1 801 127 CENTRAL AND PERIPHERAL IMMUNE DYSREGULATION IN POSTTRAUMATIC STRESS DISORDER: CONVERGENT MULTI-OMICS EVIDENCE. POSTTRAUMATIC STRESS DISORDER (PTSD) IS A CHRONIC AND MULTIFACTORIAL DISORDER WITH A PREVALENCE RANGING BETWEEN 6-10% IN THE GENERAL POPULATION AND ~35% IN INDIVIDUALS WITH HIGH LIFETIME TRAUMA EXPOSURE. GROWING EVIDENCE INDICATES THAT THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE ETIOLOGY OF PTSD, SUGGESTING THE INFLAMMATORY DYSREGULATION AS A HALLMARK FEATURE OF PTSD. HOWEVER, THE POTENTIAL INTERPLAY BETWEEN THE CENTRAL AND PERIPHERAL IMMUNE SYSTEM, AS WELL AS THE BIOLOGICAL MECHANISMS UNDERLYING THIS DYSREGULATION REMAIN POORLY UNDERSTOOD. THE ACTIVATION OF THE HPA AXIS AFTER TRAUMA EXPOSURE AND THE SUBSEQUENT ACTIVATION OF THE INFLAMMATORY SYSTEM MEDIATED BY GLUCOCORTICOIDS IS THE MOST COMMON MECHANISM THAT ORCHESTRATES AN EXACERBATED IMMUNOLOGICAL RESPONSE IN PTSD. RECENT HIGH-THROUGHPUT ANALYSES IN PERIPHERAL AND BRAIN TISSUE FROM BOTH HUMANS WITH AND ANIMAL MODELS OF PTSD HAVE FOUND THAT CHANGES IN GENE REGULATION VIA EPIGENETIC ALTERATIONS MAY PARTICIPATE IN THE IMPAIRED INFLAMMATORY SIGNALING IN PTSD. THE GOAL OF THIS REVIEW IS TO ASSESS THE ROLE OF THE INFLAMMATORY SYSTEM IN PTSD ACROSS TISSUE AND SPECIES, WITH A PARTICULAR FOCUS ON THE GENOMICS, TRANSCRIPTOMICS, EPIGENOMICS, AND PROTEOMICS DOMAINS. WE CONDUCTED AN INTEGRATIVE MULTI-OMICS APPROACH IDENTIFYING TNF (TUMOR NECROSIS FACTOR) SIGNALING, INTERLEUKINS, CHEMOKINES, TOLL-LIKE RECEPTORS AND GLUCOCORTICOIDS AMONG THE COMMON DYSREGULATED PATHWAYS IN BOTH CENTRAL AND PERIPHERAL IMMUNE SYSTEMS IN PTSD AND PROPOSE POTENTIAL NOVEL DRUG TARGETS FOR PTSD TREATMENT. 2022 2 5164 38 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 3 2963 29 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 4 6414 37 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 5 3123 42 GETTING AN INSIGHT INTO THE COMPLEXITY OF MAJOR CHRONIC INFLAMMATORY AND DEGENERATIVE DISEASES: A POTENTIAL NEW SYSTEMIC APPROACH TO THEIR TREATMENT. AS THE MODERN SOCIETY IS TROUBLED BY MULTI-FACTORIAL DISEASES, RESEARCH HAS BEEN CONDUCTED ON COMPLEX REALITIES INCLUDING CHRONIC INFLAMMATION, CANCER, OBESITY, HIV INFECTION, METABOLIC SYNDROME AND ITS DETRIMENTAL CARDIOVASCULAR COMPLICATIONS AS WELL AS DEPRESSION AND OTHER BRAIN DISORDERS. DETERIORATION OF CRUCIAL HOMEOSTATIC MECHANISMS IN SUCH DISEASES INVARIABLY RESULTS IN ACTIVATION OF INFLAMMATORY MEDIATORS, CHRONIC INFLAMMATION, LOSS IN IMMUNOLOGICAL FUNCTION, INCREASED SUSCEPTIBILITY TO DISEASES, ALTERATION OF METABOLISM, DECREASE OF ENERGY PRODUCTION AND NEURO-COGNITIVE DECLINE. REGULATION OF GENES EXPRESSION BY EPIGENETIC CODE IS THE DOMINANT MECHANISM FOR THE TRANSDUCTION OF ENVIRONMENTAL