1 2235 102 EPIGENETIC MODIFICATIONS, ALCOHOLIC BRAIN AND POTENTIAL DRUG TARGETS. ACUTE AND CHRONIC ALCOHOL EXPOSURE EVIDENTLY INFLUENCES EPIGENETIC CHANGES, BOTH TRANSIENTLY AND PERMANENTLY, AND THESE CHANGES IN TURN INFLUENCE A VARIETY OF CELLS AND ORGAN SYSTEMS THROUGHOUT THE BODY. MANY OF THE ALCOHOL-INDUCED EPIGENETIC MODIFICATIONS CAN CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THE PERSISTENCE OF BEHAVIORAL CHANGES DEMONSTRATES THAT LONG-LASTING CHANGES IN GENE EXPRESSION, WITHIN PARTICULAR REGIONS OF THE BRAIN, MAY CONTRIBUTE IMPORTANTLY TO THE ADDICTION PHENOTYPE. THE RESEARCH ACTIVITIES OVER THE PAST YEARS HAVE DEMONSTRATED A CRUCIAL ROLE OF EPIGENETIC MECHANISMS IN CAUSING LONG LASTING AND TRANSIENT CHANGES IN THE EXPRESSION OF SEVERAL GENES IN DIVERSE TISSUES, INCLUDING BRAIN. THIS HAS STIMULATED RECENT RESEARCH WORK THAT IS AIMED AT CHARACTERIZING THE INFLUENCE OF EPIGENETIC REGULATORY EVENTS IN MEDIATING THE LONG LASTING AND TRANSIENT EFFECTS OF ALCOHOL ABUSE ON THE BRAIN IN HUMANS AND ANIMAL MODELS OF ALCOHOL ADDICTION. IN THIS STUDY, WE UPDATE OUR CURRENT UNDERSTANDING OF THE IMPACT OF ALCOHOL EXPOSURE ON EPIGENETIC MECHANISMS IN THE BRAIN AND REFURBISH THE KNOWLEDGE OF EPIGENETICS IN THE DIRECTION OF NEW DRUGS DEVELOPMENT. 2016 2 2058 38 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 3 6886 34 [ROLE OF EPIGENETIC MODIFICATION IN HIGHER BRAIN DYSFUNCTION AND AGING]. EPIGENETIC MECHANISMS TYPICALLY INVOLVE HERITABLE ALTERATIONS IN CHROMATIN STRUCTURE, WHICH, IN TURN, REGULATE GENE EXPRESSION. FUNDAMENTAL INSIGHTS ABOUT EPIGENETIC HERITABILITY HAVE COME FROM STUDIES OF CELL DIVISION AND DEVELOPMENT. HOWEVER, THERE IS INCREASING EVIDENCE THAT THE REGULATION OF CHROMATIN STRUCTURE THROUGH HISTONE MODIFICATIONS AND DNA METHYLATION MIGHT MEDIATE THE EXPRESSION OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS. THIS IDEA IS FASCINATING BECAUSE SIMILAR MECHANISMS ARE USED FOR TRIGGERING AND STORING LONG-TERM MEMORIES AT THE CELLULAR LEVEL DURING, FOR EXAMPLE, HIGHER-BRAIN DYSFUNCTION, STRESS DISEASE, DRUG DEPENDENCE, AGING, AND CHRONIC PAIN. THIS REVIEW WILL EXPLORE THE MOST CURRENT ISSUES IN THE FIELD OF EPIGENETICS, WITH A FOCUS ON NEXT LEVELS OF TRANSCRIPTIONAL MECHANISMS UNDERLYING AGING, ENRICHED ENVIRONMENT AND DRUG ADDICTION. EPIGENETIC MECHANISMS, WHICH ARE KEY CELLULAR AND MOLECULAR PROCESSES THAT INTEGRATE DIVERSE ENVIRONMENTAL STIMULI TO EXERT POTENT AND OFTEN LONG-LASTING CHANGES IN GENE EXPRESSION THROUGH THE REGULATION OF CHROMATIN STRUCTURE, CONTRIBUTE TO TRANSCRIPTIONAL AND BEHAVIORAL CHANGES. 