1 5837 156 STRESSED MITOCHONDRIA: A TARGET TO INTRUDE ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE INOPERABLE, INCAPACITATING, NEUROPSYCHIATRIC, AND DEGENERATIVE MANIFESTATION THAT DRASTICALLY AFFECTS HUMAN LIFE QUALITY. THE CURRENT MEDICATIONS TARGET EXTRA-NEURONAL SENILE PLAQUES, OXIDATIVE STRESS, NEUROINFLAMMATION, INTRANEURONAL NEUROFIBRILLARY TANGLES, CHOLINERGIC DEFICITS, AND EXCITOTOXICITY. AMONG NOVEL PATHWAYS AND TARGETS, BIOENERGETIC AND RESULTANT MITOCHONDRIAL DYSFUNCTION HAS BEEN RECOGNIZED AS ESSENTIAL FACTORS THAT DECIDE THE NEURONAL FATE AND CONSEQUENT NEURODEGENERATION IN AD. THE CRUCIAL ATTRIBUTES OF MITOCHONDRIA, INCLUDING BIOENERGESIS, SIGNALING, SENSING, INTEGRATING, AND TRANSMITTING BIOLOGICAL SIGNALS CONTRIBUTE TO OPTIMUM NETWORKING OF NEURONAL DYNAMICS AND MAKE THEM INDISPENSABLE FOR CELL SURVIVAL. IN AD, MITOCHONDRIAL DYSFUNCTION AND MITOPHAGY ARE A PRELIMINARY AND CRITICAL EVENT THAT AGGRAVATES THE PATHOLOGICAL CASCADE. STRESS IS KNOWN TO PROMOTE AND EXAGGERATE THE NEUROPATHOLOGICAL ALTERATION DURING NEURODEGENERATION AND METABOLIC IMPAIRMENTS, ESPECIALLY IN THE CORTICO-LIMBIC SYSTEM, BESIDES ADVERSELY AFFECTING THE NORMAL PHYSIOLOGY AND MITOCHONDRIAL DYNAMICS. STRESS INVOLVES THE ALLOCATION OF ENERGY RESOURCES FOR NEURONAL SURVIVAL. CHRONIC AND AGGRAVATED STRESS RESPONSE LEADS TO EXCESSIVE RELEASE OF GLUCOCORTICOIDS BY ACTIVATION OF THE HYPOTHALAMIC-PITUITARYADRENAL (HPA) AXIS. BY ACTING THROUGH THEIR RECEPTORS, GLUCOCORTICOIDS INFLUENCE ADVERSE MITOCHONDRIAL CHANGES AND ALTER MTDNA TRANSCRIPTION, MTRNA EXPRESSION, HIPPOCAMPAL MITOCHONDRIAL NETWORK, AND ULTIMATELY MITOCHONDRIAL PHYSIOLOGY. CHRONIC STRESS ALSO AFFECTS MITOCHONDRIAL DYNAMICS BY CHANGING METABOLIC AND NEURO-ENDOCRINAL SIGNALLING, AGGRAVATING OXIDATIVE STRESS, PROVOKING INFLAMMATORY MEDIATORS, ALTERING TROPIC FACTORS, INFLUENCING GENE EXPRESSION, AND MODIFYING EPIGENETIC PATHWAYS. THUS, EXPLORING CHRONIC STRESS-INDUCED GLUCOCORTICOID DYSREGULATION AND RESULTANT BIO-BEHAVIORAL AND PSYCHOSOMATIC MITOCHONDRIAL ALTERATIONS MAY BE A FEASIBLE NARRATIVE TO INVESTIGATE AND UNRAVEL THE MYSTERIOUS PATHOBIOLOGY OF AD. 2021 2 1199 28 CORTICOTROPIN RELEASING FACTOR-BINDING PROTEIN (CRF-BP) AS A POTENTIAL NEW THERAPEUTIC TARGET IN ALZHEIMER'S DISEASE AND STRESS DISORDERS. ALZHEIMER'S DISEASE IS THE MOST COMMON CAUSE OF DEMENTIA AND ONE OF THE MOST COMPLEX HUMAN NEURODEGENERATIVE DISEASES. NUMEROUS STUDIES HAVE DEMONSTRATED A CRITICAL ROLE OF THE ENVIRONMENT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF THE DISEASE, WHERE DAILY LIFE STRESS PLAYS AN IMPORTANT ROLE. A LOT OF EPIGENETIC STUDIES HAVE LED TO THE CONCLUSION