSION, EPIGENETICS IS OF CONSIDERABLE INTEREST FOR THE UNDERSTANDING EFFECT OF STRESS IN DEPRESSION. DOPAMINE IS A KEY NEUROTRANSMITTER IMPORTANT IN MANY PHYSIOLOGICAL FUNCTIONS, INCLUDING MOTOR CONTROL, MOOD, AND THE REWARD PATHWAY. THESE FACTORS LEAD MANY DRUGS TO TARGET DOPAMINE RECEPTORS IN TREATING DEPRESSIVE DISORDERS. IN THIS REVIEW, WE TRY TO PORTRAY HOW CHRONIC STRESS AS AN EPIGENETIC FACTOR CHANGES THE GENE REGULATION PATTERN BY INTERRUPTING DOPAMINE SIGNALING MECHANISM. 2013 5 5828 36 STRESS, EPIGENETICS, AND ALCOHOLISM. ACUTE AND CHRONIC STRESSORS HAVE BEEN ASSOCIATED WITH ALTERATIONS IN MOOD AND INCREASED ANXIETY THAT MAY EVENTUALLY RESULT IN THE DEVELOPMENT OF STRESS-RELATED PSYCHIATRIC DISORDERS. STRESS AND ASSOCIATED DISORDERS, INCLUDING ANXIETY, ARE KEY FACTORS IN THE DEVELOPMENT OF ALCOHOLISM BECAUSE ALCOHOL CONSUMPTION CAN TEMPORARILY REDUCE THE DRINKER'S DYSPHORIA. ONE MOLECULE THAT MAY HELP MEDIATE THE RELATIONSHIP BETWEEN STRESS AND ALCOHOL CONSUMPTION IS BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), A PROTEIN THAT REGULATES THE STRUCTURE AND FUNCTION OF THE SITES WHERE TWO NERVE CELLS INTERACT AND EXCHANGE NERVE SIGNALS (I.E., SYNAPSES) AND WHICH IS INVOLVED IN NUMEROUS PHYSIOLOGICAL PROCESSES. ABERRANT REGULATION OF BDNF SIGNALING AND ALTERATIONS IN SYNAPSE ACTIVITY (I.E., SYNAPTIC PLASTICITY) HAVE BEEN ASSOCIATED WITH THE PATHOPHYSIOLOGY OF STRESS-RELATED DISORDERS AND ALCOHOLISM. MECHANISMS THAT CONTRIBUTE TO THE REGULATION OF GENETIC INFORMATION WITHOUT MODIFICATION OF THE DNA SEQUENCE (I.E., EPIGENETIC MECHANISMS) MAY PLAY A ROLE IN THE COMPLEX CONTROL OF BDNF SIGNALING AND SYNAPTIC PLASTICITY-FOR EXAMPLE, BY MODIFYING THE STRUCTURE OF THE DNA-PROTEIN COMPLEXES (I.E., CHROMATIN) THAT MAKE UP THE CHROMOSOMES AND THEREBY MODULATING THE EXPRESSION OF CERTAIN GENES. STUDIES REGARDING THE EPIGENETIC CONTROL OF BDNF SIGNALING AND SYNAPTIC PLASTICITY PROVIDE A PROMISING DIRECTION TO UNDERSTAND THE MECHANISMS MEDIATING THE INTERACTION BETWEEN STRESS AND ALCOHOLISM. 2012 6 6174 37 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 7 3708 29 INFLUENCE OF PHARMACOLOGICAL AND EPIGENETIC FACTORS TO SUPPRESS NEUROTROPHIC FACTORS AND ENHANCE NEURAL PLASTICITY IN STRESS AND MOOD DISORDERS. STRESS-INDUCED MAJOR DEPRESSION AND MOOD DISORDERS ARE CHARACTERIZED BY BEHAVIOURAL ABNORMALITIES AND PSYCHIATRIC ILLNESS, LEADING TO DISABILITY AND IMMATURE MORTALITY WORLDWIDE. NEUROBIOLOGICAL MECHANISMS