1 4982 123 PATHOPHYSIOLOGY OF THE BLOOD-BRAIN BARRIER: ANIMAL MODELS AND METHODS. THE SPECIALIZED CEREBRAL MICROVASCULAR ENDOTHELIUM INTERACTS WITH THE CELLULAR MILIEU OF THE BRAIN AND EXTRACELLULAR MATRIX TO FORM A NEUROVASCULAR UNIT, ONE ASPECT OF WHICH IS A REGULATED INTERFACE BETWEEN THE BLOOD AND CENTRAL NERVOUS SYSTEM (CNS). THE CONCEPT OF THIS BLOOD-BRAIN BARRIER (BBB) AS A DYNAMICALLY REGULATED SYSTEM RATHER THAN A STATIC BARRIER HAS WIDE-RANGING IMPLICATIONS FOR PATHOPHYSIOLOGY OF THE CNS. WHILE IN VITRO MODELS OF THE BBB ARE USEFUL FOR SCREENING DRUGS TARGETED TO THE CNS AND INDISPENSABLE FOR STUDIES OF CEREBRAL ENDOTHELIAL CELL BIOLOGY, THE COMPLEX INTERACTIONS OF THE NEUROVASCULAR UNIT MAKE ANIMAL-BASED MODELS AND METHODS ESSENTIAL TOOLS FOR UNDERSTANDING THE PATHOPHYSIOLOGY OF THE BBB. BBB DYSFUNCTION IS A COMPLICATION OF NEURODEGENERATIVE DISEASE AND BRAIN INJURY. STUDIES ON ANIMAL MODELS HAVE SHOWN THAT DISEASES OF THE PERIPHERY, SUCH AS DIABETES AND INFLAMMATORY PAIN, HAVE DELETERIOUS EFFECTS ON THE BBB WHICH MAY CONTRIBUTE TO NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH THESE CONDITIONS. FURTHERMORE, GENETIC AND/OR EPIGENETIC ABNORMALITIES IN CONSTITUENTS OF THE BBB MAY BE SIGNIFICANT CONTRIBUTING FACTORS IN DISEASE ETIOLOGY. RESEARCH THAT APPROACHES THE BBB AS A DYNAMIC SYSTEM INTEGRATED WITH BOTH THE CNS AND THE PERIPHERY IS THEREFORE CRITICAL TO UNDERSTANDING AND TREATING DISEASES OF THE CNS. HEREIN, WE REVIEW VARIOUS METHODOLOGICAL APPROACHES USED TO STUDY BBB FUNCTION IN THE CONTEXT OF DISEASE. THESE INCLUDE MEASUREMENT OF TRANSPORT BETWEEN BLOOD AND BRAIN, IMAGING-BASED TECHNOLOGIES, AND GENOMIC/PROTEOMIC APPROACHES. 2008 2 3120 38 GESTATIONAL HYPOXIA AND BLOOD-BRAIN BARRIER PERMEABILITY: EARLY ORIGINS OF CEREBROVASCULAR DYSFUNCTION INDUCED BY EPIGENETIC MECHANISMS. FETAL CHRONIC HYPOXIA LEADS TO INTRAUTERINE GROWTH RESTRICTION (IUGR), WHICH IS LIKELY TO REDUCE OXYGEN DELIVERY TO THE BRAIN AND INDUCE LONG-TERM NEUROLOGICAL IMPAIRMENTS. THESE INDICATE A MODULATORY ROLE FOR OXYGEN IN CEREBROVASCULAR DEVELOPMENT. DURING INTRAUTERINE HYPOXIA, THE FETAL CIRCULATION SUFFERS MARKED ADAPTATIONS IN THE FETAL CARDIAC OUTPUT TO MAINTAIN OXYGEN AND NUTRIENT DELIVERY TO VITAL ORGANS, KNOWN AS THE "BRAIN-SPARING PHENOTYPE." THIS IS A WELL-CHARACTERIZED RESPONSE; HOWEVER, LITTLE IS KNOWN ABOUT THE POSTNATAL COURSE AND OUTCOMES OF THIS FETAL CEREBROVASCULAR ADAPTATION. IN ADDITION, SEVERAL NEURODEVELOPMENTAL DISORDERS HAVE THEIR ORIGINS DURING GESTATION. STILL, FEW STUDIES HAVE FOCUSED ON HOW INTRAUTERINE FETAL HYPOXIA MODULATES THE NORMAL BRAIN DEVELOPMENT OF THE BLOOD-BRAIN BARRIER (BBB) IN THE IUGR NEONATE. THE BBB IS A CELLULAR STRUCTURE FORMED BY THE NEUROVASCULAR UNIT (NVU) AND IS ORGANIZED BY A MONOLAYER OF ENDOTHELIAL AND MURAL CELLS. THE BBB