1 1869 118 EMERGING ROLE OF DREAM IN HEALTHY BRAIN AND NEUROLOGICAL DISEASES. THE DOWNSTREAM REGULATORY ELEMENT ANTAGONIST MODULATOR (DREAM) IS A MULTIFUNCTIONAL CA(2+)-SENSITIVE PROTEIN EXERTING A DUAL MECHANISM OF ACTION TO REGULATE SEVERAL CA(2+)-DEPENDENT PROCESSES. UPON SUMOYLATION, DREAM ENTERS IN NUCLEUS WHERE IT DOWNREGULATES THE EXPRESSION OF SEVERAL GENES PROVIDED WITH A CONSENSUS SEQUENCE NAMED DREAM REGULATORY ELEMENT (DRE). ON THE OTHER HAND, DREAM COULD ALSO DIRECTLY MODULATE THE ACTIVITY OR THE LOCALIZATION OF SEVERAL CYTOSOLIC AND PLASMA MEMBRANE PROTEINS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES IN THE KNOWLEDGE OF DREAM DYSREGULATION AND DREAM-DEPENDENT EPIGENETIC REMODELING AS A CENTRAL MECHANISM IN THE PROGRESSION OF SEVERAL DISEASES AFFECTING CENTRAL NERVOUS SYSTEM, INCLUDING STROKE, ALZHEIMER'S AND HUNTINGTON'S DISEASES, AMYOTROPHIC LATERAL SCLEROSIS, AND NEUROPATHIC PAIN. INTERESTINGLY, DREAM SEEMS TO EXERT A COMMON DETRIMENTAL ROLE IN THESE DISEASES BY INHIBITING THE TRANSCRIPTION OF SEVERAL NEUROPROTECTIVE GENES, INCLUDING THE SODIUM/CALCIUM EXCHANGER ISOFORM 3 (NCX3), BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), PRO-DYNORPHIN, AND C-FOS. THESE FINDINGS LEAD TO THE CONCEPT THAT DREAM MIGHT REPRESENT A PHARMACOLOGICAL TARGET TO AMELIORATE SYMPTOMS AND REDUCE NEURODEGENERATIVE PROCESSES IN SEVERAL PATHOLOGICAL CONDITIONS AFFECTING CENTRAL NERVOUS SYSTEM. 2023 2 6347 30 THE ROLE OF EPIGENETICS IN NEUROINFLAMMATORY-DRIVEN DISEASES. NEURODEGENERATIVE DISORDERS ARE CHARACTERIZED BY THE PROGRESSIVE LOSS OF CENTRAL AND/OR PERIPHERAL NERVOUS SYSTEM NEURONS. WITHIN THIS CONTEXT, NEUROINFLAMMATION COMES UP AS ONE OF THE MAIN FACTORS LINKED TO NEURODEGENERATION PROGRESSION. IN FACT, NEUROINFLAMMATION HAS BEEN RECOGNIZED AS AN OUTSTANDING FACTOR FOR ALZHEIMER'S DISEASE (AD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), PARKINSON'S DISEASE (PD), AND MULTIPLE SCLEROSIS (MS). INTERESTINGLY, NEUROINFLAMMATORY DISEASES ARE CHARACTERIZED BY DRAMATIC CHANGES IN THE EPIGENETIC PROFILE, WHICH MIGHT PROVIDE NOVEL PROGNOSTIC AND THERAPEUTIC FACTORS TOWARDS NEUROINFLAMMATORY TREATMENT. DEEP CHANGES IN DNA AND HISTONE METHYLATION, ALONG WITH HISTONE ACETYLATION AND ALTERED NON-CODING RNA EXPRESSION, HAVE BEEN REPORTED AT THE ONSET OF INFLAMMATORY DISEASES. THE AIM OF THIS WORK IS TO REVIEW THE CURRENT KNOWLEDGE ON THIS FIELD. 2022 3 4643 25 NEUROPATHIC PAIN AS A TRIGGER FOR HISTONE MODIFICATIONS IN LIMBIC CIRCUITRY. CHRONIC PAIN INVOLVES BOTH CENTRAL AND PERIPHERAL NEURONAL PLASTICITY THAT ENCOMPASSES CHANGES IN THE BRAIN, SPINAL CORD, AND PERIPHERAL NOCICEPTORS. WITHIN THE FOREBRAIN, MESOCORTICOLIMBIC REGIONS ASSOCIATED WITH EMOTIONAL REGULATION HAVE RECENTLY BEEN SHOWN TO EXHIBIT LASTING GENE EXPRESSION CHANGES IN MODELS OF CHRONIC PAIN. TO BETTER UNDERSTAND HOW SUCH ENDURING TRANSCRIPTIONAL CHANGES MIGHT BE REGULATED WITHIN BRAIN STRUCTURES ASSOCIATED WITH PROCESSING OF PAIN OR AFFECT, WE EXAMINED EPIGENETIC MODIFICATIONS INVOLVED WITH ACTIVE OR PERMISSIVE TRANSCRIPTIONAL STATES (HISTONE H3 LYSINE 4 MONO AND TRIMETHYLATION, AND HISTONE H3 LYSINE 27 ACETYLATION) IN PERIAQUEDUCTAL GRAY (PAG), LATERAL HYPOTHALAMUS (LH), NUCLEUS ACCUMBENS (NAC), AND VENTRAL TEGMENTAL AREA (VTA) 5 WEEKS AFTER SCIATIC NERVE INJURY IN MICE TO MODEL CHRONIC PAIN. FOR BOTH MALE AND FEMALE MICE IN CHRONIC PAIN, WE OBSERVED AN OVERALL TREND FOR A REDUCTION OF THESE EPIGENETIC MARKERS IN PERIAQUEDUCTAL GRAY, LH, AND NAC, BUT NOT VTA. MOREOVER, WE DISCOVERED THAT SOME EPIGENETIC MODIFICATIONS EXHIBITED CHANGES ASSOCIATED WITH PAIN HISTORY, WHILE OTHERS WERE ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN PAIN SENSITIVITY. WHEN TAKEN TOGETHER, THESE RESULTS SUGGEST THAT NERVE INJURY LEADS TO CHRONIC CHROMATIN-MEDIATED SUPPRESSION OF TRANSCRIPTION IN KEY LIMBIC BRAIN STRUCTURES AND CIRCUITS, WHICH MAY UNDERLIE ENDURING CHANGES IN PAIN PROCESSING AND SENSITIVITY WITHIN THESE SYSTEMS. 2023 4 6364 33 THE ROLE OF LONG NONCODING RNAS IN NEURODEGENERATIVE DISEASES. LONG NONCODING RNAS (LNCRNAS) ARE TRANSCRIPTS WITH LOW PROTEIN-CODING POTENTIAL BUT OCCUPY A LARGE PART OF TRANSCRIPTIONAL OUTPUT. THEIR ROLES INCLUDE REGULATING GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSCRIPTIONAL LEVEL IN CELLULAR HOMEOSTASIS. HOWEVER, LNCRNA STUDIES ARE STILL IN THEIR INFANCY AND THE FUNCTIONS OF THE VAST MAJORITY OF LNCRNA TRANSCRIPTS REMAIN UNKNOWN. IT IS GENERALLY KNOWN THAT THE FUNCTION OF THE HUMAN NERVOUS SYSTEM LARGELY RELIES ON THE PRECISE REGULATION OF GENE EXPRESSION. VARIOUS STUDIES HAVE SHOWN THAT LNCRNAS HAVE A SIGNIFICANT IMPACT ON NORMAL NEURAL DEVELOPMENT AND ON THE DEVELOPMENT AND PROGRESSION OF NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE FOCUSED ON RECENT STUDIES ASSOCIATED WITH LNCRNAS IN NEURODEGENERATIVE DISEASES, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), HUNTINGTON'S DISEASE (HD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), MULTIPLE SYSTEM ATROPHY (MSA), FRONTOTEMPORAL LOBAR DEGENERATION (FTLD), AND GLAUCOMA. GLAUCOMA, CAUSED BY UNEXPLAINED GANGLION CELL LESION AND APOPTOSIS, IS NOW LABELED AS A CHRONIC NEURODEGENERATIVE DISORDER [1], AND THEREFORE, WE DISCUSSED THE ASSOCIATION OF LNCRNAS WITH GLAUCOMA AS WELL. WE ILLUSTRATE THE ROLE OF SOME SPECIFIC LNCRNAS, WHICH MAY PROVIDE NEW INSIGHTS INTO OUR UNDERSTANDING OF THE ETIOLOGY AND PATHOPHYSIOLOGY OF THE NEURODEGENERATIVE DISEASES MENTIONED ABOVE. 2017 5 6039 37 THE CHEMOKINE RECEPTOR CXCR2 SUPPORTS NOCICEPTIVE SENSITIZATION AFTER TRAUMATIC BRAIN INJURY. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. CHEMOKINE RECEPTORS PLAY AN IMPORTANT ROLE IN BOTH PAIN AND BRAIN INJURY. IN THE CURRENT WORK, WE PURSUED THE HYPOTHESIS THAT THE EPIGENETICALLY REGULATED CXC CHEMOKINE RECEPTOR 2 (CXCR2) IS A CRUCIAL MODULATOR OF NOCICEPTIVE SENSITIZATION INDUCED BY TBI. FOR THESE STUDIES, WE USED THE RAT LATERAL FLUID PERCUSSION MODEL OF TBI. HISTONE ACTYLTRANSFERASE ACTIVITY WAS BLOCKED USING ANACARDIC ACID BEGINNING IMMEDIATELY FOLLOWING INJURY, OR DELAYED FOR SEVEN DAYS PRIOR TO ADMINISTRATION. THE SELECTIVE CXCR2 ANTAGONIST SCH527123 ADMINISTERED SYSTEMICALLY OR INTRATHECALLY WAS USED TO PROBE THE ROLE OF CHEMOKINE SIGNALING ON MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE EXPRESSION OF THE CXCR2 RECEPTOR WAS ACCOMPLISHED USING REAL-TIME PCR, IMMUNOHISTOCHEMISTRY, AND WESTERN BLOTTING, WHILE EPIGENETIC REGULATION WAS ASSESSED USING