OF STRESS AND MOOD DISORDERS ARE DISCUSSED CONSIDERING RECENT FINDINGS, AND CHALLENGES TO ENHANCE PHARMACOLOGICAL EFFECTS OF ANTIDEPRESSANT, AND MOOD STABILIZERS. PHARMACOLOGICAL ENHANCEMENT OF KETAMINE AND SCOPOLAMINE REGULATES DEPRESSION AT THE MOLECULAR LEVEL, INCREASING SYNAPTIC PLASTICITY IN PREFRONTAL REGIONS. BLOOD-DERIVED NEUROTROPHIC FACTORS FACILITATE MOOD-DEFICIT SYMPTOMS. EPIGENETIC FACTORS MAINTAIN STRESS-RESILIENCE IN HIPPOCAMPAL REGION. REGULATION OF NEUROTROPHIC FACTORS BLOCKADES STRESS, AND ENHANCES NEURONAL SURVIVAL THOUGH IT PARALYZES LIMBIC REGIONS. MOLECULAR AGENTS AND NEUROTROPHIC FACTORS ALSO CONTROL BEHAVIORAL AND SYNAPTIC PLASTICITY IN ADDICTION AND STRESS DISORDERS. FUTURE RESEARCH ON NEURONAL DYNAMICS AND CELLULAR ACTIONS CAN BE DIRECTED TO OBTAIN THE ETIOLOGY OF SYNAPTIC DYSREGULATION IN MOOD DISORDER AND STRESS. FOR THE FIRST TIME, THE CURRENT REVIEW CONTRIBUTES TO THE LITERATURE OF SYNAPTIC PLASTICITY REPRESENTING THE ROLE OF EPIGENETIC MECHANISMS AND GLUCOCORTICOID RECEPTORS TO PREDICT DEPRESSION AND ANXIETY IN CLINICAL CONDITIONS. 2019 8 534 33 ASTROGLIA IN THE VULNERABILITY TO AND MAINTENANCE OF STRESS-MEDIATED NEUROPATHOLOGY AND DEPRESSION. SIGNIFICANT STRESS EXPOSURE AND PSYCHIATRIC DEPRESSION ARE ASSOCIATED WITH MORPHOLOGICAL, BIOCHEMICAL, AND PHYSIOLOGICAL DISTURBANCES OF ASTROCYTES IN SPECIFIC BRAIN REGIONS RELEVANT TO THE PATHOPHYSIOLOGY OF THOSE DISORDERS, SUGGESTING THAT ASTROCYTES ARE INVOLVED IN THE MECHANISMS UNDERLYING THE VULNERABILITY TO OR MAINTENANCE OF STRESS-RELATED NEUROPATHOLOGY AND DEPRESSION. TO UNDERSTAND THOSE MECHANISMS A VARIETY OF STUDIES HAVE PROBED THE EFFECT OF VARIOUS MODALITIES OF STRESS EXPOSURE ON THE METABOLISM, GENE EXPRESSION AND PLASTICITY OF ASTROCYTES. THESE STUDIES HAVE UNCOVERED THE PARTICIPATION OF VARIOUS CELLULAR PATHWAYS, SUCH AS THOSE FOR INTRACELLULAR CALCIUM REGULATION, NEUROIMMUNE RESPONSES, EXTRACELLULAR IONIC REGULATION, GAP JUNCTIONS-BASED CELLULAR COMMUNICATION, AND REGULATION OF NEUROTRANSMITTER AND GLIOTRANSMITTER RELEASE AND UPTAKE. MORE RECENTLY EPIGENETIC MODIFICATIONS RESULTING FROM EXPOSURE TO CHRONIC FORMS OF STRESS OR TO EARLY LIFE ADVERSITY HAVE BEEN SUGGESTED TO AFFECT NOT ONLY NEURONAL MECHANISMS BUT ALSO GENE EXPRESSION AND PHYSIOLOGY OF ASTROCYTES AND OTHER GLIAL CELLS. HOWEVER, MUCH REMAINS TO BE LEARNED TO UNDERSTAND THE SPECIFIC ROLE OF THOSE AND OTHER MODIFICATIONS IN THE ASTROGLIAL CONTRIBUTION TO THE VULNERABILITY TO AND MAINTENANCE OF STRESS-RELATED DISORDERS AND DEPRESSION, AND FOR LEVERAGING THAT KNOWLEDGE TO ACHIEVE MORE EFFECTIVE PSYCHIATRIC THERAPIES. 