THAT CHRONIC STRESS AND STRESS-RELATED DISORDERS PLAY AN IMPORTANT PART IN THE ONSET OF NEURODEGENERATIVE DISORDERS, AND AN ENORMOUS AMOUNT OF RESEARCH YIELDED VALUABLE DISCOVERIES BUT HAS SO FAR NOT LED TO THE DEVELOPMENT OF EFFECTIVE TREATMENT STRATEGIES FOR ALZHEIMER'S DISEASE. CORTICOTROPIN-RELEASING FACTOR (CRF) IS ONE OF THE MAJOR HORMONES AND AT THE SAME TIME A NEUROPEPTIDE ACTING IN STRESS RESPONSE. DEREGULATION OF PROTEIN LEVELS OF CRF IS INVOLVED IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE, BUT LITTLE IS KNOWN ABOUT THE PRECISE ROLES OF CRF AND ITS BINDING PROTEIN, CRF-BP, IN NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE KEY EVIDENCE FOR AND AGAINST THE INVOLVEMENT OF STRESS-ASSOCIATED MODULATION OF THE CRF SYSTEM IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE AND DISCUSS HOW RECENT FINDINGS COULD LEAD TO NEW POTENTIAL TREATMENT POSSIBILITIES IN ALZHEIMER'S DISEASE BY USING CRF-BP AS A THERAPEUTIC TARGET. 2019 3 4635 34 NEUROINFLAMMATORY MECHANISMS IN PARKINSON'S DISEASE: POTENTIAL ENVIRONMENTAL TRIGGERS, PATHWAYS, AND TARGETS FOR EARLY THERAPEUTIC INTERVENTION. MOST ACUTE AND CHRONIC NEURODEGENERATIVE CONDITIONS ARE ACCOMPANIED BY NEUROINFLAMMATION; YET THE EXACT NATURE OF THE INFLAMMATORY PROCESSES AND WHETHER THEY MODIFY DISEASE PROGRESSION IS NOT WELL UNDERSTOOD. IN THIS REVIEW, WE DISCUSS THE KEY EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL EVIDENCE IMPLICATING INFLAMMATORY PROCESSES IN THE PROGRESSIVE DEGENERATION OF THE DOPAMINERGIC (DA) NIGROSTRIATAL PATHWAY AND THEIR POTENTIAL CONTRIBUTION TO THE PATHOPHYSIOLOGY OF PARKINSON'S DISEASE (PD). GIVEN THAT INTERPLAY BETWEEN GENETICS AND ENVIRONMENT ARE LIKELY TO CONTRIBUTE TO RISK FOR DEVELOPMENT OF IDIOPATHIC PD, RECENT DATA SHOWING INTERACTIONS BETWEEN PRODUCTS OF GENES LINKED TO HERITABLE PD THAT FUNCTION TO PROTECT DA NEURONS AGAINST OXIDATIVE OR PROTEOLYTIC STRESS AND INFLAMMATION PATHWAYS WILL BE DISCUSSED. CELLULAR MECHANISMS ACTIVATED OR ENHANCED BY INFLAMMATORY PROCESSES THAT MAY CONTRIBUTE TO MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, OR APOPTOSIS OF DOPAMINERGIC (DA) NEURONS WILL BE REVIEWED, WITH SPECIAL EMPHASIS ON TUMOR NECROSIS FACTOR (TNF) AND INTERLEUKIN-1-BETA (IL-1BETA) SIGNALING PATHWAYS. EPIGENETIC FACTORS WHICH HAVE THE POTENTIAL TO TRIGGER NEUROINFLAMMATION, INCLUDING ENVIRONMENTAL EXPOSURES AND AGE-ASSOCIATED CHRONIC INFLAMMATORY CONDITIONS, WILL BE DISCUSSED AS POSSIBLE 'SECOND-HIT' TRIGGERS THAT MAY AFFECT DISEASE ONSET OR PROGRESSION OF IDIOPATHIC PD. IF INFLAMMATORY PROCESSES HAVE AN ACTIVE ROLE IN NIGROSTRIATAL PATHWAY DEGENERATION, THEN EVIDENCE SHOULD EXIST TO