REGULATES THE ENTRY OF PLASMA CELLS AND MOLECULES FROM THE SYSTEMIC CIRCULATION TO THE BRAIN. A HIGHLY SELECTIVE PERMEABILITY SYSTEM ACHIEVES THIS THROUGH INTEGRAL MEMBRANE PROTEINS IN BRAIN ENDOTHELIAL CELLS. BBB BREAKDOWN AND DYSFUNCTION IN CEREBROVASCULAR DISEASES LEAD TO LEAKAGE OF BLOOD COMPONENTS INTO THE BRAIN PARENCHYMA, CONTRIBUTING TO NEUROLOGICAL DEFICITS. THE FETAL BRAIN CIRCULATION IS PARTICULARLY SUSCEPTIBLE IN IUGR AND IS PROPOSED TO BE ONE OF THE MAIN PATHOLOGICAL PROCESSES DERIVING BBB DISRUPTION. IN THE LAST DECADE, SEVERAL EPIGENETIC MECHANISMS ACTIVATED BY IU HYPOXIA HAVE BEEN PROPOSED TO REGULATE THE POSTNATAL BBB PERMEABILITY. HOWEVER, FEW MECHANISTIC STUDIES ABOUT THIS TOPIC ARE AVAILABLE, AND LITTLE EVIDENCE SHOWS CONTROVERSY. THEREFORE, IN THIS MINI-REVIEW, WE ANALYZE THE BBB PERMEABILITY-ASSOCIATED EPIGENETIC MECHANISMS IN THE BRAIN EXPOSED TO CHRONIC INTRAUTERINE HYPOXIA. 2021 3 3540 32 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 4 4277 34 MICROGLIA SEQUELAE: BRAIN SIGNATURE OF INNATE IMMUNITY IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A PSYCHIATRIC DISORDER WITH SIGNIFICANT IMPACT ON INDIVIDUALS AND SOCIETY. THE CURRENT PHARMACOLOGIC TREATMENT, WHICH PRINCIPALLY ALLEVIATES PSYCHOSIS, IS FOCUSED ON NEUROTRANSMITTERS MODULATION, RELYING ON DRUGS WITH SEVERE SIDE EFFECTS AND INEFFECTIVENESS IN A SIGNIFICANT PERCENTAGE OF CASES. THEREFORE, AND DUE TO DIFFICULTIES INHERENT TO DIAGNOSIS AND TREATMENT, IT IS VITAL TO REASSESS ALTERNATIVE CELLULAR AND MOLECULAR DRUG TARGETS. DISTINCT RISK FACTORS - GENETIC, DEVELOPMENTAL, EPIGENETIC, AND ENVIRONMENTAL - HAVE BEEN ASSOCIATED WITH DISEASE ONSET AND PROGRESSION, GIVING RISE TO THE PROPOSAL OF DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS AND PUTATIVE PHARMACOLOGICAL TARGETS. IMMUNITY IS INVOLVED AND, PARTICULARLY MICROGLIA - INNATE IMMUNE CELLS OF THE CENTRAL NERVOUS SYSTEM, CRITICALLY INVOLVED IN BRAIN DEVELOPMENT - HAVE CAPTURED ATTENTION AS CELLULAR PLAYERS. MICROGLIA UNDERGO MARKED MORPHOLOGIC AND FUNCTIONAL ALTERATIONS IN THE HUMAN DISEASE, AS WELL AS IN ANIMAL MODELS OF SCHIZOPHRENIA, AS REPORTED IN SEVERAL ORIGINAL PAPERS. WE CLUSTER THE MAIN FINDINGS OF CLINICAL STUDIES BY GROUPS OF PATIENTS: (1) AT ULTRA-HIGH RISK OF PSYCHOSIS, (2) WITH A FIRST EPISODE OF PSYCHOSIS OR RECENT-ONSET SCHIZOPHRENIA, AND (3) WITH CHRONIC SCHIZOPHRENIA; IN TRANSLATIONAL STUDIES, WE HIGHLIGHT THE TIME WINDOW OF APPEARANCE OF PARTICULAR MICROGLIA ALTERATIONS IN THE MOST WELL STUDIED ANIMAL MODEL IN THE FIELD (MATERNAL IMMUNE ACTIVATION). THE ORGANIZATION OF CLINICAL AND TRANSLATIONAL FINDINGS BASED ON SCHIZOPHRENIA-ASSOCIATED MICROGLIA CHANGES IN DIFFERENT PHASES OF THE DISEASE COURSE MAY HELP DEFINING A TEMPORAL PATTERN OF MICROGLIA CHANGES AND MAY DRIVE THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES. 2022 5 5369 28 RECENT ADVANCES IN UNDERSTANDING NEUROPATHIC PAIN: GLIA, SEX DIFFERENCES, AND EPIGENETICS. NEUROPATHIC PAIN RESULTS FROM DISEASES OR TRAUMA AFFECTING THE NERVOUS SYSTEM. THIS PAIN CAN BE DEVASTATING AND IS POORLY CONTROLLED. THE PATHOPHYSIOLOGY IS COMPLEX, AND IT IS ESSENTIAL TO UNDERSTAND THE UNDERLYING MECHANISMS IN ORDER TO IDENTIFY THE RELEVANT TARGETS FOR THERAPEUTIC INTERVENTION. IN THIS ARTICLE, WE FOCUS ON THE RECENT RESEARCH INVESTIGATING NEURO-IMMUNE COMMUNICATION AND EPIGENETIC PROCESSES, WHICH GAIN PARTICULAR ATTENTION IN THE CONTEXT OF NEUROPATHIC PAIN. SPECIFICALLY, WE ANALYZE THE ROLE OF GLIAL CELLS, INCLUDING MICROGLIA, ASTROCYTES, AND OLIGODENDROCYTES, IN THE MODULATION OF THE CENTRAL NERVOUS SYSTEM INFLAMMATION TRIGGERED BY NEUROPATHY. CONSIDERING EPIGENETICS, WE ADDRESS DNA METHYLATION, HISTONE MODIFICATIONS, AND THE NON-CODING RNAS IN THE REGULATION OF ION CHANNELS, G-PROTEIN-COUPLED RECEPTORS, AND TRANSMITTERS FOLLOWING NEURONAL DAMAGE. THE GOAL WAS NOT ONLY TO HIGHLIGHT THE EMERGING CONCEPTS BUT ALSO TO DISCUSS CONTROVERSIES, METHODOLOGICAL COMPLICATIONS, AND INTRIGUING OPINIONS. 2016 6 6414 31 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 4620 28 NEURO-IMMUNE DYSFUNCTION DURING BRAIN AGING: NEW INSIGHTS IN MICROGLIAL CELL REGULATION. MICROGLIA, THE RESIDENT IMMUNE CELLS OF THE BRAIN, ARE AT THE CENTER OF COMMUNICATION BETWEEN THE CENTRAL NERVOUS SYSTEM AND IMMUNE SYSTEM. WHILE THESE BRAIN-IMMUNE INTERACTIONS ARE BALANCED IN HEALTHY ADULTHOOD, THE ABILITY TO MAINTAIN HOMEOSTASIS DURING AGING IS IMPAIRED. MICROGLIA DEVELOP A LOSS OF INTEGRATED REGULATORY NETWORKS INCLUDING ABERRANT SIGNALING FROM OTHER BRAIN CELLS, IMMUNE SENSORS, AND EPIGENETIC MODIFIERS. THE LOW-GRADE CHRONIC NEUROINFLAMMATION ASSOCIATED WITH THIS DYSFUNCTIONAL ACTIVITY LIKELY CONTRIBUTES TO COGNITIVE DEFICITS AND SUSCEPTIBILITY TO AGE-RELATED PATHOLOGIES. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS RESPONSIBLE FOR NEURO-IMMUNE DYSREGULATION WITH AGE IS CRUCIAL FOR PROVIDING TARGETED THERAPEUTIC STRATEGIES TO SUPPORT BRAIN REPAIR AND HEALTHY AGING. 2016 8 1329 37 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 9 6701 31 VASCULAR FACTORS AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A DEBILITATING ILLNESS WITH NO KNOWN CURE. NOWADAYS ACCUMULATING EVIDENCE SUGGESTED THAT THE VASCULAR ENDOTHELIUM AND CHRONIC HYPOPERFUSION MAY PLAY IMPORTANT ROLE IN PATHOBIOLOGY OF AD. THE VASCULAR ENDOTHELIUM WHICH REGULATES THE PASSAGE OF MACROMOLECULES AND CIRCULATING CELLS FROM BLOOD TO TISSUE, IS A MAJOR TARGET OF OXIDATIVE STRESS, PLAYING A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF VASCULAR DISEASES. SINCE THE VASCULAR ENDOTHELIUM, NEURONS AND GLIA ARE ALL ABLE TO SYNTHESIZE, STORE AND RELEASE REACTIVE