CHROMATIN IMMUNOPRECIPITATION ASSAY. THE SPINAL LEVELS OF SEVERAL PAIN-RELATED MEDIATORS INCLUDING CXCL1, AN ENDOGENOUS LIGAND FOR CXCR2, AS WELL AS BRAIN-DERIVED NEUROTROPHIC FACTOR AND PRODYNORPHIN WERE MEASURED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. WE OBSERVED THAT ANACARDIC ACID POTENTLY BLOCKED AND REVERSED MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE SAME DRUG WAS ABLE TO PREVENT THE UPREGULATION OF CXCR2 AFTER TBI, BUT DID NOT AFFECT THE SPINAL EXPRESSION OF OTHER PAIN MEDIATORS. ON THE OTHER HAND, BOTH SYSTEMICALLY AND INTRATHECALLY ADMINISTERED SCH527123 REVERSED HINDPAW ALLODYNIA AFTER TBI. MOST OF THE SPINAL CXCR2 APPEARED TO BE EXPRESSED BY SPINAL CORD NEURONS. CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS DEMONSTRATED TBI-ENHANCED ASSOCIATION OF THE CXCR2 PROMOTER WITH ACETYLATED-H3K9 HISTONE PROTEIN THAT WAS ALSO REVERSIBLE USING ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS SUGGESTED THAT TBI CAUSES THE UPREGULATION OF SPINAL CXCR2 THROUGH AN EPIGENETIC MECHANISM ULTIMATELY SUPPORTING NOCICEPTIVE SENSITIZATION. THE USE OF CXCR2 ANTAGONISTS MAY, THEREFORE, BE USEFUL IN PAIN RESULTING FROM TBI. 2017 6 3314 34 HIPPOCAMPAL CANNABINOID 1 RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN MALE RATS. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCING LONG-TERM NEUROPLASTIC CHANGES THAT, IN TURN, CONTRIBUTE TO MALADAPTIVE BEHAVIORS. THIS BEHAVIORAL DYSREGULATION IS ASSOCIATED WITH TRANSCRIPTIONAL REPROGRAMMING IN BRAIN REWARD CIRCUITRY, ALTHOUGH THE MECHANISMS UNDERLYING THIS MODULATION REMAIN POORLY UNDERSTOOD. THE ENDOGENOUS CANNABINOID SYSTEM MAY PLAY A ROLE IN THIS PROCESS IN THAT CANNABINOID MECHANISMS MODULATE DRUG REWARD AND CONTRIBUTE TO COCAINE-INDUCED NEURAL ADAPTATIONS. IN THIS STUDY, WE INVESTIGATED WHETHER COCAINE SELF-ADMINISTRATION INDUCES LONG-TERM ADAPTATIONS, INCLUDING TRANSCRIPTIONAL MODIFICATIONS AND ASSOCIATED EPIGENETIC PROCESSES. WE FIRST EXAMINED ENDOCANNABINOID GENE EXPRESSION IN REWARD-RELATED BRAIN REGIONS OF THE RAT FOLLOWING SELF-ADMINISTERED (0.33 MG/KG INTRAVENOUS, FR1, 10 DAYS) COCAINE INJECTIONS. INTERESTINGLY, WE FOUND INCREASED CNR1 EXPRESSION IN SEVERAL STRUCTURES, INCLUDING PREFRONTAL CORTEX, NUCLEUS ACCUMBENS, DORSAL STRIATUM, HIPPOCAMPUS, HABENULA, AMYGDALA, LATERAL HYPOTHALAMUS, VENTRAL TEGMENTAL AREA, AND ROSTROMEDIAL TEGMENTAL NUCLEUS, WITH MOST PRONOUNCED EFFECTS IN THE HIPPOCAMPUS. ENDOCANNABINOID LEVELS, MEASURED BY MASS SPECTROMETRY, WERE ALSO ALTERED IN THIS STRUCTURE. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR IN THE HIPPOCAMPUS REVEALED THAT TWO ACTIVATING HISTONE MARKS, H3K4ME3 AND H3K27AC, WERE ENRICHED AT SPECIFIC ENDOCANNABINOID GENES FOLLOWING COCAINE INTAKE. TARGETING CB1 RECEPTORS USING CHROMOSOME CONFORMATION CAPTURE, WE HIGHLIGHTED SPATIAL CHROMATIN RE-ORGANIZATION IN THE HIPPOCAMPUS, AS WELL AS IN THE NUCLEUS ACCUMBENS, SUGGESTING THAT DESTABILIZATION OF THE CHROMATIN MAY CONTRIBUTE TO NEURONAL RESPONSES TO COCAINE. OVERALL, OUR RESULTS HIGHLIGHT A KEY ROLE FOR THE HIPPOCAMPUS IN COCAINE-INDUCED PLASTICITY AND BROADEN THE UNDERSTANDING OF NEURONAL ALTERATIONS ASSOCIATED WITH ENDOCANNABINOID SIGNALING. THE LATTER SUGGESTS THAT EPIGENETIC MODIFICATIONS CONTRIBUTE TO MALADAPTIVE BEHAVIORS ASSOCIATED WITH CHRONIC DRUG USE. 2022 7 5954 30 TBI-INDUCED NOCICEPTIVE SENSITIZATION IS REGULATED BY HISTONE ACETYLATION. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. IN THESE STUDIES WE PURSUED THE HYPOTHESIS THAT TBI PAIN SENSITIZATION IS ASSOCIATED WITH HISTONE ACETYLATION IN THE RAT LATERAL FLUID PERCUSSION MODEL. SOME ANIMALS RECEIVED HINDPAW INCISIONS IN ADDITION TO TBI TO MIMIC POLYTRAUMA. NEUROPATHOLOGICAL ANALYSIS OF BRAIN TISSUE FROM SHAM AND TBI ANIMALS REVEALED EVIDENCE OF BLEEDING, BREAKDOWN OF THE BLOOD BRAIN BARRIER, IN THE CORTEX, HIPPOCAMPUS, THALAMUS AND OTHER STRUCTURES RELATED TO PAIN SIGNAL PROCESSING. MECHANICAL ALLODYNIA WAS MEASURED IN THESE ANIMALS FOR UP TO EIGHT WEEKS POST-INJURY. INHIBITORS OF HISTONE ACETYLTRANSFERASE (HAT) AND HISTONE DEACETYLASE (HDAC) WERE USED TO PROBE THE ROLE OF HISTONE ACETYLATION IN SUCH PAIN PROCESSING. WE FOLLOWED SERUM MARKERS INCLUDING GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), NEURON-SPECIFIC ENOLASE 2 (NSE) MYELIN BASIC PROTEIN (MBP) AND S100BETA TO GAUGE TBI INJURY SEVERITY. OUR RESULTS SHOWED THAT TBI CAUSED MECHANICAL ALLODYNIA IN THE HINDPAWS OF THE RATS LASTING SEVERAL WEEKS. HINDPAWS CONTRALATERAL TO TBI SHOWED MORE RAPID AND PROFOUND SENSITIZATION THAN IPSILATERAL HINDPAWS. THE INHIBITION OF HAT USING CURCUMIN 50 MG/KG S.C REDUCED MECHANICAL SENSITIZATION WHILE THE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID 50 MG/KG I.P. PROLONGED SENSITIZATION IN THE TBI RATS. IMMUNOHISTOCHEMICAL ANALYSES OF SPINAL CORD TISSUE LOCALIZED CHANGES IN THE LEVEL OF ACETYLATION OF THE H3K9 HISTONE MARK TO DORSAL HORN NEURONS. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE THAT TBI INDUCES SUSTAINED NOCICEPTIVE SENSITIZATION, AND CHANGES IN SPINAL NEURONAL HISTONE PROTEINS MAY PLAY AN IMPORTANT ROLE. 2017 8 1803 15 EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS ON THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NUCLEI OF HIPPOCAMPAL NEURONS IN RATS WITH DIFFERENT EXCITABILITY OF THE NERVOUS SYSTEM. IN RATS WITH LOW EXCITABILITY THRESHOLD OF THE NERVOUS SYSTEM DEMONSTRATING SIGNIFICANT AND PERSISTENT BEHAVIORAL DISORDERS UNDER STRESS CONDITIONS, THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NEURONAL NUCLEI OF HIPPOCAMPAL FIELD CA3 DECREASED OVER 2 WEEKS AFTER LONG-TERM EMOTIONAL AND PAIN STRESS. IT WAS HYPOTHESIZED THAT PROTEIN MECP2 TRIGGERS EPIGENETIC CHANGES IN DNA THAT UNDERLIE "STRESS MEMORY". 2006 9 1466 19 DISTINCT ACTIONS OF ANCESTRAL VINCLOZOLIN AND JUVENILE STRESS ON NEURAL GENE EXPRESSION IN THE MALE RAT. EXPOSURE TO THE ENDOCRINE DISRUPTING CHEMICAL VINCLOZOLIN DURING GESTATION OF AN F0 GENERATION AND/OR CHRONIC RESTRAINT STRESS DURING ADOLESCENCE OF THE F3 DESCENDANTS AFFECTS BEHAVIOR, PHYSIOLOGY, AND GENE EXPRESSION IN THE BRAIN. GENES RELATED TO THE NETWORKS OF GROWTH FACTORS, SIGNALING PEPTIDES, AND RECEPTORS, STEROID HORMONE RECEPTORS AND ENZYMES, AND EPIGENETIC RELATED FACTORS WERE MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION VIA TAQMAN LOW DENSITY ARRAYS TARGETING 48 GENES IN THE CENTRAL AMYGDALOID NUCLEUS, MEDIAL AMYGDALOID NUCLEUS, MEDIAL PREOPTIC AREA (MPOA), LATERAL HYPOTHALAMUS (LH), AND THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS. WE FOUND THAT GROWTH FACTORS ARE PARTICULARLY VULNERABLE TO ANCESTRAL EXPOSURE IN THE CENTRAL AND MEDIAL AMYGDALA; RESTRAINT STRESS DURING ADOLESCENCE AFFECTED NEURAL GROWTH FACTORS IN THE MEDIAL AMYGDALA. SIGNALING PEPTIDES WERE AFFECTED BY BOTH ANCESTRAL EXPOSURE AND STRESS DURING ADOLESCENCE PRIMARILY IN HYPOTHALAMIC NUCLEI. STEROID HORMONE RECEPTORS AND ENZYMES WERE STRONGLY AFFECTED BY RESTRAINT STRESS IN THE MPOA. EPIGENETIC RELATED GENES WERE AFFECTED BY STRESS IN THE VENTROMEDIAL NUCLEUS AND BY BOTH ANCESTRAL EXPOSURE AND STRESS DURING ADOLESCENCE INDEPENDENTLY IN THE CENTRAL AMYGDALA. IT IS NOTEWORTHY THAT THE LH SHOWED NO EFFECTS OF EITHER MANIPULATION. GENE EXPRESSION IS DISCUSSED IN THE CONTEXT OF BEHAVIORAL AND PHYSIOLOGICAL MEASURES PREVIOUSLY PUBLISHED. 2015 10 4848 25 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021 11 5818 37 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES. 2014 12 6227 26 THE LINK OF ORGANOPHOSPHORUS PESTICIDES WITH NEURODEGENERATIVE AND NEURODEVELOPMENTAL DISEASES BASED ON EVIDENCE AND MECHANISMS. ORGANOPHOSPHORUS (OP) COMPOUNDS HAVE BEEN KNOWN AS THE MOST WIDELY USED PESTICIDES DURING THE PAST HALF CENTURY AND THERE HAVE BEEN A HUGE BODY OF LITERATURE REGARDING THEIR ASSOCIATION WITH HUMAN CHRONIC DISEASES. NEURODEGENERATIVE AND NEURODEVELOPMENTAL DISORDERS INCLUDING ALZHEIMER, PARKINSON, AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD), AND AUTISM ARE AMONG THE AFFLICTING NEUROLOGICAL DISEASES WHICH OVERSHADOW HUMAN LIFE AND THEIR HIGHER RISK IN RELATION TO OP EXPOSURES HAVE BEEN UNCOVERED BY EPIDEMIOLOGICAL STUDIES. IN ADDITION, EXPERIMENTAL STUDIES EXPLORING THE UNDERLYING MECHANISMS HAVE PROVIDED SOME EVIDENCE FOR INVOLVEMENT OF CHOLINERGIC DEFICIT, OXIDATIVE STRESS, NEURO-INFLAMMATION, AND EPIGENETIC MODIFICATIONS AS THE PROCESSES WHICH ARE COMMON IN THE TOXICITY OF THE OP AND PATHOPHYSIOLOGY OF THE MENTIONED DISEASES. IN ADDITION, GENETIC MUTATIONS AND POLYMORPHISMS OF DIFFERENT VARIANTS OF SOME GENES LIKE PARAOXONASE HAVE BEEN SHOWN TO BE IMPLICATED IN BOTH SUSCEPTIBILITY TO OPS TOXICITY AND NEUROLOGICAL DISEASES. IN THIS ARTICLE, WE REVIEWED THE EPIDEMIOLOGICAL AS WELL AS EXPERIMENTAL STUDIES EVIDENCING THE ASSOCIATION OF EXPOSURE TO OPS AND INCIDENCE OF NEURODEGENERATIVE AND NEURODEVELOPMENTAL DISEASES. 2018 13 2858 19 FROM RILUZOLE TO DEXPRAMIPEXOLE VIA SUBSTITUTED-BENZOTHIAZOLE DERIVATIVES FOR AMYOTROPHIC LATERAL SCLEROSIS DISEASE TREATMENT: CASE STUDIES. THE 1,3-BENZOTHIAZOLE (BTZ) RING MAY OFFER A VALID OPTION FOR SCAFFOLD-HOPPING FROM INDOLE DERIVATIVES. SEVERAL BTZS HAVE CLINICALLY RELEVANT ROLES, MAINLY AS CNS MEDICINES AND DIAGNOSTIC AGENTS, WITH RILUZOLE BEING ONE OF THE MOST FAMOUS EXAMPLES. RILUZOLE IS CURRENTLY THE ONLY APPROVED DRUG TO TREAT AMYOTROPHIC LATERAL SCLEROSIS (ALS) BUT ITS EFFICACY IS MARGINAL. SEVERAL CLINICAL STUDIES HAVE DEMONSTRATED ONLY LIMITED IMPROVEMENTS IN SURVIVAL, WITHOUT BENEFITS TO MOTOR FUNCTION IN PATIENTS WITH ALS. DESPITE SIGNIFICANT CLINICAL TRIAL EFFORTS TO UNDERSTAND THE GENETIC, EPIGENETIC, AND MOLECULAR PATHWAYS LINKED TO ALS PATHOPHYSIOLOGY, THERAPEUTIC TRANSLATION HAS REMAINED DISAPPOINTINGLY