INPUTS, SUCH AS STRESS AND INFLAMMATION TO LASTING PHYSIOLOGICAL CHANGES. ACUTE AND CHRONIC STRESS DETERMINES DNA METHYLATION AND HISTONE MODIFICATIONS IN BRAIN REGIONS WHICH MAY CONTRIBUTE TO NEURO-DEGENERATIVE DISORDERS. NUCLEAR GLUCOCORTICOIDS RECEPTOR INTERACTS WITH THE EPIGENOMA RESULTING IN A CORTISOL RESISTANCE STATUS ASSOCIATED WITH A DETERIORATION OF THE METABOLIC AND IMMUNE FUNCTIONS. GONADAL STEROIDS RECEPTORS HAVE A SIMILAR CAPACITY TO PRODUCE EPIGENOMIC REORGANIZATION OF CHROMATINE STRUCTURE. EPIGENOMIC-INDUCED REDUCTION IN IMMUNE CELLS TELOMERES LENGTH HAS BEEN OBSERVED IN MANY DEGENERATIVE DISEASES, INCLUDING ALL TYPES OF CANCER. THE FINAL RESULT OF THESE EPIGENETIC ALTERATIONS IS A SERIOUS DAMAGE TO THE NEURO-ENDOCRINE-IMMUNE-METABOLIC ADAPTIVE SYSTEMS. IN THIS STUDY, WE PROPOSE A TREATMENT WITH STEM CELLS DIFFERENTIATION STAGE FACTORS TAKEN FROM ZEBRAFISH EMBRYOS WHICH ARE ABLE TO REGULATE THE GENES EXPRESSION OF NORMAL AND PATHOLOGICAL STEM CELLS IN A DIFFERENT SPECIFIC WAY. 2015 6 2523 33 EPIGENETICS AND THE TRANSITION FROM ACUTE TO CHRONIC PAIN. OBJECTIVE: THE OBJECTIVE OF THIS STUDY WAS TO REVIEW THE EPIGENETIC MODIFICATIONS INVOLVED IN THE TRANSITION FROM ACUTE TO CHRONIC PAIN AND TO IDENTIFY POTENTIAL TARGETS FOR THE DEVELOPMENT OF NOVEL, INDIVIDUALIZED PAIN THERAPEUTICS. BACKGROUND: EPIGENETICS IS THE STUDY OF HERITABLE MODIFICATIONS IN GENE EXPRESSION AND PHENOTYPE THAT DO NOT REQUIRE A CHANGE IN GENETIC SEQUENCE TO MANIFEST THEIR EFFECTS. ENVIRONMENTAL TOXINS, MEDICATIONS, DIET, AND PSYCHOLOGICAL STRESSES CAN ALTER EPIGENETIC PROCESSES SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND RNA INTERFERENCE. AS EPIGENETIC MODIFICATIONS POTENTIALLY PLAY AN IMPORTANT ROLE IN INFLAMMATORY CYTOKINE METABOLISM, STEROID RESPONSIVENESS, AND OPIOID SENSITIVITY, THEY ARE LIKELY KEY FACTORS IN THE DEVELOPMENT OF CHRONIC PAIN. ALTHOUGH OUR KNOWLEDGE OF THE HUMAN GENETIC CODE AND DISEASE-ASSOCIATED POLYMORPHISMS HAS GROWN SIGNIFICANTLY IN THE PAST DECADE, WE HAVE NOT YET BEEN ABLE TO ELUCIDATE THE MECHANISMS THAT LEAD TO THE DEVELOPMENT OF PERSISTENT PAIN AFTER NERVE INJURY OR SURGERY. DESIGN: THIS IS A FOCUSED LITERATURE REVIEW OF EPIGENETIC SCIENCE AND ITS RELATIONSHIP TO CHRONIC PAIN. RESULTS: SIGNIFICANT LABORATORY AND CLINICAL DATA SUPPORT THE NOTION THAT EPIGENETIC MODIFICATIONS ARE AFFECTED BY THE ENVIRONMENT AND LEAD TO DIFFERENTIAL GENE EXPRESSION. SIMILAR TO MECHANISMS INVOLVED IN THE DEVELOPMENT OF CANCER, NEURODEGENERATIVE DISEASE, AND INFLAMMATORY DISORDERS, THE LITERATURE ENDORSES AN IMPORTANT POTENTIAL ROLE FOR EPIGENETICS IN CHRONIC PAIN. CONCLUSIONS: EPIGENETIC ANALYSIS MAY IDENTIFY MECHANISMS CRITICAL TO THE DEVELOPMENT OF CHRONIC PAIN AFTER INJURY, AND MAY PROVIDE NEW PATHWAYS AND TARGET MECHANISMS FOR FUTURE DRUG DEVELOPMENT AND INDIVIDUALIZED MEDICINE. 