2022 9 4642 34 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 10 4420 27 MOLECULAR AND EPIGENETIC MECHANISMS FOR THE COMPLEX EFFECTS OF STRESS ON SYNAPTIC PHYSIOLOGY AND COGNITIVE FUNCTIONS. EVIDENCE OVER THE PAST DECADES HAS FOUND THAT STRESS, PARTICULARLY THROUGH THE CORTICOSTERONE STRESS HORMONES, PRODUCES COMPLEX CHANGES IN GLUTAMATERGIC SIGNALING IN PREFRONTAL CORTEX, WHICH LEADS TO THE ALTERATION OF COGNITIVE PROCESSES MEDICATED BY THIS BRAIN REGION. INTERESTINGLY, THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION APPEAR TO BE "U-SHAPED," DEPENDING UPON THE DURATION AND SEVERITY OF THE STRESSOR. THESE BIPHASIC EFFECTS OF ACUTE VS CHRONIC STRESS REPRESENT THE ADAPTIVE VS MALADAPTIVE RESPONSES TO STRESSFUL STIMULI. ANIMAL STUDIES SUGGEST THAT THE STRESS-INDUCED MODULATION OF EXCITATORY SYNAPTIC TRANSMISSION INVOLVES CHANGES IN PRESYNAPTIC GLUTAMATE RELEASE, POSTSYNAPTIC GLUTAMATE RECEPTOR MEMBRANE TRAFFICKING AND DEGRADATION, SPINE STRUCTURE AND CYTOSKELETON NETWORK, AND EPIGENETIC CONTROL OF GENE EXPRESSION. THIS REVIEW WILL DISCUSS CURRENT FINDINGS ON THE KEY MOLECULES INVOLVED IN THE STRESS-INDUCED REGULATION OF PREFRONTAL CORTEX SYNAPTIC PHYSIOLOGY AND PREFRONTAL CORTEX-MEDIATED FUNCTIONS. UNDERSTANDING THE MOLECULAR AND EPIGENETIC MECHANISMS THAT UNDERLIE THE COMPLEX EFFECTS OF STRESS WILL HELP TO DEVELOP NOVEL STRATEGIES TO COPE WITH STRESS-RELATED MENTAL DISORDERS. 2017 11 2598 32 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 12 4206 33 METABOTROPIC GLUTAMATE 2/3 RECEPTORS AND EPIGENETIC MODIFICATIONS IN PSYCHOTIC DISORDERS: A REVIEW. SCHIZOPHRENIA AND BIPOLAR DISORDER ARE CHRONIC PSYCHIATRIC DISORDERS, BOTH CONSIDERED AS "MAJOR PSYCHOSIS"; THEY ARE THOUGHT TO SHARE SOME PATHOGENETIC FACTORS INVOLVING A DYSFUNCTIONAL GENE X ENVIRONMENT INTERACTION. ALTERATIONS IN THE GLUTAMATERGIC TRANSMISSION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF PSYCHOSIS. OUR GROUP DEVELOPED AN EPIGENETIC MODEL OF SCHIZOPHRENIA ORIGINATED BY PRENATAL RESTRAINT STRESS (PRS) PARADIGM IN MICE. PRS MICE DEVELOPED SOME BEHAVIORAL ALTERATIONS OBSERVED IN SCHIZOPHRENIC PATIENTS AND CLASSIC ANIMAL MODELS OF SCHIZOPHRENIA, I.E. DEFICITS IN SOCIAL INTERACTION, LOCOMOTOR ACTIVITY AND PREPULSE INHIBITION. THEY ALSO SHOWED SPECIFIC CHANGES IN PROMOTER DNA