2012 4 6324 32 THE ROLE OF ALPHA-SYNUCLEIN IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. ALCOHOLISM HAS COMPLEX ETIOLOGY AND THERE IS EVIDENCE FOR BOTH GENETIC AND ENVIRONMENTAL FACTORS IN ITS PATHOPHYSIOLOGY. CHRONIC, LONG-TERM ALCOHOL ABUSE AND ALCOHOL DEPENDENCE ARE ASSOCIATED WITH NEURONAL LOSS WITH THE PREFRONTAL CORTEX BEING PARTICULARLY SUSCEPTIBLE TO NEUROTOXIC DAMAGE. THIS BRAIN REGION IS INVOLVED IN THE DEVELOPMENT AND PERSISTENCE OF ALCOHOL ADDICTION AND NEUROTOXIC DAMAGE IS LIKELY TO EXACERBATE THE REINFORCING EFFECTS OF ALCOHOL AND MAY HINDER TREATMENT. UNDERSTANDING THE MECHANISM OF ALCOHOL'S NEUROTOXIC EFFECTS ON THE BRAIN AND THE GENETIC RISK FACTORS ASSOCIATED WITH ALCOHOL ABUSE ARE THE FOCUS OF CURRENT RESEARCH. BECAUSE OF ITS WELL-ESTABLISHED ROLE IN NEURODEGENERATIVE AND NEUROPSYCHOLOGICAL DISORDERS, AND ITS EMERGING ROLE IN THE PATHOPHYSIOLOGY OF ADDICTION, HERE WE REVIEW THE GENETIC AND EPIGENETIC FACTORS INVOLVED IN REGULATING ALPHA-SYNUCLEIN EXPRESSION AND ITS POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC ALCOHOL ABUSE. ELUCIDATION OF THE MECHANISMS OF ALPHA-SYNUCLEIN REGULATION MAY PROVE BENEFICIAL IN UNDERSTANDING THE ROLE OF THIS KEY SYNAPTIC PROTEIN IN DISEASE AND ITS POTENTIAL FOR THERAPEUTIC MODULATION IN THE TREATMENT OF SUBSTANCE USE DISORDERS AS WELL AS OTHER NEURODEGENERATIVE DISEASES. 2013 5 2606 39 EPIGENETICS-BEYOND THE GENOME IN ALCOHOLISM. GENETIC AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF ALCOHOLISM. WHOLE-GENOME EXPRESSION PROFILING HAS HIGHLIGHTED THE IMPORTANCE OF SEVERAL GENES THAT MAY CONTRIBUTE TO ALCOHOL ABUSE DISORDERS. IN ADDITION, MORE RECENT FINDINGS HAVE ADDED YET ANOTHER LAYER OF COMPLEXITY TO THE OVERALL MOLECULAR MECHANISMS INVOLVED IN A PREDISPOSITION TO ALCOHOLISM AND ADDICTION BY DEMONSTRATING THAT PROCESSES RELATED TO GENETIC FACTORS THAT DO NOT MANIFEST AS DNA SEQUENCE CHANGES (I.E., EPIGENETIC PROCESSES) PLAY A ROLE. BOTH ACUTE AND CHRONIC ETHANOL EXPOSURE CAN ALTER GENE EXPRESSION LEVELS IN SPECIFIC NEURONAL CIRCUITS THAT GOVERN THE BEHAVIORAL CONSEQUENCES RELATED TO TOLERANCE AND DEPENDENCE. THE UNREMITTING CYCLE OF ALCOHOL CONSUMPTION OFTEN INCLUDES SATIATION AND SELF-MEDICATION WITH ALCOHOL, FOLLOWED BY EXCRUCIATING WITHDRAWAL SYMPTOMS AND THE RESULTANT RELAPSE, WHICH REFLECTS BOTH THE POSITIVE AND NEGATIVE AFFECTIVE STATES OF ALCOHOL ADDICTION. RECENT STUDIES HAVE INDICATED THAT BEHAVIORAL CHANGES INDUCED BY ACUTE AND CHRONIC ETHANOL EXPOSURE MAY INVOLVE CHROMATIN REMODELING RESULTING FROM COVALENT HISTONE MODIFICATIONS AND DNA METHYLATION IN THE NEURONAL CIRCUITS INVOLVING A BRAIN REGION CALLED THE AMYGDALA. THESE FINDINGS HAVE HELPED IDENTIFY ENZYMES INVOLVED IN EPIGENETIC MECHANISMS, SUCH AS THE HISTONE DEACETYLASE, HISTONE ACETYLTRANSFERASE, AND DNA METHYLTRANSFERASE ENZYMES, AS NOVEL THERAPEUTIC TARGETS FOR THE DEVELOPMENT OF FUTURE PHARMACOTHERAPIES FOR THE TREATMENT OF ALCOHOLISM. 