2012 7 2520 30 EPIGENETICS AND THE GLUCOCORTICOID RECEPTOR: A REVIEW OF THE IMPLICATIONS IN DEPRESSION. DEPRESSION IS A SERIOUS PSYCHIATRIC DISORDER THAT EFFECTS AT LEAST 350 MILLION PEOPLE WORLDWIDE TODAY. DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (HPAA) IS A ROBUST FINDING IN THE PATHOPHYSIOLOGY OF DEPRESSION. THIS DYSREGULATION IS HYPOTHESIZED TO RESULT FROM ALTERED CENTRAL GLUCOCORTICOID RECEPTOR (GR) LEVELS AND/OR FUNCTION AS A CONSEQUENCE OF CHRONIC GLUCOCORTICOID (GC) RELEASE, LEADING TO RECEPTOR RESISTANCE. PIVOTAL ANIMAL AND HUMAN RESEARCH TO DATE HAS IDENTIFIED THAT EARLY LIFE EXPOSURE TO PROLONGED LEVELS OF GCS, STRESS AND/OR DEPRESSION, CAN INDUCE EPIGENETIC MODIFICATIONS AT KEY REGIONS ON THE GR GENE THAT LEAD TO ALTERATIONS IN GR EXPRESSION AND FUNCTION. EPIGENETICS PROVIDES AN ATTRACTIVE MECHANISM TO EXPLAIN HOW ONES' GENES AND ENVIRONMENT CAN INTERACT TO PRODUCE DIFFERENT DISEASE PHENOTYPES. THIS REVIEW AIMS TO COMPILE THE INFORMATION THAT HAS BEEN COLLECTED TO DATE AND TO IDENTIFY KEY AREAS FOR FURTHER INVESTIGATION. 2016 8 6228 26 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 9 110 31 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 10 6866 31 [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 11 2011 46 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 12 5756 31 SOCIOECONOMIC DEPRIVATION, ADVERSE CHILDHOOD EXPERIENCES AND MEDICAL DISORDERS IN ADULTHOOD: MECHANISMS AND ASSOCIATIONS. SEVERE SOCIOECONOMIC DEPRIVATION (SED) AND ADVERSE CHILDHOOD EXPERIENCES (ACE) ARE SIGNIFICANTLY ASSOCIATED WITH THE DEVELOPMENT IN ADULTHOOD OF (I) ENHANCED INFLAMMATORY STATUS AND/OR HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSFUNCTION AND (II) NEUROLOGICAL, NEUROPROGRESSIVE, INFLAMMATORY AND AUTOIMMUNE DISEASES. THE MECHANISMS BY WHICH THESE ASSOCIATIONS TAKE PLACE ARE DETAILED. THE TWO SETS OF CONSEQUENCES ARE THEMSELVES STRONGLY ASSOCIATED, WITH THE FIRST SET LIKELY CONTRIBUTING TO THE SECOND. MECHANISMS ENABLING BIDIRECTIONAL COMMUNICATION BETWEEN THE IMMUNE SYSTEM AND THE BRAIN ARE DESCRIBED, INCLUDING COMPLEX SIGNALLING PATHWAYS FACILITATED BY FACTORS AT THE LEVEL OF IMMUNE CELLS. ALSO DETAILED ARE MECHANISMS UNDERPINNING THE ASSOCIATION BETWEEN SED, ACE AND THE GENESIS OF PERIPHERAL INFLAMMATION, INCLUDING EPIGENETIC CHANGES TO IMMUNE SYSTEM-RELATED GENE EXPRESSION. THE DURATION AND MAGNITUDE OF INFLAMMATORY RESPONSES CAN BE INFLUENCED BY GENETIC FACTORS, INCLUDING SINGLE NUCLEOTIDE POLYMORPHISMS, AND BY EPIGENETIC FACTORS, WHEREBY PRO-INFLAMMATORY CYTOKINES, REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES AND NUCLEAR FACTOR-KAPPAB AFFECT GENE DNA METHYLATION AND