INDICATE THAT SUCH PROCESSES BEGIN IN THE EARLY STAGES OF DISEASE AND THAT THEY CONTRIBUTE TO NEURONAL DYSFUNCTION AND/OR HASTEN NEURODEGENERATION OF THE NIGROSTRIATAL PATHWAY. THERAPEUTICALLY, IF ANTI-INFLAMMATORY INTERVENTIONS CAN BE SHOWN TO RESCUE NIGRAL DA NEURONS FROM DEGENERATION AND LOWER PD RISK, THEN TIMELY USE OF ANTI-INFLAMMATORY THERAPIES SHOULD BE INVESTIGATED FURTHER IN WELL-DESIGNED CLINICAL TRIALS FOR THEIR ABILITY TO PREVENT OR DELAY THE PROGRESSIVE LOSS OF NIGRAL DA NEURONS IN GENETICALLY SUSCEPTIBLE POPULATIONS. 2007 4 5811 23 STRESS - (SELF) EATING: EPIGENETIC REGULATION OF AUTOPHAGY IN RESPONSE TO PSYCHOLOGICAL STRESS. AUTOPHAGY IS A CONSTITUTIVE AND CYTOPROTECTIVE CATABOLIC PROCESS. ABERRATIONS IN AUTOPHAGY LEAD TO A MULTITUDE OF DEGENERATIVE DISORDERS, WITH NEURODEGENERATION BEING ONE OF THE MOST WIDELY STUDIED AUTOPHAGY-RELATED DISORDERS. WHILE THE FIELD HAS LARGELY BEEN FOCUSING ON THE CYTOSOLIC CONSTITUENTS AND PROCESSES OF AUTOPHAGY, RECENT STUDIES ARE INCREASINGLY APPRECIATING THE ROLE OF CHROMATIN MODIFICATIONS AND EPIGENETIC REGULATION IN AUTOPHAGY MAINTENANCE. AUTOPHAGY HAS BEEN IMPLICATED IN THE REGULATION OF NEUROGENESIS, AND DISRUPTION OF NEUROGENESIS IN RESPONSE TO PSYCHOLOGICAL STRESS IS A PROXIMAL RISK FACTOR FOR DEVELOPMENT OF NEUROPSYCHIATRIC DISORDERS SUCH AS MAJOR DEPRESSIVE DISORDER (MDD). IN THIS REVIEW, WE WILL DISCUSS THE REGULATION OF AUTOPHAGY IN NORMAL NEUROGENESIS AS WELL AS DURING CHRONIC PSYCHOLOGICAL STRESS, FOCUSING ON THE EPIGENETIC CONTROL OF AUTOPHAGY IN THESE CONTEXTS, AND ALSO HIGHLIGHT THE LACUNAE IN OUR UNDERSTANDING OF THIS PROCESS. THE SYSTEMATIC STUDY OF THESE REGULATORY MECHANISMS WILL PROVIDE A NOVEL THERAPEUTIC STRATEGY, BASED ON THE USE EPIGENETIC REGULATORS OF AUTOPHAGY TO ENHANCE NEUROGENESIS AND POTENTIALLY ALLEVIATE STRESS-RELATED BEHAVIORAL DISORDERS. 2019 5 3123 37 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 5829 29 STRESS, PSYCHIATRIC DISORDERS, MOLECULAR TARGETS, AND MORE. MENTAL HEALTH IS CENTRAL TO NORMAL HEALTH OUTCOMES. A WIDELY ACCEPTED THEORY IS THAT CHRONIC PERSISTENT STRESS DURING ADULTHOOD AS WELL AS DURING EARLY LIFE TRIGGERS ONSET OF NEUROPSYCHIATRIC AILMENTS. HOWEVER, QUESTIONS RELATED TO HOW THAT OCCURS, AND WHY ARE SOME INDIVIDUALS RESISTANT TO STRESS WHILE OTHERS ARE NOT, REMAIN UNANSWERED. AN INTEGRATED, MULTISYSTEMIC STRESS RESPONSE INVOLVING NEUROINFLAMMATORY, NEUROENDOCRINE, EPIGENETIC AND METABOLIC CASCADES HAVE BEEN SUGGESTED TO HAVE CAUSATIVE LINKS. SEVERAL THEORIES HAVE BEEN PROPOSED OVER THE YEARS TO CONCEPTUALIZE THIS LINK INCLUDING THE CYTOKINE HYPOTHESIS, THE ENDOCRINE HYPOTHESIS, THE OXIDATIVE STRESS HYPOTHESIS AND THE OXIDO-NEUROINFLAMMATION HYPOTHESIS. THE DATA DISCUSSED IN THIS REVIEW DESCRIBES POTENTIAL BIOCHEMICAL BASIS OF THE LINK BETWEEN STRESS, AND STRESS-INDUCED NEURONAL, BEHAVIORAL AND EMOTIONAL DEFICITS, PROVIDING INSIGHTS INTO POTENTIALLY NOVEL DRUG TARGETS. 