SLOW, PROBABLY DUE TO THE COMPLEXITY AND THE HETEROGENEITY OF THIS DISEASE. MANY OTHER DRUGS TO TACKLE ALS HAVE BEEN TESTED FOR 20 YEARS WITHOUT ANY SUCCESS. DEXPRAMIPEXOLE IS A BTZ STRUCTURAL ANALOG OF RILUZOLE AND WAS A GREAT HOPE FOR THE TREATMENT OF ALS. IN THIS REVIEW, AS AN INTERESTING CASE STUDY IN THE DEVELOPMENT OF A NEW MEDICINE TO TREAT ALS, WE PRESENT THE STRATEGY OF THE DEVELOPMENT OF DEXPRAMIPEXOLE, WHICH WAS ONE OF THE MOST PROMISING DRUGS AGAINST ALS. 2020 14 6536 23 TRANSCRIPTIONAL REGULATION OF TYPE-2 METABOTROPIC GLUTAMATE RECEPTORS: AN EPIGENETIC PATH TO NOVEL TREATMENTS FOR CHRONIC PAIN. ACTIVATION OF METABOTROPIC GLUTAMATE 2 (MGLU2) RECEPTORS INHIBITS PAIN TRANSMISSION AT THE SYNAPSES BETWEEN PRIMARY AFFERENT FIBERS AND NEURONS IN THE DORSAL HORN OF THE SPINAL CORD. IN ADDITION, MGLU2 RECEPTORS ARE FOUND IN PERIPHERAL NOCICEPTORS, AND IN PAIN-REGULATORY CENTERS OF THE BRAIN STEM AND FOREBRAIN. MGLU2 RECEPTOR AGONISTS PRODUCE ANALGESIA IN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN, BUT THEIR USE IS LIMITED BY THE DEVELOPMENT OF TOLERANCE. A NEW THERAPEUTIC STRATEGY COULD BE BASED ON THE TRANSCRIPTIONAL REGULATION OF MGLU2 RECEPTORS VIA THE ACETYLATION-PROMOTED ACTIVATION OF THE P65/RELA TRANSCRIPTION FACTOR. "EPIGENETIC" DRUGS THAT INCREASE MGLU2 RECEPTOR EXPRESSION, INCLUDING L-ACETYLCARNITINE AND INHIBITORS OF HISTONE DEACETYLASES, HAVE A DIFFERENT ANALGESIC PROFILE WITH NO TOLERANCE TO THE THERAPEUTIC EFFECT AFTER REPEATED DOSING. 2010 15 6139 32 THE ETIOLOGICAL CONTRIBUTION OF GABAERGIC PLASTICITY TO THE PATHOGENESIS OF NEUROPATHIC PAIN. NEUROPATHIC PAIN DEVELOPING AFTER PERIPHERAL OR CENTRAL NERVE INJURY IS THE RESULT OF PATHOLOGICAL CHANGES GENERATED THROUGH COMPLEX MECHANISMS. DISRUPTION IN THE HOMEOSTASIS OF EXCITATORY AND INHIBITORY NEURONS WITHIN THE CENTRAL NERVOUS SYSTEM IS A CRUCIAL FACTOR IN THE FORMATION OF HYPERALGESIA OR ALLODYNIA OCCURRING WITH NEUROPATHIC PAIN. THE CENTRAL GABAERGIC PATHWAY HAS RECEIVED ATTENTION FOR ITS EXTENSIVE DISTRIBUTION AND FUNCTION IN NEURAL CIRCUITS, INCLUDING THE GENERATION AND DEVELOPMENT OF NEUROPATHIC PAIN. GABAERGIC INHIBITORY CHANGES THAT OCCUR IN THE INTERNEURONS ALONG DESCENDING MODULATORY AND NOCICEPTIVE PATHWAYS IN THE CENTRAL NERVOUS SYSTEM ARE BELIEVED TO GENERATE NEURONAL PLASTICITY, SUCH AS SYNAPTIC PLASTICITY OR FUNCTIONAL PLASTICITY OF THE RELATED GENES OR PROTEINS, THAT IS THE FOUNDATION OF PERSISTENT NEUROPATHIC PAIN. THE PRIMARY GABAERGIC PLASTICITY OBSERVED IN NEUROPATHIC PAIN INCLUDES GABAERGIC SYNAPSE HOMO- AND HETEROSYNAPTIC PLASTICITY, DECREASED SYNTHESIS OF GABA, DOWN-EXPRESSION OF GLUTAMIC ACID DECARBOXYLASE AND GABA TRANSPORTER, ABNORMAL EXPRESSION OF NKCC1 OR KCC2, AND DISTURBED FUNCTION OF GABA RECEPTORS. IN THIS REVIEW, WE DESCRIBE POSSIBLE MECHANISMS ASSOCIATED WITH GABAERGIC PLASTICITY, SUCH AS CENTRAL SENSITIZATION AND GABAERGIC INTERNEURON APOPTOSIS, AND THE EPIGENETIC ETIOLOGIES OF GABAERGIC PLASTICITY IN NEUROPATHIC PAIN. MOREOVER, WE SUMMARIZE POTENTIAL THERAPEUTIC TARGETS OF GABAERGIC PLASTICITY THAT MAY ALLOW FOR SUCCESSFUL RELIEF OF HYPERALGESIA FROM NERVE INJURY. FINALLY, WE COMPARE THE EFFECTS OF THE GABAERGIC SYSTEM IN NEUROPATHIC PAIN TO OTHER TYPES