2012 6 2292 32 EPIGENETIC REGULATION IN SUBSTANCE USE DISORDERS. SUBSTANCE USE DISORDER IS A CHRONIC CONDITION OF COMPULSIVE DRUG SEEKING AND USE THAT IS MEDIATED BY STABLE CHANGES IN CENTRAL REWARD PATHWAYS. REPEATED USE OF ABUSED DRUGS CAUSES PERSISTENT ALTERATIONS IN GENE EXPRESSION RESPONSIBLE FOR THE LONG-TERM BEHAVIORAL AND STRUCTURAL CHANGES. RECENTLY, IT HAS BEEN SUGGESTED THAT EPIGENETIC MECHANISMS ARE RESPONSIBLE IN PART FOR THESE DRUG-INDUCED CHANGES IN GENE EXPRESSION. ONE OF THE ALLURING ASPECTS OF EPIGENETIC REGULATION OF GENE EXPRESSION IS THAT EPIGENETIC MECHANISMS MAY PROVIDE TRANSIENT AND POTENTIALLY STABLE CONDITIONS THAT IN TURN MAY ULTIMATELY PARTICIPATE IN THE MOLECULAR MECHANISMS REQUIRED FOR NEURONAL CHANGES SUBSERVING LONG-LASTING CHANGES IN BEHAVIOR. THIS REVIEW DESCRIBES EPIGENETIC MECHANISMS OF GENE REGULATION AND THEN DISCUSSES THE EMERGING ROLE OF EPIGENETICS IN DRUG-INDUCED PLASTICITY AND BEHAVIOR. UNDERSTANDING THESE MECHANISMS THAT ESTABLISH AND MAINTAIN DRUG-DEPENDENT PLASTICITY CHANGES MAY LEAD TO DEEPER UNDERSTANDING OF SUBSTANCE USE DISORDERS AS WELL AS NOVEL APPROACHES TO TREATMENT. 2010 7 1870 46 EMERGING ROLE OF EPIGENETIC MECHANISMS IN ALCOHOL ADDICTION. ALCOHOL USE DISORDER (AUD) IS A COMPLEX BRAIN DISORDER WITH AN ARRAY OF PERSISTENT BEHAVIORAL AND NEUROCHEMICAL MANIFESTATIONS. BOTH GENETIC AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD, AND RECENT STUDIES ON ALCOHOL EXPOSURE AND SUBSEQUENT CHANGES IN GENE EXPRESSION SUGGEST THE IMPORTANCE OF EPIGENETIC MECHANISMS. IN PARTICULAR, HISTONE MODIFICATIONS AND DNA METHYLATION HAVE EMERGED AS IMPORTANT REGULATORS OF GENE EXPRESSION AND ASSOCIATED PHENOTYPES OF AUD. GIVEN THE THERAPEUTIC POTENTIAL OF EPIGENETIC TARGETS, THIS REVIEW AIMS TO SUMMARIZE THE ROLE OF EPIGENETIC REGULATION IN OUR CURRENT UNDERSTANDING OF AUD BY EVALUATING KNOWN EPIGENETIC SIGNATURES OF BRAIN REGIONS CRITICAL TO ADDICTIVE BEHAVIORS IN BOTH ANIMAL AND HUMAN STUDIES THROUGHOUT VARIOUS STAGES OF AUD. MORE SPECIFICALLY, THE EFFECTS OF ACUTE AND CHRONIC ALCOHOL EXPOSURE, TOLERANCE, AND POSTEXPOSURE WITHDRAWAL ON EPIGENETICALLY INDUCED CHANGES TO GENE EXPRESSION AND SYNAPTIC PLASTICITY WITHIN KEY BRAIN REGIONS AND THE ASSOCIATED BEHAVIORAL PHENOTYPES HAVE BEEN DISCUSSED. UNDERSTANDING THE CONTRIBUTION OF EPIGENETIC REGULATION TO CRUCIAL SIGNALING PATHWAYS MAY PROVE VITAL FOR FUTURE DEVELOPMENT OF NOVEL BIOMARKERS AND TREATMENT AGENTS IN AMELIORATING OR PREVENTING AUD. 2017 8 2598 34 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 9 2573 24 EPIGENETICS OF DRUG ABUSE: PREDISPOSITION OR RESPONSE. DRUG ADDICTION CONTINUES TO