2019 7 1364 36 DEVELOPMENTAL NEUROENDOCRINOLOGY OF EARLY-LIFE STRESS: IMPACT ON CHILD DEVELOPMENT AND BEHAVIOR. OUR INTERNAL BALANCE, OR HOMEOSTASIS, IS THREATENED OR PERCEIVED AS THREATENED BY STRESSFUL STIMULI, THE STRESSORS. THE STRESS SYSTEM IS A HIGHLY CONSERVED SYSTEM THAT ADJUSTS HOMEOSTASIS TO THE RESTING STATE. THROUGH THE CONCURRENT ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE LOCUS COERULEUS/NOREPINEPHRINE-AUTONOMIC NERVOUS SYSTEMS, THE STRESS SYSTEM PROVIDES THE APPROPRIATE PHYSICAL AND BEHAVIORAL RESPONSES, COLLECTIVELY TERMED AS "STRESS RESPONSE", TO RESTORE HOMEOSTASIS. IF THE STRESS RESPONSE IS PROLONGED, EXCESSIVE OR EVEN INADEQUATE, SEVERAL ACUTE OR CHRONIC STRESS-RELATED PATHOLOGIC CONDITIONS MAY DEVELOP IN CHILDHOOD, ADOLESCENCE AND ADULT LIFE. ON THE OTHER HAND, EARLY-LIFE EXPOSURE TO STRESSORS HAS BEEN RECOGNIZED AS A MAJOR CONTRIBUTING FACTOR UNDERLYING THE PATHOGENESIS OF NON-COMMUNICABLE DISORDERS, INCLUDING NEURODEVELOPMENTAL DISORDERS. ACCUMULATING EVIDENCE SUGGESTS THAT EARLY-LIFE STRESS HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR ATTENTION DEFICIT HYPERACTIVITY DISORDER AND AUTISM SPECTRUM DISORDER IN THE OFFSPRING, ALTHOUGH FINDINGS ARE STILL CONTROVERSIAL. NEVERTHELESS, AT THE MOLECULAR LEVEL, EARLY-LIFE STRESSORS ALTER THE CHEMICAL STRUCTURE OF CYTOSINES LOCAT- ED IN THE REGULATORY REGIONS OF GENES, MOSTLY THROUGH THE ADDITION OF METHYL GROUPS. THESE EPIGENETIC MODIFICATIONS RESULT IN THE SUPPRESSION OF GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. IN ADDITION TO DNA METHYLATION, SEVERAL LINES OF EVIDENCE SUPPORT THE ROLE OF NON-CODING RNAS IN THE EVOLVING FIELD OF EPIGENETICS. IN THIS REVIEW ARTICLE, WE PRESENT THE ANATOMICAL AND FUNCTIONAL COMPO- NENTS OF THE STRESS SYSTEM, DISCUSS THE PROPER, IN TERMS OF QUALITY AND QUANTITY, STRESS RESPONSE, AND PROVIDE AN UPDATE ON THE IMPACT OF EARLY-LIFE STRESS ON CHILD DEVELOPMENT AND BEHAVIOR. 2023 8 5810 27 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC. 2020 9 6097 15 THE EFFECTS OF STRESS ON GLUTAMATERGIC TRANSMISSION IN THE BRAIN. STRESS LEADS TO DETRIMENTAL EFFECTS ON BRAIN FUNCTIONS AND RESULTS IN VARIOUS DISEASES. RECENT STUDIES HIGHLIGHT THE INVOLVEMENT OF GLUTAMATERGIC TRANSMISSION IN PATHOGENESIS OF DEPRESSIVE BEHAVIORS AND FEARS. ACUTE STRESS GENERATES DIFFERENT IMPACTS ON THE EXCITATORY TRANSMISSION COMPARED TO CHRONIC STRESS. DIFFERENT NEUROMODULATORS AND EPIGENETIC FACTORS ALSO PARTICIPATE IN THE ALTERATION OF SYNAPTIC TRANSMISSION AND THE REGULATION OF SYNAPTIC PLASTICITY. RESTORATION OF THE GLUTAMATERGIC TRANSMISSION IN STRESS-AFFECTED BRAIN AREAS THEREFORE PROVIDES NOVEL DIRECTIONS OF THERAPEUTIC INTERVENTIONS AGAINST STRESS. 