OXYGEN SPECIES (ROS) AND VASCULAR ACTIVE SUBSTANCES IN RESPONSE TO CERTAIN STIMULI, THEIR CONTRIBUTION TO THE PATHOPHYSIOLOGY OF AD CAN BE VERY IMPORTANT. NEW EVIDENCE INDICATES THAT CONTINUOUS FORMATION OF FREE ROS INDUCES CELLULAR DAMAGE AND DECREASES ANTIOXIDANT DEFENSES. SPECIFICALLY, OXIDATIVE STRESS INCREASES VASCULAR ENDOTHELIAL PERMEABILITY AND PROMOTES LEUKOCYTE ADHESION. WE SUMMARIZE THE REPORTS THAT SPORADIC, LATE-ONSET OF AD RESULTS FROM VASCULAR ETIOLOGY. RECENTLY AN INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ETIOLOGY OF AD IS ALSO INTENSIVELY INVESTIGATED. GAINING A MORE COMPLETE UNDERSTANDING OF THE ESSENTIAL COMPONENTS AND UNDERLYING MECHANISMS INVOLVED IN EPIGENETIC REGULATION COULD LEAD TO NOVEL TREATMENTS FOR A NUMBER OF NEUROLOGICAL AND PSYCHIATRIC CONDITIONS. 2012 10 4278 35 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES. 2021 11 4128 28 MECHANISMS OF DRUG RESISTANCE IN THE PATHOGENESIS OF EPILEPSY: ROLE OF NEUROINFLAMMATION. A LITERATURE REVIEW. EPILEPSY IS A CHRONIC NEUROLOGICAL DISORDER CHARACTERIZED BY RECURRING SPONTANEOUS SEIZURES. DRUG RESISTANCE APPEARS IN 30% OF PATIENTS AND IT CAN LEAD TO PREMATURE DEATH, BRAIN DAMAGE OR A REDUCED QUALITY OF LIFE. THE PURPOSE OF THE STUDY WAS TO ANALYZE THE DRUG RESISTANCE MECHANISMS, ESPECIALLY NEUROINFLAMMATION, IN THE EPILEPTOGENESIS. THE INFORMATION BASES OF BIOMEDICAL LITERATURE SCOPUS, PUBMED, GOOGLE SCHOLAR AND SCIVERSE WERE USED. TO OBTAIN FULL-TEXT DOCUMENTS, ELECTRONIC RESOURCES OF PUBMED CENTRAL AND RESEARCH GATE WERE USED. THE ARTICLE EXAMINES THE RECENT RESEARCH OF THE MECHANISMS OF DRUG RESISTANCE IN EPILEPSY AND DISCUSSES THE HYPOTHESES OF DRUG RESISTANCE DEVELOPMENT (GENETIC, EPIGENETIC, TARGET HYPOTHESIS, ETC.). DRUG-RESISTANT EPILEPSY IS ASSOCIATED WITH NEUROINFLAMMATORY, AUTOIMMUNE AND NEURODEGENERATIVE PROCESSES. NEUROINFLAMMATION CAUSES IMMUNE, PATHOPHYSIOLOGICAL, BIOCHEMICAL AND PSYCHOLOGICAL CONSEQUENCES. FOCAL OR SYSTEMIC UNREGULATED INFLAMMATORY PROCESSES LEAD TO THE FORMATION OF ABERRANT NEURAL CONNECTIONS AND HYPEREXCITABLE NEURAL NETWORKS. INFLAMMATORY MEDIATORS AFFECT THE ENDOTHELIUM OF CEREBRAL VESSELS, DESTROY CONTACTS BETWEEN ENDOTHELIAL CELLS AND INDUCE ABNORMAL ANGIOGENESIS (THE FORMATION OF "LEAKY" VESSELS), THEREBY AFFECTING THE BLOOD-BRAIN BARRIER PERMEABILITY. THUS, THE ANALYSIS OF PRO-INFLAMMATORY AND OTHER COMPONENTS OF EPILEPTOGENESIS CAN CONTRIBUTE TO THE FURTHER DEVELOPMENT OF THE THERAPEUTIC TREATMENT OF DRUG-RESISTANT EPILEPSY. 2021 12 6866 39 [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 13 2963 26 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 14 2404 37 EPIGENETIC RESEARCH IN MULTIPLE SCLEROSIS: PROGRESS, CHALLENGES, AND OPPORTUNITIES. MULTIPLE SCLEROSIS (MS) IS A CHRONIC INFLAMMATORY AND DEMYELINATING DISEASE OF THE CENTRAL NERVOUS SYSTEM. MS LIKELY RESULTS FROM A COMPLEX INTERPLAY BETWEEN PREDISPOSING CAUSAL GENE VARIANTS (THE STRONGEST INFLUENCE COMING FROM HLA CLASS II LOCUS) AND ENVIRONMENTAL RISK FACTORS SUCH AS SMOKING, INFECTIOUS MONONUCLEOSIS, AND LACK OF SUN EXPOSURE/VITAMIN D. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS UNDERLYING MS DEVELOPMENT AND PROGRESSION. MOREOVER, THE CLINICAL HETEROGENEITY AND VARIABLE RESPONSE TO TREATMENT REPRESENT ADDITIONAL CHALLENGES TO A COMPREHENSIVE UNDERSTANDING AND EFFICIENT TREATMENT OF DISEASE. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INTEGRATE INFLUENCES FROM THE GENES AND THE ENVIRONMENT TO REGULATE GENE EXPRESSION ACCORDINGLY. STUDYING EPIGENETIC MODIFICATIONS, WHICH ARE STABLE AND REVERSIBLE, MAY PROVIDE AN ALTERNATIVE APPROACH TO BETTER UNDERSTAND AND MANAGE DISEASE. WE HERE AIM TO REVIEW FINDINGS FROM EPIGENETIC STUDIES IN MS AND FURTHER DISCUSS THE CHALLENGES AND CLINICAL OPPORTUNITIES ARISING FROM EPIGENETIC RESEARCH, MANY OF WHICH APPLY TO OTHER DISEASES WITH SIMILAR COMPLEX ETIOLOGY. A GROWING BODY OF EVIDENCE SUPPORTS A ROLE OF EPIGENETIC PROCESSES IN THE MECHANISMS UNDERLYING IMMUNE PATHOGENESIS AND NERVOUS SYSTEM DYSFUNCTION IN MS. HOWEVER, DISPARITIES BETWEEN STUDIES SHED LIGHT ON THE NEED TO CONSIDER POSSIBLE CONFOUNDERS AND METHODOLOGICAL LIMITATIONS FOR A BETTER INTERPRETATION OF THE DATA. NEVERTHELESS, TRANSLATIONAL USE OF EPIGENETICS MIGHT OFFER NEW OPPORTUNITIES IN EPIGENETIC-BASED DIAGNOSTICS AND THERAPEUTIC TOOLS FOR A PERSONALIZED CARE OF MS PATIENTS. 2017 15 2567 38 EPIGENETICS MODIFIERS: POTENTIAL HUB FOR UNDERSTANDING AND TREATING NEURODEVELOPMENTAL DISORDERS FROM HYPOXIC INJURY. BACKGROUND: THE FETAL BRAIN IS ADAPTED TO THE HYPOXIC CONDITIONS PRESENT DURING NORMAL IN UTERO DEVELOPMENT. RELATIVELY MORE HYPOXIC STATES, EITHER CHRONIC OR ACUTE, ARE PATHOLOGIC AND CAN LEAD TO SIGNIFICANT LONG-TERM NEURODEVELOPMENTAL SEQUELAE. IN UTERO HYPOXIC INJURY IS ASSOCIATED WITH NEONATAL MORTALITY AND MILLIONS OF LIVES LIVED WITH VARYING DEGREES OF DISABILITY. MAIN BODY: GENETIC STUDIES OF CHILDREN WITH NEURODEVELOPMENTAL DISEASE INDICATE THAT EPIGENETIC MODIFIERS REGULATING DNA METHYLATION AND HISTONE REMODELING ARE CRITICAL FOR NORMAL BRAIN DEVELOPMENT. EPIGENETIC MODIFIERS ARE ALSO REGULATED BY ENVIRONMENTAL STIMULI, SUCH AS HYPOXIA. INDEED, EPIGENETIC MODIFIERS THAT ARE MUTATED IN CHILDREN WITH GENETIC NEURODEVELOPMENTAL DISEASES ARE REGULATED BY HYPOXIA IN A NUMBER OF PRECLINICAL MODELS AND MAY BE PART OF THE MECHANISM FOR THE LONG-TERM NEURODEVELOPMENTAL SEQUELAE SEEM IN CHILDREN WITH HYPOXIC BRAIN INJURY. THUS, A COMPREHENSIVE UNDERSTANDING THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN HYPOXIC INJURY IS CRITICAL FOR DEVELOPING NOVEL STRATEGIES TO TREAT CHILDREN WITH HYPOXIC INJURY. CONCLUSIONS: THIS REVIEW FOCUSES ON OUR CURRENT UNDERSTANDING OF THE INTERSECTION BETWEEN EPIGENETICS, BRAIN DEVELOPMENT, AND HYPOXIA. OPPORTUNITIES FOR THE USE OF EPIGENETICS AS BIOMARKERS OF NEURODEVELOPMENTAL DISEASE AFTER HYPOXIC INJURY AND POTENTIAL CLINICAL EPIGENETICS TARGETS TO IMPROVE OUTCOMES AFTER INJURY ARE ALSO DISCUSSED. WHILE THERE HAVE BEEN MANY PUBLISHED STUDIES ON THE EPIGENETICS OF HYPOXIA, MORE ARE NEEDED IN THE DEVELOPING BRAIN IN ORDER TO DETERMINE WHICH EPIGENETIC PATHWAYS MAY BE MOST IMPORTANT FOR MITIGATING THE LONG-TERM CONSEQUENCES OF HYPOXIC BRAIN INJURY. 2020 16 806 32 CHALLENGES FOR MODELING AND INTERPRETING THE COMPLEX BIOLOGY OF SEVERE INJURY AND INFLAMMATION. HUMAN INJURY IS ASSOCIATED WITH INFLAMMATORY RESPONSES THAT ARE MODULATED BY THE ACUTE AND CHRONIC ACTIVITY OF ENDOGENOUS FACTORS AND EXOGENOUS INTERVENTIONS. A CHARACTERISTIC FEATURE OF CHRONIC, SEVERE INFLAMMATORY STATES IS THE DIMINISHED SIGNAL OUTPUT VARIABILITY OF MANY ORGAN SYSTEMS, INCLUDING INNATE IMMUNE RESPONSIVENESS AND ENDOGENOUS NEURAL AND ENDOCRINE-MEDIATED FUNCTIONS. THE ATTENUATION OF SIGNAL/RESPONSE VARIABILITY AND INTEGRATION OF FEEDBACK CAPACITY MAY CONTRIBUTE TO SYSTEMIC AND TISSUE-SPECIFIC DETERIORATION OF FUNCTION. SOME WELL-INTENTIONED THERAPIES DIRECTED TOWARD SUPPORT OF SYSTEMIC AND TISSUE FUNCTIONS MAY ACTUALLY PROMOTE THE LOSS OF SYSTEM(S) ADAPTABILITY AND CONTRIBUTE TO ADVERSE OUTCOMES IN SEVERELY STRESSED PATIENTS. IN VIVO AND IN SILICO MODELS OF STRESS, INJURY, AND INFECTION HAVE YET TO FULLY DEFINE THE INFLUENCES OF ONGOING STRESSFUL STIMULAE AS WELL AS GENETIC VARIATION AND EPIGENETIC FACTORS IN THE CONTEXT OF AN EVOLVING INFLAMMATORY STATE. EXPERIMENTAL AND HUMAN MODELS INCORPORATING VARIABLE, ANTECEDENT STRESS(ES) AND ALTERED NEUROENDOCRINE RHYTHMS MIGHT APPROXIMATE THE ALTERED ADAPTABILITY IN IMMUNE AND ORGAN FUNCTION RESPONSES. SUCH MODELS MAY ALSO PROVIDE INSIGHTS INTO THE SALIENT MECHANISMS OF RISK AND OUTCOME MORE PRECISELY THAN DO THE CONSTRAINED STUDY CONDITIONS OF CURRENT ANIMAL OR HUMAN MODELS OF SYSTEMIC INFLAMMATION. 2008 17 2526 30 EPIGENETICS APPLIED TO PSYCHIATRY: CLINICAL OPPORTUNITIES AND FUTURE CHALLENGES. PSYCHIATRIC DISORDERS ARE CLINICALLY HETEROGENEOUS AND DEBILITATING CHRONIC DISEASES RESULTING FROM A COMPLEX INTERPLAY BETWEEN GENE VARIANTS AND ENVIRONMENTAL FACTORS. EPIGENETIC PROCESSES, SUCH AS DNA METHYLATION AND HISTONE POSTTRANSLATIONAL MODIFICATIONS, INSTRUCT THE CELL/TISSUE TO CORRECTLY INTERPRET EXTERNAL SIGNALS AND ADJUST ITS FUNCTIONS ACCORDINGLY. GIVEN THAT EPIGENETIC MODIFICATIONS ARE SENSITIVE TO ENVIRONMENT, STABLE, AND REVERSIBLE, EPIGENETIC STUDIES IN PSYCHIATRY COULD REPRESENT A PROMISING APPROACH TO BETTER UNDERSTANDING AND TREATING DISEASE. IN THE PRESENT REVIEW, WE AIM TO DISCUSS THE CLINICAL OPPORTUNITIES AND