1 4206 135 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 2 6174 46 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 3 4642 43 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 4 2598 35 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 5 110 35 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 6 6414 43 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 7 5828 35 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 8 534 31 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 4420 37 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 10 6097 18 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 11 2963 27 GENETIC AND EPIGENETIC MECHANISMS LINKING PAIN AND PSYCHIATRIC DISORDERS. THE NEUROPHYSIOLOGICAL LINK BETWEEN NEUROPATHIC PAIN AND DEPRESSION REMAINS UNKNOWN DESPITE EVIDENT HIGH COMORBIDITY OF THESE TWO DISORDERS. HOWEVER, THERE IS CONVINCING EVIDENCE THAT GENOTYPE PLAYS A ROLE IN BOTH PAIN AND DEPRESSION. USING VARIOUS TYPES OF GENETIC ANALYSIS - POPULATION GENETICS, CYTOGENETICS AND MOLECULAR TECHNOLOGIES - SPECIFIC GENES HAVE BEEN IMPLICATED IN MEDIATING ALMOST ALL ASPECTS OF NOCICEPTION AND MOOD DISORDERS. THE CURRENT REVIEW ATTEMPTS TO IDENTIFY SPECIFIC GENES AND EPIGENETIC MECHANISMS COMMON TO BOTH DISORDERS. IT IS CONCLUDED THAT EXTERNAL AND INTERNAL FACTORS (INFLAMMATION, STRESS, GENDER, ETC.) THAT CONTRIBUTE TO THE PATHOLOGIES MAY DO SO THROUGH EPIGENETIC MECHANISMS THAT MAY AFFECT EXPRESSION OF THESE PARTICULAR GENES. THE POSSIBLE INVOLVEMENT OF EPIGENETIC REGULATION IN PAIN AND PSYCHIATRIC DISORDERS SUGGESTS THAT TREATMENTS TARGETING EPIGENETIC MECHANISMS THAT MEDIATE ADVERSE LIFE EVENTS SHOULD BE CONSIDERED. 2015 12 1981 40 EPIGENETIC ALTERATIONS IN DNA AND HISTONE MODIFICATIONS CAUSED BY DEPRESSION AND ANTIDEPRESSANT DRUGS: LESSONS FROM THE RODENT MODELS. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN FOLDING AND FUNCTION. EPIGENETIC MECHANISMS REGULATE TRANSCRIPTION MEDIATING EFFECTS OF VARIOUS STIMULI ON GENE EXPRESSION. THESE MECHANISMS ARE INVOLVED IN TRANSCRIPTIONAL CONTROL IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS INCLUDING NEUROPSYCHIATRIC DISORDERS AND BEHAVIORAL ABNORMALITIES SUCH AS DEPRESSION. IN RODENTS, EXPOSURE TO CHRONIC SOCIAL STRESS WAS SHOWN TO INDUCE BEHAVIORAL IMPAIRMENTS AND MEMORY/LEARNING DEFICITS THAT RESEMBLE DEPRESSIVE-LIKE PHENOTYPE IN HUMANS. THE RODENT MODELS OF CHRONIC STRESS WERE WIDELY USED TO STUDY MOLECULAR MECHANISMS OF DEPRESSION. IN THESE MODELS, EARLY EXPOSURE TO CHRONIC STRESS SUCH AS PRENATAL OR POSTNATAL STRESS INDUCES LONG-TERM HYPERACTIVE STRESS RESPONSES, BEHAVIORAL ABNORMALITIES, AND FUNCTIONAL IMPAIRMENTS IN BRAIN FUNCTION THAT PERSIST IN ADULTHOOD. FURTHERMORE, THESE ALTERATIONS CAN BE TRANSMITTED TO OFFSPRING