2015 10 5879 27 SYNTHETIC MITOCHONDRIA AS THERAPEUTICS AGAINST SYSTEMIC AGING: A HYPOTHESIS. WE HYPOTHESIZE HEREIN THAT SYNTHETIC MITOCHONDRIA, ENGINEERED, OR REPROGRAMMED TO BE MORE ENERGETICALLY EFFICIENT AND TO HAVE MILDLY ELEVATED LEVELS OF REACTIVE OXYGEN SPECIES (ROS) PRODUCTION, WOULD BE AN EFFECTIVE FORM OF THERAPEUTICS AGAINST SYSTEMIC AGING. THE FREE RADICAL AND MITOCHONDRIA THEORIES OF AGING HOLD THAT MITOCHONDRIA-GENERATED ROS UNDERLIES CHRONIC ORGANELLE, CELL AND TISSUES DAMAGES THAT CONTRIBUTE TO SYSTEMIC AGING. MORE RECENT FINDINGS, HOWEVER, COLLECTIVELY SUGGEST THAT WHILE ACUTE AND MASSIVE ROS GENERATION DURING EVENTS SUCH AS TISSUE INJURY IS INDEED DETRIMENTAL, SUBACUTE STRESSES, AND CHRONIC ELEVATION IN ROS PRODUCTION MAY INSTEAD INDUCE A STATE OF MITOCHONDRIAL HORMESIS (OR "MITOHORMESIS") THAT COULD EXTEND LIFESPAN. MITOHORMESIS APPEARS TO BE A CONVERGENT MECHANISM FOR SEVERAL KNOWN ANTI-AGING SIGNALING PATHWAYS. IMPORTANTLY, MITOHORMETIC SIGNALING COULD ALSO OCCUR IN A NON-CELL AUTONOMOUS MANNER, WITH ITS INDUCTION IN NEURONS AFFECTING GUT CELLS, FOR EXAMPLE. TECHNOLOGIES ARE OUTLINED THAT COULD LEAD TOWARDS TESTING OF THE HYPOTHESIS, WHICH INCLUDE GENETIC AND EPIGENETIC ENGINEERING OF THE MITOCHONDRIA, AS WELL AS INTERCELLULAR TRANSFER OF MITOCHONDRIA FROM TRANSPLANTED HELPER CELLS TO TARGET TISSUES. 2015 11 534 30 ASTROGLIA IN THE VULNERABILITY TO AND MAINTENANCE OF STRESS-MEDIATED NEUROPATHOLOGY AND DEPRESSION. SIGNIFICANT STRESS EXPOSURE AND PSYCHIATRIC DEPRESSION ARE ASSOCIATED WITH MORPHOLOGICAL, BIOCHEMICAL, AND PHYSIOLOGICAL DISTURBANCES OF ASTROCYTES IN SPECIFIC BRAIN REGIONS RELEVANT TO THE PATHOPHYSIOLOGY OF THOSE DISORDERS, SUGGESTING THAT ASTROCYTES ARE INVOLVED IN THE MECHANISMS UNDERLYING THE VULNERABILITY TO OR MAINTENANCE OF STRESS-RELATED NEUROPATHOLOGY AND DEPRESSION. TO UNDERSTAND THOSE MECHANISMS A VARIETY OF STUDIES HAVE PROBED THE EFFECT OF VARIOUS MODALITIES OF STRESS EXPOSURE ON THE METABOLISM, GENE EXPRESSION AND PLASTICITY OF ASTROCYTES. THESE STUDIES HAVE UNCOVERED THE PARTICIPATION OF VARIOUS CELLULAR PATHWAYS, SUCH AS THOSE FOR INTRACELLULAR CALCIUM REGULATION, NEUROIMMUNE RESPONSES, EXTRACELLULAR IONIC REGULATION, GAP JUNCTIONS-BASED CELLULAR COMMUNICATION, AND REGULATION OF NEUROTRANSMITTER AND GLIOTRANSMITTER RELEASE AND UPTAKE. MORE RECENTLY