METHYLATION ACTIVITY OF GENES RELATED TO SCHIZOPHRENIA SUCH AS REELIN, BDNF AND GAD67, AND ALTERED EXPRESSION AND FUNCTION OF MGLU2/3 RECEPTORS IN THE FRONTAL CORTEX. INTERESTINGLY, BEHAVIORAL AND MOLECULAR ALTERATIONS WERE REVERSED BY TREATMENT WITH MGLU2/3 AGONISTS. BASED ON THESE FINDINGS, WE SPECULATE THAT PHARMACOLOGICAL MODULATION OF THESE RECEPTORS COULD HAVE A GREAT IMPACT ON EARLY PHASE TREATMENT OF PSYCHOSIS TOGETHER WITH THE POSSIBILITY TO MODULATE SPECIFIC EPIGENETIC KEY PROTEIN INVOLVED IN THE DEVELOPMENT OF PSYCHOSIS. IN THIS REVIEW, WE WILL DISCUSS IN MORE DETAILS THE SPECIFIC FEATURES OF THE PRS MICE AS A SUITABLE EPIGENETIC MODEL FOR MAJOR PSYCHOSIS. WE WILL THEN FOCUS ON KEY PROTEINS OF CHROMATIN REMODELING MACHINERY AS POTENTIAL TARGET FOR NEW PHARMACOLOGICAL TREATMENT THROUGH THE ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS. 2016 13 4625 42 NEUROBIOLOGY OF VITAMIN C: EXPANDING THE FOCUS FROM ANTIOXIDANT TO ENDOGENOUS NEUROMODULATOR. ASCORBIC ACID (AA) IS A WATER-SOLUBLE VITAMIN (C) FOUND IN ALL BODILY ORGANS. MOST MAMMALS SYNTHESIZE IT, HUMANS ARE REQUIRED TO EAT IT, BUT ALL MAMMALS NEED IT FOR HEALTHY FUNCTIONING. AA REACHES ITS HIGHEST CONCENTRATION IN THE BRAIN WHERE BOTH NEURONS AND GLIA RELY ON TIGHTLY REGULATED UPTAKE FROM BLOOD VIA THE GLUCOSE TRANSPORT SYSTEM AND SODIUM-COUPLED ACTIVE TRANSPORT TO ACCUMULATE AND MAINTAIN AA AT MILLIMOLAR LEVELS. AS A PROTOTYPE ANTIOXIDANT, AA IS NOT ONLY NEUROPROTECTIVE, BUT ALSO FUNCTIONS AS A COFACTOR IN REDOX-COUPLED REACTIONS ESSENTIAL FOR THE SYNTHESIS OF NEUROTRANSMITTERS (E.G., DOPAMINE AND NOREPINEPHRINE) AND PARACRINE LIPID MEDIATORS (E.G., EPOXIECOISATRIENOIC ACIDS) AS WELL AS THE EPIGENETIC REGULATION OF DNA. ALTHOUGH REDOX CAPACITY LED TO THE PROMOTION OF AA IN HIGH DOSES AS POTENTIAL TREATMENT FOR VARIOUS NEUROPATHOLOGICAL AND PSYCHIATRIC CONDITIONS, AMPLE EVIDENCE HAS NOT SUPPORTED THIS THERAPEUTIC STRATEGY. HERE, WE FOCUS ON SOME LONG-NEGLECTED ASPECTS OF AA NEUROBIOLOGY, INCLUDING ITS MODULATORY ROLE IN SYNAPTIC TRANSMISSION AS DEMONSTRATED BY THE LONG-ESTABLISHED LINK BETWEEN RELEASE OF ENDOGENOUS AA IN BRAIN EXTRACELLULAR FLUID AND THE CLEARANCE OF GLUTAMATE, AN EXCITATORY AMINO ACID. EVIDENCE THAT THIS LINK CAN BE DISRUPTED IN ANIMAL MODELS OF HUNTINGTON S DISEASE IS REVEALING OPPORTUNITIES FOR NEW RESEARCH PATHWAYS AND THERAPEUTIC APPLICATIONS (E.G., EPILEPSY AND PAIN MANAGEMENT). IN FACT, WE SUGGEST THAT IMPROVED UNDERSTANDING OF THE REGULATION OF ENDOGENOUS AA AND ITS INTERACTION WITH KEY BRAIN NEUROTRANSMITTER SYSTEMS, RATHER THAN ADMINISTRATION OF AA IN EXCESS, SHOULD BE THE TARGET OF FUTURE BRAIN-BASED THERAPIES. 