HISTONE ACETYLATION AND ALSO INDUCE SEVERAL MICRORNAS INCLUDING MIR-155, MIR-181B-1 AND MIR-146A. ADULT HPA AXIS ACTIVITY IS REGULATED BY (I) GENETIC FACTORS, SUCH AS GLUCOCORTICOID RECEPTOR POLYMORPHISMS; (II) EPIGENETIC FACTORS AFFECTING GLUCOCORTICOID RECEPTOR FUNCTION OR EXPRESSION, INCLUDING THE METHYLATION STATUS OF ALTERNATIVE PROMOTER REGIONS OF NR3C1 AND THE METHYLATION OF FKBP5 AND HSD11BETA2; (III) CHRONIC INFLAMMATION AND CHRONIC NITROSATIVE AND OXIDATIVE STRESS. FINALLY, IT IS SHOWN HOW SEVERE PSYCHOLOGICAL STRESS ADVERSELY AFFECTS MITOCHONDRIAL STRUCTURE AND FUNCTIONING AND IS ASSOCIATED WITH CHANGES IN BRAIN MITOCHONDRIAL DNA COPY NUMBER AND TRANSCRIPTION; MITOCHONDRIA CAN ACT AS COURIERS OF CHILDHOOD STRESS INTO ADULTHOOD. 2019 13 679 23 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021 14 806 30 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 15 802 42 CENTRAL AND PERIPHERAL STRESS-INDUCED EPIGENETIC MECHANISMS OF RESILIENCE. PURPOSE OF REVIEW: RESILIENCE IS AN ADAPTATION PROCESS PRESENTED BY AN INDIVIDUAL DESPITE FACING ADVERSITIES. EPIGENETIC CHANGES, SUCH AS HISTONE ACETYLATION/METHYLATION AND DNA METHYLATION, HAVE BEEN DEMONSTRATED TO MEDIATE STRESS RESPONSE. IN THIS REVIEW, WE SUMMARIZE RECENT FINDINGS ON EPIGENETIC MECHANISMS CONTRIBUTING TO STRESS RESILIENCE. RECENT FINDINGS: EPIGENETIC MODIFICATIONS OF GENES INVOLVED IN SYNAPTIC PLASTICITY, ENDOCRINE, IMMUNE, AND VASCULAR SYSTEMS ARE LINKED TO RESILIENCE. FOR INSTANCE, INCREASED DNA METHYLATION OF THE NONNEURONAL GROWTH FACTOR GDNF IN SPECIFIC BRAIN REGIONS PROMOTES STRESS RESILIENCE. ADDITIONALLY, HIGH DNA METHYLATION AT THE GLUCOCORTICOID RECEPTOR GENE WAS ASSOCIATED WITH RESILIENCE IN BOTH RODENTS AND HUMANS. AT THE IMMUNE LEVEL, CHRONIC STRESS INDUCES INCREASED DNA METHYLATION AT IL6 GENE, A MEDIATOR OF STRESS VULNERABILITY. MOREOVER, EPIGENETIC ADAPTATIONS OF THE BLOOD--BRAIN BARRIER HAVE BEEN RECENTLY ASSOCIATED WITH STRESS RESILIENCE, WHICH COULD LEAD TO INNOVATIVE THERAPEUTIC APPROACHES TO TREAT DEPRESSION. SUMMARY: IDENTIFICATION OF BOTH CENTRAL AND PERIPHERAL EPIGENETIC CHANGES PROMOTING STRESS RESILIENCE REPRESENT PROMISING NOVEL TARGETS IN THE DEVELOPMENT OF PREVENTIVE AND PERSONALIZED MEDICINE. NEVERTHELESS, MORE RESEARCH IS NEEDED TO ESTABLISH SEX SPECIFIC DIFFERENCES AND TO IDENTIFY NOVEL EPIGENETIC MECHANISMS, SUCH AS SEROTONYLATION AND DOPAMINYLATION, THAT HOLD GREAT PROMISES FOR THE FIELD OF PSYCHIATRY. 