EPIGENETIC MODIFICATIONS RESULTING FROM EXPOSURE TO CHRONIC FORMS OF STRESS OR TO EARLY LIFE ADVERSITY HAVE BEEN SUGGESTED TO AFFECT NOT ONLY NEURONAL MECHANISMS BUT ALSO GENE EXPRESSION AND PHYSIOLOGY OF ASTROCYTES AND OTHER GLIAL CELLS. HOWEVER, MUCH REMAINS TO BE LEARNED TO UNDERSTAND THE SPECIFIC ROLE OF THOSE AND OTHER MODIFICATIONS IN THE ASTROGLIAL CONTRIBUTION TO THE VULNERABILITY TO AND MAINTENANCE OF STRESS-RELATED DISORDERS AND DEPRESSION, AND FOR LEVERAGING THAT KNOWLEDGE TO ACHIEVE MORE EFFECTIVE PSYCHIATRIC THERAPIES. 2022 12 5519 34 RISK FACTORS FOR ALZHEIMER'S DISEASE: ROLE OF MULTIPLE ANTIOXIDANTS, NON-STEROIDAL ANTI-INFLAMMATORY AND CHOLINERGIC AGENTS ALONE OR IN COMBINATION IN PREVENTION AND TREATMENT. THE ETIOLOGY OF ALZHEIMER'S DISEASE (AD) IS NOT WELL UNDERSTOOD. ETIOLOGIC FACTORS, CHRONIC INFLAMMATORY REACTIONS, OXIDATIVE AND NITROSYLATIVE STRESSES AND HIGH CHOLESTEROL LEVELS ARE THOUGHT TO BE IMPORTANT FOR INITIATING AND PROMOTING NEURODEGENERATIVE CHANGES COMMONLY FOUND IN AD BRAINS. EVEN IN FAMILIAL AD, OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE EARLY ONSET OF THE DISEASE. MITOCHONDRIAL DAMAGE AND PROTEASOME INHIBITION REPRESENT EARLY EVENTS IN THE PATHOGENESIS OF AD, WHEREAS INCREASED PROCESSING OF AMYLOID PRECURSOR PROTEIN (APP) TO BETA-AMYLOID (ABETA) FRAGMENTS (ABETA(40) AND ABETA(42)) AND FORMATION OF SENILE PLAQUES AND NEUROFIBRILLARY TANGLES (NFTS) REPRESENT LATE EVENTS. WE PROPOSE A HYPOTHESIS THAT IN IDIOPATHIC AD, EPIGENETIC COMPONENTS OF NEURONS SUCH AS MITOCHONDRIA, PROTEASOMES AND POST-TRANSLATION PROTEIN MODIFICATIONS (PROCESSING OF AMYLOID PRECURSOR PROTEIN TO BETA-AMYLOID AND HYPERPHOSPHORYLATION OF TAU), RATHER THAN NUCLEAR GENES, ARE THE PRIMARY TARGETS FOR THE ACTION OF DIVERSE GROUPS OF NEUROTOXINS. BASED ON EPIDEMIOLOGIC, LABORATORY AND LIMITED CLINICAL STUDIES, WE PROPOSE THAT A COMBINATION OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND APPROPRIATE LEVELS AND TYPES OF MULTIPLE MICRONUTRIENTS, INCLUDING ANTIOXIDANTS, MAY BE MORE EFFECTIVE THAN THE INDIVIDUAL AGENTS IN THE PREVENTION, AND THEY, IN COMBINATION WITH A CHOLINERGIC AGENT, MAY BE MORE EFFECTIVE IN THE TREATMENT OF AD THAN THE INDIVIDUAL AGENTS ALONE. IN ADDITION, AGENTS, WHICH CAN PREVENT FORMATION OF PLAQUES OR DISSOLVE THESE PLAQUES MAY FURTHER ENHANCE THE EFFICACY OF OUR PROPOSED TREATMENT STRATEGY. 