BE A SERIOUS MEDICAL AND SOCIAL PROBLEM. VULNERABILITY TO DEVELOP AN ADDICTION TO DRUGS IS DEPENDENT ON GENETIC, ENVIRONMENTAL, SOCIAL AND BIOLOGICAL FACTORS. IN PARTICULAR, THE INTERACTIONS OF ENVIRONMENTAL AND GENETIC FACTORS INDICATE THE SIGNIFICANCE OF EPIGENETIC MECHANISMS, WHICH HAVE BEEN FOUND TO OCCUR IN RESPONSE TO ILLICIT DRUG USE OR AS UNDERLYING FACTORS IN CHRONIC SUBSTANCE ABUSE AND RELAPSE. EPIGENETICS IS DEFINED AS THE HERITABLE AND POSSIBLY REVERSIBLE MODIFICATIONS IN GENE EXPRESSION THAT DO NOT INVOLVE ALTERATIONS IN THE DNA SEQUENCE. THIS REVIEW DISCUSSES THE VARIOUS TYPES OF EPIGENETIC MODIFICATIONS AND THEIR RELEVANCE TO DRUG ADDICTION TO ELUCIDATE WHETHER EPIGENETICS IS A PREDISPOSING FACTOR, OR A RESPONSE TO, DEVELOPING AN ADDICTION TO DRUGS OF ABUSE. 2012 10 2186 41 EPIGENETIC MECHANISMS UNDERLYING PATHOBIOLOGY OF ALCOHOL USE DISORDER. PURPOSE OF REVIEW: CHRONIC ALCOHOL USE IS A WORLDWIDE PROBLEM WITH MULTIFACETED CONSEQUENCES INCLUDING MULTIPLYING MEDICAL COSTS AND SEQUELAE, SOCIETAL EFFECTS LIKE DRUNK DRIVING AND ASSAULT, AND LOST ECONOMIC PRODUCTIVITY. THESE LARGE-SCALE OUTCOMES ARE DRIVEN BY THE CONSUMPTION OF ETHANOL, A SMALL PERMEABLE MOLECULE THAT HAS MYRIAD EFFECTS IN THE HUMAN BODY, PARTICULARLY IN THE LIVER AND BRAIN. IN THIS REVIEW, WE HAVE SUMMARIZED EFFECTS OF ACUTE AND CHRONIC ALCOHOL CONSUMPTION ON EPIGENETIC MECHANISMS THAT MAY DRIVE PATHOBIOLOGY OF ALCOHOL USE DISORDER (AUD) WHILE IDENTIFYING AREAS OF NEED FOR FUTURE RESEARCH. RECENT FINDINGS: EPIGENETICS HAS EMERGED AS AN INTERESTING FIELD OF BIOLOGY AT THE INTERSECTION OF GENETICS AND THE ENVIRONMENT, AND ETHANOL IN PARTICULAR HAS BEEN IDENTIFIED AS A POTENT MODULATOR OF THE EPIGENOME WITH VARIOUS EFFECTS ON DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNAS. THESE CHANGES ALTER CHROMATIN DYNAMICS AND REGULATE GENE EXPRESSION THAT CONTRIBUTE TO BEHAVIORAL AND PHYSIOLOGICAL CHANGES LEADING TO THE DEVELOPMENT OF AUD PSYCHOPATHOLOGY AND CANCER PATHOLOGY. SUMMARY: EVIDENCE AND DISCUSSION PRESENTED HERE FROM PRECLINICAL RESULTS AND AVAILABLE TRANSLATIONAL STUDIES HAVE INCREASED OUR KNOWLEDGE OF THE EPIGENETIC EFFECTS OF ALCOHOL CONSUMPTION. THESE STUDIES HAVE IDENTIFIED TARGETS THAT CAN BE USED TO DEVELOP BETTER THERAPIES TO REDUCE CHRONIC ALCOHOL ABUSE AND MITIGATE ITS SOCIETAL BURDEN AND PATHOPHYSIOLOGY. 