2019 14 310 41 ALCOHOL AND NMDA RECEPTOR: CURRENT RESEARCH AND FUTURE DIRECTION. THE BRAIN IS ONE OF THE MAJOR TARGETS OF ALCOHOL ACTIONS. MOST OF THE EXCITATORY SYNAPTIC TRANSMISSION IN THE CENTRAL NERVOUS SYSTEM IS MEDIATED BY N-METHYL-D-ASPARTATE (NMDA) RECEPTORS. HOWEVER, ONE OF THE MOST DEVASTATING EFFECTS OF ALCOHOL LEADS TO BRAIN SHRINKAGE, LOSS OF NERVE CELLS AT SPECIFIC REGIONS THROUGH A MECHANISM INVOLVING EXCITOTOXICITY, OXIDATIVE STRESS. EARLIER STUDIES HAVE INDICATED THAT CHRONIC EXPOSURE TO ETHANOL BOTH IN VIVO AND IN VITRO, INCREASES NR1 AND NR2B GENE EXPRESSION AND THEIR POLYPEPTIDE LEVELS. THE EFFECT OF ALCOHOL AND MOLECULAR CHANGES ON THE REGULATORY PROCESS, WHICH MODULATES NMDAR FUNCTIONS INCLUDING FACTORS ALTERING TRANSCRIPTION, TRANSLATION, POST-TRANSLATIONAL MODIFICATIONS, AND PROTEIN EXPRESSION, AS WELL AS THOSE INFLUENCING THEIR INTERACTIONS WITH DIFFERENT REGULATORY PROTEINS (DOWNSTREAM EFFECTORS) ARE INCESSANTLY INCREASING AT THE CELLULAR LEVEL. FURTHER, I DISCUSS THE VARIOUS GENETICALLY ALTERED MICE APPROACHES THAT HAVE BEEN USED TO STUDY NMDA RECEPTOR SUBUNITS AND THEIR FUNCTIONAL IMPLICATION. IN A RECENT COUNTABLE REVIEW, EPIGENETIC DIMENSION (I.E., HISTONE MODIFICATION-INDUCED CHROMATIN REMODELING AND DNA METHYLATION, IN THE PROCESS OF ALCOHOL RELATED NEUROADAPTATION) IS ONE OF THE KEY MOLECULAR MECHANISMS IN ALCOHOL MEDIATED NMDAR ALTERATION. HERE, I PROVIDE A RECOUNT ON WHAT HAS ALREADY BEEN ACHIEVED, CURRENT TRENDS AND HOW THE FUTURE RESEARCH/STUDIES OF THE NMDA RECEPTOR MIGHT LEAD TO EVEN GREATER ENGAGEMENT WITH MANY POSSIBLE NEW INSIGHTS INTO THE NEUROBIOLOGY AND TREATMENT OF ALCOHOLISM. 2013 15 4654 36 NEUROSTEROIDS (ALLOPREGNANOLONE) AND ALCOHOL USE DISORDER: FROM MECHANISMS TO POTENTIAL PHARMACOTHERAPY. ALCOHOL USE DISORDER (AUD) IS A MULTIFACETED RELAPSING DISORDER THAT IS COMMONLY COMORBID WITH PSYCHIATRIC DISORDERS, INCLUDING ANXIETY. ALCOHOL EXPOSURE PRODUCES A PLETHORA OF EFFECTS ON NEUROBIOLOGY. CURRENTLY, THERAPEUTIC STRATEGIES ARE LIMITED, AND ONLY A FEW TREATMENTS - DISULFIRAM, ACAMPROSATE, AND NALTREXONE - ARE AVAILABLE. GIVEN THE COMPLEXITY OF THIS DISORDER, THERE IS A GREAT NEED FOR THE IDENTIFICATION OF NOVEL TARGETS TO DEVELOP NEW PHARMACOTHERAPY. THE GABAERGIC SYSTEM, THE