2002 13 5756 41 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 14 678 35 BRAIN DEVELOPMENT UNDER STRESS: HYPOTHESES OF GLUCOCORTICOID ACTIONS REVISITED. ONE OF THE CONUNDRUMS IN TODAY'S STRESS RESEARCH IS WHY SOME INDIVIDUALS FLOURISH AND OTHERS PERISH UNDER SIMILAR STRESSFUL CONDITIONS. IT IS RECOGNIZED THAT THIS INDIVIDUAL VARIABILITY IN ADAPTATION TO STRESS DEPENDS ON THE OUTCOME OF THE INTERACTION OF GENETIC AND COGNITIVE/EMOTIONAL INPUTS IN WHICH GLUCOCORTICOID HORMONES AND RECEPTORS PLAY A CRUCIAL ROLE. HENCE ONE APPROACH TOWARDS UNDERSTANDING INDIVIDUAL VARIATION IN STRESS COPING IS HOW GLUCOCORTICOID ACTIONS CAN CHANGE FROM PROTECTIVE TO HARMFUL. TO ADDRESS THIS QUESTION WE FOCUS ON FOUR HYPOTHESES THAT ARE CONNECTED AND NOT MUTUAL EXCLUSIVE. FIRST, THE CLASSICAL GLUCOCORTICOID CASCADE HYPOTHESIS, IN WHICH THE INABILITY TO COPE WITH CHRONIC STRESS CAUSES A VICIOUS CYCLE OF EXCESS GLUCOCORTICOID AND DOWNREGULATION OF GLUCOCORTICOID RECEPTORS (GR) IN THE HIPPOCAMPUS TRIGGERING A FEED-FORWARD CASCADE OF DEGENERATION AND DISEASE. SECOND, THE BALANCE HYPOTHESIS, WHICH TAKES ALSO THE LIMBIC MINERALOCORTICOID RECEPTORS (MR) INTO ACCOUNT AND PROPOSES THAT AN INTEGRAL LIMBIC MR:GR IMBALANCE IS CAUSAL TO ALTERED PROCESSING OF INFORMATION IN CIRCUITS UNDERLYING FEAR, REWARD, SOCIAL BEHAVIOUR AND RESILIENCE, DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND IMPAIRMENT OF BEHAVIOURAL ADAPTATION. THE MR:GR BALANCE IS ALTERED BY GENE VARIANTS OF THESE RECEPTOR COMPLEXES AND EXPERIENCE-RELATED FACTORS, WHICH CAN INDUCE LASTING EPIGENETIC CHANGES IN THE EXPRESSION OF THESE RECEPTORS. A PARTICULAR POTENT EPIGENETIC STIMULUS IS THE MATERNAL ENVIRONMENT WHICH IS FUNDAMENTAL FOR THE MATERNAL MEDIATION HYPOTHESIS. THE OUTCOME OF PERINATAL GENE X ENVIRONMENT INTERACTION, AND THUS OF MR:GR-MEDIATED FUNCTIONS DEPENDS HOWEVER, ON THE DEGREE OF 'MATCHING' WITH ENVIRONMENTAL DEMANDS IN LATER LIFE. THE PREDICTIVE ADAPTATION HYPOTHESIS THEREFORE PRESENTS A CONCEPTUAL FRAMEWORK TO EXAMINE THE ROLE OF GLUCOCORTICOIDS IN UNDERSTANDING INDIVIDUAL PHENOTYPIC DIFFERENCES IN STRESS-RELATED BEHAVIOURS OVER THE LIFESPAN. 2010 15 4620 27 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 16 2350 34 EPIGENETIC REGULATION OF NEUROINFLAMMATION IN PARKINSON'S DISEASE. NEUROINFLAMMATION IS ONE OF THE MOST SIGNIFICANT FACTORS INVOLVED IN THE INITIATION AND PROGRESSION OF PARKINSON'S DISEASE. PD IS A NEURODEGENERATIVE DISORDER WITH A MOTOR DISABILITY LINKED WITH VARIOUS COMPLEX AND DIVERSIFIED RISK FACTORS. THESE FACTORS TRIGGER MYRIADS OF CELLULAR AND MOLECULAR PROCESSES, SUCH AS MISFOLDING DEFECTIVE PROTEINS, OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND NEUROTOXIC SUBSTANCES THAT INDUCE SELECTIVE NEURODEGENERATION OF DOPAMINE NEURONS. THIS NEURONAL DAMAGE ACTIVATES THE NEURONAL IMMUNE SYSTEM, INCLUDING GLIAL CELLS AND INFLAMMATORY CYTOKINES, TO TRIGGER NEUROINFLAMMATION. THE TRANSITION OF ACUTE TO