2020 11 3398 31 HOW ALCOHOL DRINKING AFFECTS OUR GENES: AN EPIGENETIC POINT OF VIEW. THIS WORK HIGHLIGHTS RECENT STUDIES IN EPIGENETIC MECHANISMS THAT PLAY A ROLE IN ALCOHOLISM, WHICH IS A COMPLEX MULTIFACTORIAL DISORDER. THERE IS A LARGE BODY OF EVIDENCE SHOWING THAT ALCOHOL CAN MODIFY GENE EXPRESSION THROUGH EPIGENETIC PROCESSES, NAMELY DNA METHYLATION AND NUCLEOSOMAL REMODELING VIA HISTONE MODIFICATIONS. IN THAT REGARD, CHRONIC EXPOSURE TO ETHANOL MODIFIES DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION. THE ALCOHOL-MEDIATED CHROMATIN REMODELING IN THE BRAIN PROMOTES THE TRANSITION FROM USE TO ABUSE AND ADDICTION. UNRAVELLING THE MULTIPLEX PATTERN OF MOLECULAR MODIFICATIONS INDUCED BY ETHANOL COULD SUPPORT THE DEVELOPMENT OF NEW THERAPIES FOR ALCOHOLISM AND DRUG ADDICTION TARGETING EPIGENETIC PROCESSES. 2019 12 3376 30 HISTONE-MEDIATED EPIGENETICS IN ADDICTION. MANY OF THE BRAIN REGIONS, NEUROTRANSMITTER SYSTEMS, AND BEHAVIORAL CHANGES THAT OCCUR AFTER OCCASIONAL DRUG USE IN HEALTHY SUBJECTS AND AFTER CHRONIC DRUG ABUSE IN ADDICTED PATIENTS ARE WELL CHARACTERIZED. AN EMERGING LITERATURE SUGGESTS THAT EPIGENETIC PROCESSES, THOSE PROCESSES THAT REGULATE THE ACCESSIBILITY OF DNA TO REGULATORY PROTEINS WITHIN THE NUCLEUS, ARE KEYS TO HOW ADDICTION DEVELOPS AND HOW IT MAY BE TREATED. INVESTIGATIONS OF THE REGULATION OF CHROMATIN, THE ORGANIZATIONAL SYSTEM OF DNA, BY HISTONE MODIFICATION ARE LEADING TO A NEW UNDERSTANDING OF THE CELLULAR AND BEHAVIORAL ALTERATIONS THAT OCCUR AFTER DRUG USE. WE WILL DESCRIBE HOW, WHEN, AND WHERE HISTONE TAILS ARE MODIFIED AND HOW SOME OF THE MOST RECOGNIZED HISTONE REGULATION PATTERNS ARE INVOLVED IN THE CYCLE OF ADDICTION, INCLUDING INITIAL AND CHRONIC DRUG INTAKE, WITHDRAWAL, ABSTINENCE, AND RELAPSE. FINALLY, WE CONSIDER HOW AN APPROACH THAT TARGETS HISTONE MODIFICATIONS MAY PROMOTE SUCCESSFUL TREATMENT. 2014 13 1796 43 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 14 2596 31 EPIGENETICS OF STRESS ADAPTATIONS IN THE BRAIN. RECENT FINDINGS IN EPIGENETICS SHED NEW LIGHT ON THE REGULATION OF GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM (CNS) DURING STRESS. THE MOST FREQUENTLY STUDIED EPIGENETIC MECHANISMS ARE DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNA ACTIVITY. THESE MECHANISMS STABLY DETERMINE CELL PHENOTYPE BUT CAN ALSO BE RESPONSIBLE FOR DYNAMIC MOLECULAR ADAPTATIONS OF THE CNS TO STRESSORS. THE LIMBIC-HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (LHPA) IS THE PRIMARY CIRCUIT THAT INITIATES, REGULATES AND TERMINATES A STRESS RESPONSE. THE SAME BRAIN AREAS THAT CONTROL STRESS ALSO REACT TO STRESS DYNAMICALLY AND WITH LONG-TERM CONSEQUENCES. ONE OF THE BIOLOGICAL PROCESSES EVOKING POTENT ADAPTIVE CHANGES IN THE CNS SUCH AS CHANGES IN BEHAVIOR, GENE ACTIVITY OR SYNAPTIC PLASTICITY IN THE HIPPOCAMPUS IS PSYCHOGENIC STRESS. THIS REVIEW SUMMARIZES THE CURRENT DATA REGARDING THE EPIGENETIC BASIS OF MOLECULAR ADAPTATIONS IN THE BRAIN INCLUDING GENOME-WIDE EPIGENETIC CHANGES OF DNA METHYLATION AND PARTICULAR GENES INVOLVED IN EPIGENETIC RESPONSES THAT PARTICIPATE IN THE BRAIN RESPONSE TO CHRONIC PSYCHOGENIC STRESSORS. IT IS CONCLUDED THAT SPECIFIC EPIGENETIC MECHANISMS IN THE CNS ARE INVOLVED IN THE STRESS RESPONSE. 