PRIMARY INHIBITORY SYSTEM IN THE BRAIN, IS ONE OF THE WELL-KNOWN TARGETS FOR ALCOHOL AND IS RESPONSIBLE FOR THE ANXIOLYTIC EFFECTS OF ALCOHOL. INTERESTINGLY, GABAERGIC NEUROTRANSMISSION IS FINE-TUNED BY NEUROACTIVE STEROIDS THAT EXERT A REGULATORY ROLE ON SEVERAL ENDOCRINE SYSTEMS INVOLVED IN NEUROPSYCHIATRIC DISORDERS INCLUDING AUD. MOUNTING EVIDENCE INDICATES THAT ALCOHOL ALTERS THE BIOSYNTHESIS OF NEUROSTEROIDS, WHEREAS ACUTE ALCOHOL INCREASES AND CHRONIC ALCOHOL DECREASES ALLOPREGNANOLONE LEVELS. OUR RECENT WORK HIGHLIGHTED THAT CHRONIC ALCOHOL-INDUCED CHANGES IN NEUROSTEROID LEVELS ARE MEDIATED BY EPIGENETIC MODIFICATIONS, E.G., DNA METHYLATION, AFFECTING KEY ENZYMES INVOLVED IN NEUROSTEROID BIOSYNTHESIS. THESE CHANGES WERE ASSOCIATED WITH CHANGES IN GABA(A) RECEPTOR SUBUNIT EXPRESSION, SUGGESTING AN IMBALANCE BETWEEN EXCITATORY AND INHIBITORY SIGNALING IN AUD. THIS REVIEW WILL RECAPITULATE THE ROLE OF NEUROSTEROIDS IN THE REGULATION OF THE NEUROENDOCRINE SYSTEM, HIGHLIGHT THEIR ROLE IN THE OBSERVED ALLOSTATIC LOAD IN AUD, AND DEVELOP A FRAMEWORK FROM MECHANISMS TO POTENTIAL PHARMACOTHERAPY. 2022 16 6775 31 [ALCOHOL DEPENDENCE MEDIATED BY MONOAMINE NEUROTRANSMITTERS IN THE CENTRAL NERVOUS SYSTEM]. ALCOHOL DEPENDENCE, A CHRONIC RELAPSING BRAIN DISEASE WITH THE CHARACTERISTICS OF DRINKING ALCOHOL OUT OF CONTROL, HAS BECOME A SERIOUS SOCIAL PROBLEM. MONOAMINE NEUROTRANSMITTERS, MAINLY INCLUDING DOPAMINE AND 5-HYDROXYTRYP NOTTAMINE, PLAY IMPORTANT ROLES IN THE OCCURRENCE, DEVELOPMENT AND NEURAL DYSFUNCTION OF ALCOHOL DEPENDENCE SYNDROME. IN THIS REVIEW, THE ROLES OF KEY FACTORS OF THE MONOAMINE SYSTEM (DOPAMINE RECEPTOR GENES, 5-HYDROXYTRYPTAMINE RECEPTOR GENES, TRANSPORTER GENES, TYROSINE HYDROXYLASE GENE, TRYPTOPHANHYDROXYLASE GENE AND MONOAMINE OXIDASE GENE) IN ALCOHOL DEPENDENCE WERE DISCUSSED, AND STRATEGIES FOR FURTHER STUDIES OF MOLECULAR MECHANISMS WERE PROPOSED BASED ON GENE KNOCKOUT MICE MODELS GENERATED IN OUR LABORATORY. THEN, COMBINING WITH STUDIES ON TYROSINE HYDROXYLASE ACTIVATOR CAMKII IN OUR LAB, THERAPEUTIC TARGETS WERE DISCUSSED. BESIDES, EPIGENETIC STRATEGIES FOR PREVENTION AND TREATMENT OF ALCOHOL DEPENDENCE SYNDROME WERE PROPOSED. FURTHERMORE, MANIPULATING METHYLATION LEVELS IN GENE REGULATORY REGIONS AND ALTERNATIVE SPLICING OF PRE-MRNAS MIGHT ALSO HAVE CLINICAL IMPLICATIONS. FINALLY, BASED ON NEW FINDINGS ON GENETIC POLYMORPHISM, IT IS OF GREAT POTENTIAL TO CARRY OUT INDIVIDUAL PREVENTION AND TREATMENT FOR PATIENTS SUFFERING FROM ALCOHOL DEPENDENCE. 