OF CHRONIC PAIN TO UNDERSTAND THE CONTRIBUTION OF GABAERGIC PLASTICITY TO NEUROPATHIC PAIN. 2019 16 2003 28 EPIGENETIC AND TRANSCRIPTIONAL CONTROL OF THE OPIOID PRODYNORPHINE GENE: IN-DEPTH ANALYSIS IN THE HUMAN BRAIN. NEUROPEPTIDES SERVE AS NEUROHORMONES AND LOCAL PARACRINE REGULATORS THAT CONTROL NEURAL NETWORKS REGULATING BEHAVIOR, ENDOCRINE SYSTEM AND SENSORIMOTOR FUNCTIONS. THEIR EXPRESSION IS CHARACTERIZED BY EXCEPTIONALLY RESTRICTED PROFILES. CIRCUIT-SPECIFIC AND ADAPTIVE EXPRESSION OF NEUROPEPTIDE GENES MAY BE DEFINED BY TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS CONTROLLED BY CELL TYPE AND SUBTYPE SEQUENCE-SPECIFIC TRANSCRIPTION FACTORS, INSULATORS AND SILENCERS. THE OPIOID PEPTIDE DYNORPHINS PLAY A CRITICAL ROLE IN NEUROLOGICAL AND PSYCHIATRIC DISORDERS, PAIN PROCESSING AND STRESS, WHILE THEIR MUTATIONS CAUSE PROFOUND NEURODEGENERATION IN THE HUMAN BRAIN. IN THIS REVIEW, WE FOCUS ON THE PRODYNORPHIN GENE AS A MODEL FOR THE IN-DEPTH EPIGENETIC AND TRANSCRIPTIONAL ANALYSIS OF EXPRESSION OF THE NEUROPEPTIDE GENES. PRODYNORPHIN STUDIES MAY PROVIDE A FRAMEWORK FOR ANALYSIS OF MECHANISMS RELEVANT FOR REGULATION OF NEUROPEPTIDE GENES IN NORMAL AND PATHOLOGICAL HUMAN BRAIN. 2021 17 76 27 A NEW ASPECT OF CHRONIC PAIN AS A LIFESTYLE-RELATED DISEASE. PHYSICAL EXERCISE HAS BEEN ESTABLISHED AS A LOW-COST, SAFE, AND EFFECTIVE WAY TO MANAGE CHRONIC INTRACTABLE PAIN. WE INVESTIGATED THE UNDERLYING MECHANISMS OF EXERCISE-INDUCED HYPOALGESIA (EIH) USING A MOUSE MODEL OF NEUROPATHIC PAIN (NPP). EPIGENETIC CHANGES IN ACTIVATED MICROGLIA AND MAINTAINED GABA SYNTHESIS IN THE SPINAL DORSAL HORN MAY CONTRIBUTE TO EIH. VOLUNTARY EXERCISE (VE), A STRONG REWARD FOR ANIMALS, ALSO INDUCED EIH, WHICH MAY BE DUE IN PART TO THE ACTIVATION OF DOPAMINE (DA) NEURONS IN THE VENTRAL TEGMENTAL AREA (VTA). VE INCREASES THE EXPRESSION OF PCREB IN DOPAMINERGIC NEURONS IN THE VTA, WHICH WOULD ENHANCE DOPAMINE PRODUCTION, AND THEREBY CONTRIBUTES TO THE ACTIVATION OF THE MESOLIMBIC REWARD SYSTEM IN NPP MODEL MICE. WE DEMONSTRATED THAT NEURONS IN THE LATERODORSAL TEGMENTAL AND PEDUNCULOPONTINE TEGMENTAL NUCLEI, A MAJOR INPUT SOURCE OF REWARDING STIMULI TO THE VTA, WERE ACTIVATED BY EXERCISE. CHRONIC PAIN IS AT LEAST PARTLY ATTRIBUTED TO SEDENTARY AND INACTIVE LIFESTYLE AS INDICATED BY THE FEAR-AVOIDANCE MODEL. THEREFORE, CHRONIC PAIN COULD BE RECOGNIZED AS A LIFESTYLE-RELATED DISEASE. PHYSICAL ACTIVITY/INACTIVITY MAY BE DETERMINED BY GENETIC/EPIGENETIC AND NEURAL FACTORS ENCODED IN OUR BRAIN. THE HYPOTHALAMUS AND REWARD SYSTEM IS CLOSELY RELATED IN THE AXIS OF FOOD INTAKE, ENERGY METABOLISM AND PHYSICAL ACTIVITY. UNDERSTANDING THE INTERACTIONS BETWEEN THE MESOLIMBIC DA SYSTEM AND THE HYPOTHALAMUS THAT SENSE AND REGULATE ENERGY BALANCE IS THUS OF SIGNIFICANT IMPORTANCE. FOR EXAMPLE, PROOPIOMELANOCORTIN NEURONS AND MELANOCORTIN 4 RECEPTORS MAY PLAY A ROLE IN CONNECTING THESE TWO SYSTEMS. THEREFORE, IN A CERTAIN SENSE, CHRONIC PAIN AND OBESITY MAY SHARE COMMON BEHAVIORAL AND NEURAL PATHOLOGY, I.E. PHYSICAL INACTIVITY, AS A RESULT OF INACTIVATION OF THE MESOLIMBIC DA SYSTEM. EXERCISE AND INCREASING PHYSICAL ACTIVITY IN DAILY LIFE MAY BE IMPORTANT IN TREATING AND PREVENTING CHRONIC PAIN, A LIFE-STYLE RELATED DISEASE. 