2021 16 1329 40 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 17 2021 26 EPIGENETIC CHANGES ASSOCIATED WITH DIFFERENT TYPES OF STRESSORS AND SUICIDE. STRESS IS ASSOCIATED WITH VARIOUS EPIGENETIC CHANGES. SOME STRESS-INDUCED EPIGENETIC CHANGES ARE HIGHLY DYNAMIC, WHEREAS OTHERS ARE ASSOCIATED WITH LASTING MARKS ON THE EPIGENOME. IN OUR STUDY, A COMPREHENSIVE NARRATIVE REVIEW OF THE LITERATURE WAS PERFORMED BY INVESTIGATING THE EPIGENETIC CHANGES THAT OCCUR WITH ACUTE STRESS, CHRONIC STRESS, EARLY CHILDHOOD STRESS, AND TRAUMATIC STRESS EXPOSURES, ALONG WITH EXAMINING THOSE OBSERVED IN POST-MORTEM BRAINS OR BLOOD SAMPLES OF SUICIDE COMPLETERS AND ATTEMPTERS. IN ADDITION, THE TRANSGENERATIONAL EFFECTS OF THESE CHANGES ARE REPORTED. FOR ALL TYPES OF STRESS STUDIES EXAMINED, THE GENES NR3C1, OXTR, SLC6A4, AND BDNF REPRODUCIBLY SHOWED EPIGENETIC CHANGES, WITH SOME MODIFICATIONS OBSERVED TO BE PASSED DOWN TO SUBSEQUENT GENERATIONS FOLLOWING STRESS EXPOSURES. THE AFOREMENTIONED GENES ARE KNOWN TO BE INVOLVED IN NEURONAL DEVELOPMENT AND HORMONAL REGULATION AND ARE ALL ASSOCIATED WITH SUSCEPTIBILITY TO MENTAL HEALTH DISORDERS INCLUDING DEPRESSION, ANXIETY, PERSONALITY DISORDERS, AND PTSD (POST-TRAUMATIC STRESS DISORDER). FURTHER RESEARCH IS WARRANTED IN ORDER TO DETERMINE THE SCOPE OF EPIGENETIC ACTIONABLE TARGETS IN INDIVIDUALS SUFFERING FROM THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES. 2023 18 2139 42 EPIGENETIC INSIGHTS INTO MULTIPLE SCLEROSIS DISEASE PROGRESSION. MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DEMYELINATING AND NEURODEGENERATIVE DISEASE OF THE CENTRAL NERVOUS SYSTEM, IS TODAY A LEADING CAUSE OF UNPREDICTABLE LIFELONG DISABILITY IN YOUNG ADULTS. THE TREATMENT OF PATIENTS IN PROGRESSIVE STAGES REMAINS HIGHLY CHALLENGING, ALLUDING TO OUR LIMITED UNDERSTANDING OF THE UNDERLYING PATHOLOGICAL PROCESSES. IN THIS REVIEW, WE PROVIDE INSIGHTS INTO THE MECHANISMS UNDERPINNING MS PROGRESSION FROM A PERSPECTIVE OF EPIGENETICS, THAT REFERS TO STABLE AND MITOTICALLY HERITABLE, YET REVERSIBLE, CHANGES IN THE GENOME ACTIVITY AND GENE EXPRESSION. WE FIRST RECAPITULATE FINDINGS FROM EPIGENETIC STUDIES EXAMINING THE BRAIN TISSUE OF PROGRESSIVE MS PATIENTS, WHICH SUPPORT A CONTRIBUTION OF DNA AND HISTONE MODIFICATIONS IN IMPAIRED OLIGODENDROCYTE DIFFERENTIATION, DEFECTIVE MYELINATION/REMYELINATION AND SUSTAINED NEURO-AXONAL VULNERABILITY. WE NEXT EXPLORE POSSIBILITIES FOR IDENTIFYING FACTORS AFFECTING PROGRESSION USING EASILY ACCESSIBLE TISSUES SUCH AS BLOOD BY COMPARING EPIGENETIC SIGNATURES IN PERIPHERAL IMMUNE CELLS AND BRAIN TISSUE. DESPITE MINOR OVERLAP AT INDIVIDUAL METHYLATION SITES, NEARLY 30% OF ALTERED GENES REPORTED IN PERIPHERAL IMMUNE CELLS OF PROGRESSIVE MS PATIENTS WERE FOUND IN BRAIN TISSUE, JOINTLY CONVERGING ON ALTERATIONS OF NEURONAL FUNCTIONS. WE FURTHER SPECULATE ABOUT THE MECHANISMS UNDERLYING SHARED EPIGENETIC PATTERNS BETWEEN BLOOD AND BRAIN, WHICH LIKELY IMPLY THE INFLUENCE OF INTERNAL (GENETIC CONTROL) AND/OR EXTERNAL (E.G. SMOKING AND AGEING) FACTORS IMPRINTING A COMMON SIGNATURE IN BOTH COMPARTMENTS. OVERALL, WE PROPOSE THAT EPIGENETICS MIGHT SHED LIGHT ON CLINICALLY RELEVANT MECHANISMS INVOLVED IN DISEASE PROGRESSION AND OPEN NEW AVENUES FOR THE TREATMENT OF PROGRESSIVE MS PATIENTS IN THE FUTURE. 