2013 15 2252 37 EPIGENETIC MODULATION OF VISCERAL NOCICEPTION. EPIGENETICS IS A PROCESS THAT ALTERS GENE ACTIVITY OR PHENOTYPE WITHOUT ANY CHANGES IN THE UNDERLYING DNA SEQUENCE OR GENOTYPE. THESE BIOLOGICAL CHANGES MAY HAVE DELETERIOUS EFFECTS AND CAN LEAD TO VARIOUS HUMAN DISEASES. ONGOING RESEARCH IS CONTINUING TO ILLUMINATE THE ROLE OF EPIGENETICS IN A VARIETY OF PATHOPHYSIOLOGIC PROCESSES. SEVERAL CATEGORIES OF EPIGENETIC MECHANISMS HAVE BEEN STUDIED INCLUDING CHROMATIN REMODELING, DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA MECHANISMS. THESE EPIGENETIC CHANGES CAN HAVE A LONG-TERM EFFECT ON GENE EXPRESSION WITHOUT ANY UNDERLYING CHANGES IN THE DNA SEQUENCES. THE UNDERLYING PATHOPHYSIOLOGY OF DISORDERS OF BRAIN-GUT INTERACTION AND STRESS-INDUCED VISCERAL PAIN ARE NOT FULLY UNDERSTOOD AND THE ROLE OF EPIGENETIC MECHANISMS IN THESE DISORDERS ARE STARTING TO BE BETTER UNDERSTOOD. CURRENT WORK IS UNDERWAY TO DETERMINE HOW EPIGENETICS PLAYS A ROLE IN THE NEUROBIOLOGY OF PATIENTS WITH CHRONIC VISCERAL PAIN AND HEIGHTENED VISCERAL NOCICEPTION. MORE RECENTLY, BOTH ANIMAL MODELS AND HUMAN STUDIES HAVE SHOWN HOW EPIGENETIC REGULATION MODULATES STRESS-INDUCED VISCERAL PAIN. WHILE MUCH MORE WORK IS NEEDED TO FULLY DELINEATE THE MECHANISTIC ROLE OF EPIGENETICS IN THE NEUROBIOLOGY OF CHRONIC VISCERAL NOCICEPTION, THE CURRENT STUDY BY LOUWIES ET AL., IN NEUROGASTROENTEROLOGY AND MOTILITY PROVIDES ADDITIONAL EVIDENCE SUPPORTING THE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE CENTRAL NUCLEUS OF THE AMYGDALA IN STRESS-INDUCED VISCERAL HYPERSENSITIVITY IN RODENTS. 2022 16 6866 30 [PAIN AND EMOTIONAL DYSREGULATION: CELLULAR MEMORY DUE TO PAIN]. GENETIC FACTORS ARE INVOLVED IN DETERMINANTS FOR THE RISK OF PSYCHIATRIC DISORDERS, AND NEUROLOGICAL AND NEURODEGENERATIVE DISEASES. CHRONIC PAIN STIMULI AND INTENSE PAIN HAVE EFFECTS AT A CELLULAR AND/OR GENE EXPRESSION LEVEL, AND WILL EVENTUALLY INDUCE "CELLULAR MEMORY DUE TO PAIN", WHICH MEANS THAT TISSUE DAMAGE, EVEN IF ONLY TRANSIENT, CAN ELICIT EPIGENETICALLY ABNORMAL TRANSCRIPTION/TRANSLATION AND POST-TRANSLATIONAL MODIFICATION IN RELATED CELLS DEPENDING ON THE DEGREE OR KIND OF INJURY OR ASSOCIATED CONDITIONS. SUCH CELL MEMORY/TRANSFORMATION DUE TO PAIN CAN CAUSE AN ABNORMALITY IN A FUNDAMENTAL INTRACELLULAR RESPONSE, SUCH AS A CHANGE IN THE THREE-DIMENSIONAL STRUCTURE OF DNA, TRANSCRIPTION, OR TRANSLATION. ON THE OTHER HAND, PAIN IS A MULTIDIMENSIONAL EXPERIENCE WITH SENSORY-DISCRIMINATIVE AND MOTIVATIONAL-AFFECTIVE COMPONENTS. RECENT HUMAN BRAIN IMAGING STUDIES HAVE