OF CHRONICALLY STRESSED ANIMALS ACROSS SEVERAL GENERATIONS. MOLECULAR STUDIES IN ANIMAL MODELS SHOWED THAT CHRONIC STRESS INDUCES STABLE EPIGENETIC CHANGES IN SPECIFIC BRAIN REGIONS, PRIMARILY IN THE LIMBIC SYSTEM. THESE CHANGES LEAD TO LONG-LASTING ABNORMALITIES IN BEHAVIOR THAT PERSIST IN ADULTHOOD AND CAN BE TRANSMITTED TO OFFSPRING. TREATMENT WITH EPIGENETICALLY ACTIVE ANTIDEPRESSANTS DISRUPTS THE ABNORMAL STRESS-INDUCED EPIGENETIC PROGRAMMING AND PROVIDES EPIGENETIC PATTERNS THAT RESEMBLE EPIGENETIC BACKGROUND OF STRESS RESILIENT INDIVIDUALS. 2017 13 6775 39 [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 14 6228 29 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016 15 6400 32 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 16 1796 44 EFFECT OF GERM-FREE STATUS ON TRANSCRIPTIONAL PROFILES IN THE NUCLEUS ACCUMBENS AND TRANSCRIPTOMIC RESPONSE TO CHRONIC MORPHINE. OPIOID USE DISORDER IS A PUBLIC HEALTH CRISIS THAT CAUSES TREMENDOUS SUFFERING FOR PATIENTS AS WELL AS SUBSTANTIAL SOCIAL AND ECONOMIC COSTS FOR SOCIETY. THERE ARE CURRENTLY AVAILABLE TREATMENTS FOR PATIENTS WITH OPIOID USE DISORDER, BUT THEY REMAIN INTOLERABLE OR INEFFECTIVE FOR MANY. THUS THE NEED TO DEVELOP NEW AVENUES FOR THERAPEUTICS DEVELOPMENT IN THIS SPACE IS GREAT. SUBSTANTIAL WORK IN MODELS OF SUBSTANCE USE DISORDERS, INCLUDING OPIOID USE DISORDER, DEMONSTRATES THAT PROLONGED EXPOSURE TO DRUGS OF ABUSE LEADS TO MARKED TRANSCRIPTIONAL AND EPIGENETIC DYSREGULATION IN LIMBIC SUBSTRUCTURES. IT IS WIDELY BELIEVED THAT THESE CHANGES IN GENE REGULATION IN RESPONSE TO DRUGS ARE A KEY DRIVING FACTOR IN THE PERPETUATION OF DRUG TAKING AND SEEKING BEHAVIORS. THUS, DEVELOPMENT OF INTERVENTIONS THAT COULD SHAPE TRANSCRIPTIONAL REGULATION IN RESPONSE TO DRUGS OF ABUSE WOULD BE OF HIGH VALUE. OVER THE PAST DECADE THERE HAS BEEN A SURGE IN RESEARCH DEMONSTRATING THAT THE RESIDENT BACTERIA OF THE GASTROINTESTINAL TRACT, COLLECTIVELY THE GUT MICROBIOME, CAN HAVE TREMENDOUS INFLUENCE ON NEUROBIOLOGICAL AND BEHAVIORAL PLASTICITY. PREVIOUS WORK FROM OUR GROUP AND OTHERS HAS DEMONSTRATED THAT ALTERATIONS IN THE GUT MICROBIOME CAN ALTER BEHAVIORAL RESPONSES TO OPIOIDS IN MULTIPLE PARADIGMS. ADDITIONALLY, WE HAVE PREVIOUSLY REPORTED THAT DEPLETION OF THE GUT MICROBIOME WITH ANTIBIOTICS MARKEDLY SHIFTS THE TRANSCRIPTOME OF THE NUCLEUS ACCUMBENS FOLLOWING PROLONGED MORPHINE EXPOSURE. IN THIS MANUSCRIPT WE PRESENT A COMPREHENSIVE ANALYSIS OF THE EFFECTS OF THE GUT MICROBIOME ON TRANSCRIPTIONAL REGULATION OF THE NUCLEUS ACCUMBENS FOLLOWING MORPHINE BY UTILIZING GERM-FREE, ANTIBIOTIC TREATED, AND CONTROL MICE. THIS ALLOWS FOR DETAILED UNDERSTANDING OF THE ROLE OF THE MICROBIOME IN REGULATING BASELINE TRANSCRIPTOMIC CONTROL, AS WELL AS RESPONSE TO MORPHINE. WE