2017 18 2827 25 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS. 2011 19 3315 21 HIPPOCAMPAL MU OPIOID RECEPTORS ARE MODULATED FOLLOWING COCAINE SELF-ADMINISTRATION IN RAT. COCAINE ADDICTION IS A COMPLEX PATHOLOGY INDUCED BY LONG-TERM BRAIN CHANGES. UNDERSTANDING THE NEUROCHEMICAL CHANGES UNDERLYING THE REINFORCING EFFECTS OF THIS DRUG OF ABUSE IS CRITICAL FOR REDUCING THE SOCIETAL BURDEN OF DRUG ADDICTION. THE MU OPIOID RECEPTOR PLAYS A MAJOR ROLE IN DRUG REWARD. THIS RECEPTOR IS MODULATED BY CHRONIC COCAINE TREATMENT IN SPECIFIC BRAIN STRUCTURES, BUT FEW STUDIES INVESTIGATED NEUROCHEMICAL ADAPTATIONS INDUCED BY VOLUNTARY COCAINE INTAKE. IN THIS STUDY, WE INVESTIGATED WHETHER INTRAVENOUS COCAINE-SELF ADMINISTRATION (0.33 MG/KG/INJECTION, FIXED-RATIO 1 [FR1], 10 DAYS) IN RATS INDUCES TRANSCRIPTIONAL AND FUNCTIONAL CHANGES OF THE MU OPIOID RECEPTOR IN REWARD-RELATED BRAIN REGIONS. EPIGENETIC PROCESSES WITH HISTONE MODIFICATIONS WERE EXAMINED FOR TWO ACTIVATING MARKS, H3K4ME3, AND H3K27AC. WE FOUND AN INCREASE OF MU OPIOID RECEPTOR GENE EXPRESSION ALONG WITH A POTENTIATION OF ITS FUNCTIONALITY IN HIPPOCAMPUS OF COCAINE SELF-ADMINISTERING ANIMALS COMPARED TO SALINE CONTROLS. CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY QPCR REVEALED NO MODIFICATIONS OF THE HISTONE MARK H3K4ME3 AND H3K27AC LEVELS AT MU OPIOID RECEPTOR PROMOTER. OUR STUDY HIGHLIGHTS THE HIPPOCAMPUS AS AN IMPORTANT TARGET TO FURTHER INVESTIGATE NEUROADAPTIVE PROCESSES LEADING TO COCAINE ADDICTION. 2021 20 4333 38 MICRORNAS: KEY PLAYERS IN MICROGLIA AND ASTROCYTE MEDIATED INFLAMMATION IN CNS PATHOLOGIES. THE SIGNIFICANCE OF MICROGLIA AND ASTROCYTES IN NEURAL DEVELOPMENT, IN MAINTAINING SYNAPTIC CONNECTIONS AND HOMEOSTASIS IN THE HEALTHY BRAIN IS WELL ESTABLISHED. MICROGLIA ARE DYNAMIC IMMUNE CELLS OF THE BRAIN THAT ELICIT AN IMMUNE RESPONSE DURING BRAIN DAMAGE AND ALSO PARTICIPATE IN TISSUE REPAIR AND REGENERATION, WHILE ASTROCYTES CONTRIBUTE TO THE LOCAL INFLAMMATORY RESPONSE BY PRODUCING PROINFLAMMATORY CYTOKINES AND RESOLVING NEURONAL DAMAGE THROUGH PRODUCTION OF ANTI-INFLAMMATORY CYTOKINES AND NEUROTROPHIC FACTORS. RECENT EFFORTS HAVE FOCUSED ON ELUCIDATING THE EPIGENETIC MECHANISMS WHICH REGULATE GLIAL CELL BEHAVIOR IN NORMAL AND PATHOLOGIC STATES. AN IMPORTANT CLASS OF EPIGENETIC REGULATORS IS MICRORNAS (MIRNAS) WHICH ARE SMALL NON-CODING RNA MOLECULES THAT REGULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY. CERTAIN DYSREGULATED MIRNAS CONTRIBUTE TO CHRONIC MICROGLIAL INFLAMMATION IN THE BRAIN, THEREBY LEADING TO PROGRESSION OF NEUROLOGICAL DISEASES LIKE ALZHEIMER'S DISEASE, TRAUMATIC INJURY, AMYOTROPHIC LATERAL SCLEROSIS AND STROKE. FURTHER, SEVERAL MIRNAS ARE DIFFERENTIALLY EXPRESSED IN ASTROCYTES AFTER ISCHEMIA AND SPINAL CORD INJURY. DESPITE KNOWLEDGE ABOUT MIRNAS IN NEUROINFLAMMATION, LITTLE IS KNOWN ABOUT EFFECTIVE DELIVERY ROUTES AND PHARMACOKINETIC DATA FOR MIRNA BASED THERAPEUTICS. THIS REVIEW SUMMARIZES THE CURRENT RESEARCH ON THE ROLE OF MIRNAS IN PROMOTING AND INHIBITING INFLAMMATORY RESPONSE OF MICROGLIA AND ASTROCYTES IN A DISEASE-SPECIFIC MANNER. IN ADDITION, MIRNA DELIVERY AS A THERAPEUTIC STRATEGY TO TREAT NEUROINFLAMMATION IS DISCUSSED. 2016