2014 17 4648 41 NEUROPEPTIDE Y IN ALCOHOL ADDICTION AND AFFECTIVE DISORDERS. NEUROPEPTIDE Y (NPY), A NEUROPEPTIDE HIGHLY CONSERVED THROUGHOUT EVOLUTION, IS PRESENT AT HIGH LEVELS IN THE CENTRAL NERVOUS SYSTEM (CNS), AS WELL AS IN PERIPHERAL TISSUES SUCH AS THE GUT AND CARDIOVASCULAR SYSTEM. THE PEPTIDE EXERTS ITS EFFECTS VIA MULTIPLE RECEPTOR SUBTYPES, ALL BELONGING TO THE G-PROTEIN-COUPLED RECEPTOR SUPERFAMILY. OF THESE SUBTYPES, THE Y1 AND THE Y2 ARE THE MOST THOROUGHLY CHARACTERIZED, FOLLOWED BY THE Y5 SUBTYPE. NPY AND ITS RECEPTORS HAVE BEEN SHOWN TO BE OF IMPORTANCE IN CENTRAL REGULATION OF EVENTS UNDERLYING, FOR EXAMPLE, AFFECTIVE DISORDERS, DRUG/ALCOHOL USE DISORDERS, AND ENERGY HOMEOSTASIS. FURTHERMORE, WITHIN THE CNS, NPY ALSO AFFECTS SLEEP REGULATION AND CIRCADIAN RHYTHM, MEMORY FUNCTION, TISSUE GROWTH, AND PLASTICITY. THE POTENTIAL ROLES OF NPY IN THE ETIOLOGY AND PATHOPHYSIOLOGY OF MOOD AND ANXIETY DISORDERS, AS WELL AS ALCOHOL USE DISORDERS, HAVE BEEN EXTENSIVELY STUDIED. THIS FOCUS WAS PROMPTED BY EARLY INDICATIONS FOR AN INVOLVEMENT OF NPY IN ACUTE RESPONSES TO STRESS, AND, LATER, ALSO DATA POINTING TO A ROLE IN ALTERATIONS WITHIN THE CNS DURING CHRONIC, OR REPEATED, EXPOSURE TO ADVERSE EVENTS. THESE FUNCTIONS OF NPY, IN ADDITION TO THE PEPTIDE'S REGULATION OF DISEASE STATES, SUGGEST THAT MODULATION OF THE ACTIVITY OF THE NPY SYSTEM VIA RECEPTOR AGONISTS/ANTAGONISTS MAY BE A PUTATIVE TREATMENT MECHANISM IN AFFECTIVE DISORDERS AS WELL AS ALCOHOL USE DISORDERS. IN THIS REVIEW, WE PRESENT AN OVERVIEW OF FINDINGS WITH REGARD TO THE NPY SYSTEM IN RELATION TO ANXIETY AND STRESS, ACUTE AS WELL AS CHRONIC; FURTHERMORE WE DISCUSS POST-TRAUMATIC STRESS DISORDER AND, IN PART DEPRESSION. IN ADDITION, WE SUMMARIZE FINDINGS ON ALCOHOL USE DISORDERS AND RELATED BEHAVIORS. FINALLY, WE BRIEFLY TOUCH UPON GENETIC AS WELL AS EPIGENETIC MECHANISMS THAT MAY BE OF IMPORTANCE FOR NPY FUNCTION AND REGULATION. IN CONCLUSION, WE SUGGEST THAT MODULATION OF NPY-ERGIC ACTIVITY WITHIN THE CNS, VIA LIGANDS AIMED AT DIFFERENT RECEPTOR SUBTYPES, MAY BE ATTRACTIVE TARGETS FOR TREATMENT DEVELOPMENT FOR AFFECTIVE DISORDERS, AS WELL AS FOR ALCOHOL USE DISORDERS. 