FIND THAT GERM-FREE STATUS LEADS TO A MARKED GENE DYSREGULATION IN A MANNER DISTINCT TO ADULT MICE TREATED WITH ANTIBIOTICS, AND THAT ALTERED GENE PATHWAYS ARE HIGHLY RELATED TO CELLULAR METABOLIC PROCESSES. THESE DATA PROVIDE ADDITIONAL INSIGHT INTO THE ROLE OF THE GUT MICROBIOME IN MODULATING BRAIN FUNCTION AND LAY A FOUNDATION FOR FURTHER STUDY IN THIS AREA. 2023 17 2011 44 EPIGENETIC BASIS OF MENTAL ILLNESS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION AS WELL AS LIKELY ABNORMALITIES IN GLIAL CELLS. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF MOST MENTAL DISORDERS, THE RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS, PARTICULARLY FOR DEPRESSION AND OTHER STRESS-RELATED SYNDROMES, CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. EXPOSURE TO SUCH ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL VERSUS ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND THE ABERRANT EPIGENETIC REGULATION THAT UNDERLIES THIS DYSREGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. HERE, WE PROVIDE A PROGRESS REPORT OF EPIGENETIC STUDIES OF THE THREE MAJOR PSYCHIATRIC SYNDROMES, DEPRESSION, SCHIZOPHRENIA, AND BIPOLAR DISORDER. WE REVIEW THE LITERATURE DERIVED FROM ANIMAL MODELS OF THESE DISORDERS AS WELL AS FROM STUDIES OF POSTMORTEM BRAIN TISSUE FROM HUMAN PATIENTS. WHILE EPIGENETIC STUDIES OF MENTAL ILLNESS REMAIN AT EARLY STAGES, UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY WITHIN SPECIFIC BRAIN REGIONS TO CAUSE LASTING CHANGES IN DISEASE SUSCEPTIBILITY AND PATHOPHYSIOLOGY IS REVEALING NEW INSIGHT INTO THE ETIOLOGY AND TREATMENT OF THESE CONDITIONS. 2016 18 2092 27 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 19 2058 26 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 20 1181 29 CONVERGENT ACTIONS OF STRESS AND STIMULANTS VIA EPIGENETIC REGULATION OF NEURAL CIRCUITRY. THE DORSAL STRIATUM INTEGRATES PRIOR AND CURRENT INFORMATION TO GUIDE APPROPRIATE DECISION-MAKING. CHRONIC STRESS AND STIMULANT EXPOSURE INTERFERES WITH DECISION-MAKING, AND CAN CONFER SIMILAR COGNITIVE AND BEHAVIORAL INFLEXIBILITIES. THIS REVIEW EXAMINES THE LITERATURE ON ACUTE AND CHRONIC REGULATION OF THE EPIGENOME BY STRESS AND STIMULANTS. RECENT EVIDENCE SUGGESTS THAT EXPOSURES TO STRESS AND STIMULANTS SHARE SIMILARITIES IN THE MANNERS IN WHICH THEY REGULATE THE DORSAL STRIATUM EPIGENOME THROUGH DNA METHYLATION, TRANSPOSABLE ELEMENT ACTIVITY, AND HISTONE POST-TRANSLATIONAL MODIFICATIONS. THESE FINDINGS SUGGEST THAT CHRONIC STRESS AND STIMULANT EXPOSURE LEADS TO THE ACCUMULATION OF EPIGENETIC MODIFICATIONS THAT IMPAIR IMMEDIATE AND FUTURE NEURON FUNCTION AND ACTIVITY. SUCH EPIGENETIC MECHANISMS REPRESENT POTENTIAL THERAPEUTIC TARGETS FOR AMELIORATING CONVERGENT SYMPTOMS OF STRESS AND ADDICTION. 2022