CHALLENGES ARISING FROM THE EPIGENETIC RESEARCH IN PSYCHIATRY. USING SELECTED EXAMPLES, WE FIRST RECAPITULATE KEY FINDINGS SUPPORTING THE ROLE OF ADVERSE LIFE EVENTS, ALONE OR IN COMBINATION WITH GENETIC RISK, IN EPIGENETIC PROGRAMMING OF NEUROPSYCHIATRIC SYSTEMS. EPIGENETIC STUDIES FURTHER REPORT ENCOURAGING FINDINGS ABOUT THE USE OF METHYLATION CHANGES AS DIAGNOSTIC MARKERS OF DISEASE PHENOTYPE AND PREDICTIVE TOOLS OF PROGRESSION AND RESPONSE TO TREATMENT. THEN WE DISCUSS THE POTENTIAL OF USING TARGETED EPIGENETIC PHARMACOTHERAPY, COMBINED WITH PSYCHOSOCIAL INTERVENTIONS, FOR FUTURE PERSONALIZED MEDICINE FOR PATIENTS. FINALLY, WE REVIEW THE METHODOLOGICAL LIMITATIONS THAT COULD HINDER INTERPRETATION OF EPIGENETIC DATA IN PSYCHIATRY. THEY MAINLY ARISE FROM HETEROGENEITY AT THE INDIVIDUAL AND TISSUE LEVEL AND REQUIRE FUTURE STRATEGIES IN ORDER TO REINFORCE THE BIOLOGICAL RELEVANCE OF EPIGENETIC DATA AND ITS TRANSLATIONAL USE IN PSYCHIATRY. OVERALL, WE SUGGEST THAT EPIGENETICS COULD PROVIDE NEW INSIGHTS INTO A MORE COMPREHENSIVE INTERPRETATION OF MENTAL ILLNESS AND MIGHT EVENTUALLY IMPROVE THE NOSOLOGY, TREATMENT, AND PREVENTION OF PSYCHIATRIC DISORDERS. 2018 18 6211 31 THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTH AND DISEASE: POTENTIAL ROLE OF AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS. OXIDATIVE STRESS CAN BE INDUCED BY VARIOUS STIMULI AND ALTERED IN CERTAIN CONDITIONS, INCLUDING EXERCISE AND PAIN. ALTHOUGH MANY STUDIES HAVE INVESTIGATED OXIDATIVE STRESS IN RELATION TO EITHER EXERCISE OR PAIN, THE LITERATURE PRESENTS CONFLICTING RESULTS. THEREFORE, THIS REVIEW CRITICALLY DISCUSSES EXISTING LITERATURE ABOUT THIS TOPIC, AIMING TO PROVIDE A CLEAR OVERVIEW OF KNOWN INTERACTIONS BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IN HEALTHY PEOPLE AS WELL AS IN PEOPLE WITH CHRONIC PAIN, AND TO HIGHLIGHT POSSIBLE CONFOUNDING FACTORS TO KEEP IN MIND WHEN REFLECTING ON THESE INTERACTIONS. IN ADDITION, AUTONOMIC REGULATION AND EPIGENETIC MECHANISMS ARE PROPOSED AS POTENTIAL MECHANISMS OF ACTION UNDERLYING THE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN. THIS REVIEW HIGHLIGHTS THAT THE RELATION BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN IS POORLY UNDERSTOOD AND NOT STRAIGHTFORWARD, AS IT IS DEPENDENT ON THE CHARACTERISTICS OF EXERCISE, BUT ALSO ON WHICH POPULATION IS INVESTIGATED. TO BE ABLE TO COMPARE STUDIES ON THIS TOPIC, STRICT GUIDELINES SHOULD BE DEVELOPED TO LIMIT THE EFFECT OF SEVERAL CONFOUNDING FACTORS. THIS WAY, THE TRUE INTERPLAY BETWEEN OXIDATIVE STRESS, EXERCISE, AND PAIN, AND THE UNDERLYING MECHANISMS OF ACTION CAN BE REVEALED AND VALIDATED VIA INDEPENDENT STUDIES. 