EXAMINED DIFFERENCES IN ACTIVITY IN THE NUCLEUS ACCUMBENS BETWEEN CONTROLS AND PATIENTS WITH CHRONIC PAIN, AND HAVE REVEALED THAT THE NUCLEUS ACCUMBENS PLAYS A ROLE IN PREDICTING THE VALUE OF A NOXIOUS STIMULUS AND ITS OFFSET, AND IN THE CONSEQUENT CHANGES IN THE MOTIVATIONAL STATE. IN THIS REVIEW, WE PROVIDE A VERY BRIEF OVERVIEW OF A COMPREHENSIVE UNDERSTANDING OF CHRONIC PAIN ASSOCIATED WITH EMOTIONAL DYSREGULATION DUE TO TRANSCRIPTIONAL REGULATION, EPIGENETIC MODIFICATION AND MIRNA REGULATION. 2015 17 5928 26 TARGETING EPIGENETIC MECHANISMS FOR PAIN RELIEF. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS TO CHROMATIN THAT MODULATE GENE ACTIVITY WITHOUT ALTERING THE DNA SEQUENCE. WHILE RESEARCH ON EPIGENETICS HAS GROWN EXPONENTIALLY OVER THE PAST FEW YEARS, VERY FEW STUDIES HAVE INVESTIGATED EPIGENETIC MECHANISMS IN RELATION TO PAIN STATES. HOWEVER, EPIGENETIC MECHANISMS ARE CRUCIAL TO MEMORY FORMATION THAT REQUIRES SIMILAR SYNAPTIC PLASTICITY TO PAIN PROCESSING, INDICATING THAT THEY MAY PLAY A KEY ROLE IN THE CONTROL OF PAIN STATES. THIS ARTICLE REVIEWS THE EARLY EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS ARE ENGAGED AFTER INJURY AND IN CHRONIC PAIN STATES, AND THAT DRUGS USED CLINICALLY TO TARGET THE EPIGENETIC MACHINERY FOR THE TREATMENT OF CANCER MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. 2012 18 110 29 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 19 5828 30 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 20 2250 35 EPIGENETIC MODULATION OF OPIOID RECEPTORS BY DRUGS OF ABUSE. CHRONIC EXPOSURE TO DRUGS OF ABUSE PRODUCES PROFOUND CHANGES IN GENE EXPRESSION AND NEURAL ACTIVITY ASSOCIATED WITH DRUG-SEEKING AND TAKING BEHAVIOR. DYSREGULATION OF OPIOID RECEPTOR GENE EXPRESSION IS COMMONLY OBSERVED ACROSS A VARIETY OF ABUSED SUBSTANCES INCLUDING OPIOIDS, COCAINE, AND ALCOHOL. EARLY STUDIES IN CULTURED CELLS SHOWED THAT THE SPATIAL AND TEMPORAL GENE EXPRESSION OF OPIOID RECEPTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA AND HISTONE MODIFICATIONS AND NON-CODING RNAS. ACCUMULATING EVIDENCE INDICATE THAT DRUGS OF ABUSE CAN MODULATE OPIOID RECEPTOR GENE EXPRESSION BY TARGETING VARIOUS EPIGENETIC REGULATORY NETWORKS. BASED ON CURRENT CELLULAR AND ANIMAL MODELS OF SUBSTANCE USE DISORDER AND CLINICAL EVIDENCE, THIS REVIEW SUMMARIZES HOW CHRONIC DRUG EXPOSURE ALTERS THE GENE EXPRESSION OF MU, DELTA, KAPPA, AND NOCICEPTIN RECEPTORS VIA DNA AND HISTONE MODIFICATIONS. THE INFLUENCE OF DRUGS OF ABUSE ON EPIGENETIC MODULATORS, SUCH AS NON-CODING RNAS AND TRANSCRIPTION FACTORS, IS ALSO PRESENTED. FINALLY, THE THERAPEUTIC POTENTIAL OF MANIPULATING EPIGENETIC PROCESSES AS AN AVENUE TO TREAT SUBSTANCE USE DISORDER IS DISCUSSED. 2022