2020 19 6034 38 THE CHALLENGE BY MULTIPLE ENVIRONMENTAL AND BIOLOGICAL FACTORS INDUCE INFLAMMATION IN AGING: THEIR ROLE IN THE PROMOTION OF CHRONIC DISEASE. THE AGING PROCESS IS DRIVEN BY MULTIPLE MECHANISMS THAT LEAD TO CHANGES IN ENERGY PRODUCTION, OXIDATIVE STRESS, HOMEOSTATIC DYSREGULATION AND EVENTUALLY TO LOSS OF FUNCTIONALITY AND INCREASED DISEASE SUSCEPTIBILITY. MOST AGED INDIVIDUALS DEVELOP CHRONIC LOW-GRADE INFLAMMATION, WHICH IS AN IMPORTANT RISK FACTOR FOR MORBIDITY, PHYSICAL AND COGNITIVE IMPAIRMENT, FRAILTY, AND DEATH. AT ANY AGE, CHRONIC INFLAMMATORY DISEASES ARE MAJOR CAUSES OF MORBIMORTALITY, AFFECTING UP TO 5-8% OF THE POPULATION OF INDUSTRIALIZED COUNTRIES. SEVERAL ENVIRONMENTAL FACTORS CAN PLAY AN IMPORTANT ROLE FOR MODIFYING THE INFLAMMATORY STATE. GENETICS ACCOUNTS FOR ONLY A SMALL FRACTION OF CHRONIC-INFLAMMATORY DISEASES, WHEREAS ENVIRONMENTAL FACTORS APPEAR TO PARTICIPATE, EITHER WITH A CAUSATIVE OR A PROMOTIONAL ROLE IN 50% TO 75% OF PATIENTS. SEVERAL OF THOSE CHANGES DEPEND ON EPIGENETIC CHANGES THAT WILL FURTHER MODIFY THE INDIVIDUAL RESPONSE TO ADDITIONAL STIMULI. THE INTERACTION BETWEEN INFLAMMATION AND THE ENVIRONMENT OFFERS IMPORTANT INSIGHTS ON AGING AND HEALTH. THESE CONDITIONS, OFTEN DEPENDING ON THE INDIVIDUAL'S SEX, APPEAR TO LEAD TO DECREASED LONGEVITY AND PHYSICAL AND COGNITIVE DECLINE. IN ADDITION TO BIOLOGICAL FACTORS, THE ENVIRONMENT IS ALSO INVOLVED IN THE GENERATION OF PSYCHOLOGICAL AND SOCIAL CONTEXT LEADING TO STRESS. POOR PSYCHOLOGICAL ENVIRONMENTS AND OTHER SOURCES OF STRESS ALSO RESULT IN INCREASED INFLAMMATION. HOWEVER, THE MECHANISMS UNDERLYING THE ROLE OF ENVIRONMENTAL AND PSYCHOSOCIAL FACTORS AND NUTRITION ON THE REGULATION OF INFLAMMATION, AND HOW THE RESPONSE ELICITED FOR THOSE FACTORS INTERACT AMONG THEM, ARE POORLY UNDERSTOOD. WHEREAS CERTAIN DELETERIOUS ENVIRONMENTAL FACTORS RESULT IN THE GENERATION OF OXIDATIVE STRESS DRIVEN BY AN INCREASED PRODUCTION OF REACTIVE OXYGEN AND NITROGEN SPECIES, ENDOPLASMIC RETICULUM STRESS, AND INFLAMMATION, OTHER FACTORS, INCLUDING NUTRITION (POLYUNSATURATED FATTY ACIDS) AND BEHAVIORAL FACTORS (EXERCISE) CONFER PROTECTION AGAINST INFLAMMATION, OXIDATIVE AND ENDOPLASMIC RETICULUM STRESS, AND THUS AMELIORATE THEIR DELETERIOUS EFFECT. HERE, WE DISCUSS PROCESSES AND MECHANISMS OF INFLAMMATION ASSOCIATED WITH ENVIRONMENTAL FACTORS AND BEHAVIOR, THEIR LINKS TO SEX AND GENDER, AND THEIR OVERALL IMPACT ON AGING. 2020 20 4620 29 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