2020 19 3404 36 HOW EPIGENETICS IMPACTS ON HUMAN DISEASES. EPIGENETICS IS A RAPIDLY GROWING FIELD OF BIOLOGY THAT STUDIES THE CHANGES IN GENE EXPRESSION THAT ARE NOT DUE TO ALTERATIONS IN THE DNA SEQUENCE BUT RATHER THE CHEMICAL MODIFICATIONS OF DNA AND ITS ASSOCIATED PROTEINS. EPIGENETIC MECHANISMS CAN PROFOUNDLY INFLUENCE GENE EXPRESSION, CELL DIFFERENTIATION, TISSUE DEVELOPMENT, AND DISEASE SUSCEPTIBILITY. UNDERSTANDING EPIGENETIC CHANGES IS ESSENTIAL TO ELUCIDATE THE MECHANISMS UNDERLYING THE INCREASINGLY RECOGNIZED ROLE OF ENVIRONMENTAL AND LIFESTYLE FACTORS IN HEALTH AND DISEASE AND THE INTERGENERATIONAL TRANSMISSION OF PHENOTYPES. RECENT STUDIES SUGGEST EPIGENETICS MAY BE CRITICAL IN VARIOUS DISEASES, FROM CARDIOVASCULAR DISEASE AND CANCER TO NEURODEVELOPMENTAL AND NEURODEGENERATIVE DISORDERS. EPIGENETIC MODIFICATIONS ARE POTENTIALLY REVERSIBLE AND COULD PROVIDE NEW THERAPEUTIC AVENUES FOR TREATING THESE DISEASES USING EPIGENETIC MODULATORS. MOREOVER, EPIGENETICS PROVIDE INSIGHT INTO DISEASE PATHOGENESIS AND BIOMARKERS FOR DISEASE DIAGNOSIS AND RISK STRATIFICATION. NEVERTHELESS, EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL FOR UNINTENDED CONSEQUENCES AND MAY POTENTIALLY LEAD TO INCREASED RISKS OF UNEXPECTED OUTCOMES, SUCH AS ADVERSE DRUG REACTIONS, DEVELOPMENTAL ABNORMALITIES, AND CANCER. THEREFORE, RIGOROUS STUDIES ARE ESSENTIAL TO MINIMIZE THE RISKS ASSOCIATED WITH EPIGENETIC THERAPIES AND TO DEVELOP SAFE AND EFFECTIVE INTERVENTIONS FOR IMPROVING HUMAN HEALTH. THIS ARTICLE PROVIDES A SYNTHETIC AND HISTORICAL VIEW OF THE ORIGIN OF EPIGENETICS AND SOME OF THE MOST RELEVANT ACHIEVEMENTS. 2023 20 2317 41 EPIGENETIC REGULATION OF G PROTEIN COUPLED RECEPTOR SIGNALING AND ITS IMPLICATIONS IN PSYCHIATRIC DISORDERS. G PROTEIN-COUPLED RECEPTORS (GPCRS) ACT AS A RELAY CENTER THROUGH WHICH EXTRACELLULAR SIGNALS, IN THE FORM OF NEUROTRANSMITTERS OR THERAPEUTICS, ARE CONVERTED INTO AN INTRACELLULAR RESPONSE, WHICH ULTIMATELY SHAPES THE OVERALL RESPONSE AT THE TISSUE AND BEHAVIORAL LEVEL. REMARKABLY IN SIMILAR WAYS, EPIGENETIC MECHANISMS ALSO MODULATE THE EXPRESSION PATTERN OF A LARGE NUMBER OF GENES IN RESPONSE TO THE DYNAMIC ENVIRONMENT INSIDE AND OUTSIDE OF THE BODY, AND CONSEQUENTLY OVERALL RESPONSE. EMERGING EVIDENCES FROM THE PHARMACOGENOMICS AND PRECLINICAL STUDIES CLEARLY SUGGEST THAT THESE TWO DISTINCT MECHANISMS CRISS-CROSS EACH OTHER IN SEVERAL NEUROLOGICAL DISORDERS. AT ONE HAND SUCH CROSS-TALKS BETWEEN TWO DISTINCT MECHANISMS MAKE DISEASE ETIOLOGY MORE CHALLENGING TO UNDERSTAND, WHILE ON THE OTHER HAND IF DEALT APPROPRIATELY, SUCH SITUATIONS MIGHT PROVIDE AN OPPORTUNITY TO FIND NOVEL DRUGGABLE TARGET AND STRATEGY FOR THE TREATMENT OF COMPLEX DISEASES. IN THIS REVIEW ARTICLE, WE HAVE SUMMARIZED AND HIGHLIGHTED THE MAIN FINDINGS THAT TIE EPIGENETIC MECHANISMS TO GPCR MEDIATED SIGNALING IN THE PATHOPHYSIOLOGY OF CENTRAL NERVOUS SYSTEM (CNS) DISORDERS, INCLUDING DEPRESSION, ADDICTION AND PAIN. 2016