2017 18 2058 23 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE ALCOHOLIC BRAIN. CHRONIC ALCOHOL EXPOSURE CAUSES WIDESPREAD CHANGES IN BRAIN GENE EXPRESSION IN HUMANS AND ANIMAL MODELS. MANY OF THESE CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THERE IS AN EMERGING APPRECIATION FOR THE ROLE OF EPIGENETIC PROCESSES IN ALCOHOL-INDUCED CHANGES IN BRAIN GENE EXPRESSION AND BEHAVIOR. FOR EXAMPLE, CHRONIC ALCOHOL EXPOSURE PRODUCES CHANGES IN DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION THAT AFFECT EXPRESSION OF MULTIPLE GENES IN VARIOUS TYPES OF BRAIN CELLS (I.E., NEURONS AND GLIA) AND CONTRIBUTE TO BRAIN PATHOLOGY AND BRAIN PLASTICITY ASSOCIATED WITH ALCOHOL ABUSE AND DEPENDENCE. DRUGS TARGETING THE EPIGENETIC "MASTER REGULATORS" ARE EMERGING AS POTENTIAL THERAPEUTICS FOR NEURODEGENERATIVE DISORDERS AND DRUG ADDICTION. 2013 19 6414 34 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 20 2194 29 EPIGENETIC MODIFICATION IN NEUROPATHIC PAIN. NEUROPATHIC PAIN IS CHARACTERIZED BY COMPLICATED COMBINATION OF POSITIVE (E.G., HYPERALGESIA AND ALLODYNIA) AND NEGATIVE (E.G., HYPOESTHESIA AND HYPOALGESIA) SYMPTOMS, AND IS OFTEN REFRACTORY TO CONVENTIONAL PHARMACOLOGICAL AGENTS, INCLUDING MORPHINE. ALTHOUGH THE MOLECULAR MECHANISMS FOR POSITIVE SYMPTOMS ARE EXTENSIVELY STUDIED, THOSE FOR NEGATIVE SYMPTOMS ARE POORLY UNDERSTOOD. THERE IS CONVINCING EVIDENCE THAT ALTERED GENE EXPRESSION WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS IS A KEY MECHANISM FOR NEUROPATHIC PAIN; HOWEVER, ITS TRANSCRIPTIONAL MECHANISMS ARE POORLY UNDERSTOOD. EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS (E.G., ACETYLATION, METHYLATION, AND PHOSPHORYLATION), ARE KNOWN TO CAUSE STABLE GENE EXPRESSION VIA CHROMATIN REMODELING. THESE MECHANISMS HAVE A ROLE NOT ONLY IN THE DETERMINATION OF DEVELOPMENTAL CELL FATES, BUT ALSO IN THE PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES IN NERVOUS SYSTEM. MOREOVER, EPIGENETIC THERAPIES USING EPIGENETIC MODIFYING COMPOUNDS ARE PROGRESSIVELY ADVANCED IN THE TREATMENTS OF DIVERSE DISEASES, INCLUDING CANCER AND NEUROLOGICAL DISEASES. IMPORTANTLY, THERE IS EMERGING EVIDENCE THAT A VARIETY OF GENES UNDERGO EPIGENETIC REGULATION VIA DNA METHYLATION AND HISTONE MODIFICATIONS WITHIN PERIPHERAL AND CENTRAL NERVOUS SYSTEMS, THEREBY CONTRIBUTING TO THE ALTERATIONS IN BOTH PAIN SENSITIVITY AND PHARMACOLOGICAL EFFICACY IN NEUROPATHIC PAIN. IN THIS REVIEW, WE WILL HIGHLIGHT THE EPIGENETIC GENE REGULATION UNDERLYING NEUROPATHIC PAIN, ESPECIALLY FOCUSING ON THE NEGATIVE SYMPTOMS. MOREOVER, WE WILL DISCUSS WHETHER EPIGENETIC MECHANISMS CAN SERVE AS A POTENTIAL TARGET TO TREAT NEUROPATHIC PAIN. 2015