CHRONIC NEUROINFLAMMATION ENHANCES THE SUSCEPTIBILITY OF INFLAMMATION-INDUCED DOPAMINERGIC NEURON DAMAGE, FORMING A VICIOUS CYCLE AND PROMPTING AN INDIVIDUAL TO PD DEVELOPMENT. EPIGENETIC MECHANISMS RECENTLY HAVE BEEN AT THE FOREFRONT OF THE REGULATION OF NEUROINFLAMMATORY FACTORS IN PD, PROPOSING A NEW DAWN FOR BREAKING THIS VICIOUS CYCLE. THIS REVIEW EXAMINED THE CORE EPIGENETIC MECHANISMS INVOLVED IN THE ACTIVATION AND PHENOTYPIC TRANSFORMATION OF GLIAL CELLS MEDIATED NEUROINFLAMMATION IN PD. WE FOUND THAT EPIGENETIC MECHANISMS DO NOT WORK INDEPENDENTLY, DESPITE BEING COORDINATED WITH EACH OTHER TO ACTIVATE NEUROINFLAMMATORY PATHWAYS. IN THIS REGARD, WE ATTEMPTED TO FIND THE SYNERGIC CORRELATION AND CONTRIBUTION OF THESE EPIGENETIC MODIFICATIONS WITH VARIOUS NEUROINFLAMMATORY PATHWAYS TO BROADEN THE CANVAS OF UNDERLYING PATHOLOGICAL MECHANISMS INVOLVED IN PD DEVELOPMENT. MOREOVER, THIS STUDY HIGHLIGHTED THE DUAL CHARACTERISTICS (NEUROPROTECTIVE/NEUROTOXIC) OF THESE EPIGENETIC MARKS, WHICH MAY COUNTERACT PD PATHOGENESIS AND MAKE THEM POTENTIAL CANDIDATES FOR DEVISING FUTURE PD DIAGNOSIS AND TREATMENT. 2021 17 291 34 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 18 2520 29 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 19 2010 32 EPIGENETIC BASIS OF LEAD-INDUCED NEUROLOGICAL DISORDERS. ENVIRONMENTAL LEAD (PB) EXPOSURE IS CLOSELY ASSOCIATED WITH PATHOGENESIS OF A RANGE OF NEUROLOGICAL DISORDERS, INCLUDING ALZHEIMER'S DISEASE (AD), PARKINSON'S DISEASE (PD), AMYOTROPHIC LATERAL SCLEROSIS (ALS), ATTENTION DEFICIT/HYPERACTIVITY DISORDER (ADHD), ETC. EPIGENETIC MACHINERY MODULATES NEURAL DEVELOPMENT AND ACTIVITIES, WHILE FAULTY EPIGENETIC REGULATION CONTRIBUTES TO THE DIVERSE FORMS OF CNS (CENTRAL NERVOUS SYSTEM) ABNORMALITIES AND DISEASES. AS A POTENT EPIGENETIC MODIFIER, LEAD IS THOUGHT TO CAUSE NEUROLOGICAL DISORDERS THROUGH MODULATING EPIGENETIC MECHANISMS. SPECIFICALLY, INCREASING EVIDENCE LINKED ABERRANT DNA METHYLATIONS, HISTONE MODIFICATIONS AS WELL AS NCRNAS (NON-CODING RNAS) WITH AD CASES, AMONG WHICH CIRCRNA (CIRCULAR RNA) STANDS OUT AS A NEW AND PROMISING FIELD FOR ASSOCIATION STUDIES. IN 23-YEAR-OLD PRIMATES WITH DEVELOPMENTAL LEAD TREATMENT, ZAWIA GROUP DISCOVERED A VARIETY OF EPIGENETIC CHANGES RELATING TO AD PATHOGENESIS. THIS IS A DIRECT EVIDENCE IMPLICATING EPIGENETIC BASIS IN LEAD-INDUCED AD ANIMALS WITH AN ENTIRE LIFESPAN. ADDITIONALLY, SOME EPIGENETIC MOLECULES ASSOCIATED WITH AD ETIOLOGY WERE ALSO KNOWN TO RESPOND TO CHRONIC LEAD EXPOSURE IN COMPARABLE DISEASE MODELS, INDICATING POTENTIALLY INTERLACED MECHANISMS WITH RESPECT TO THE STUDIED NEUROTOXIC AND PATHOLOGICAL EVENTS. OF NOTE, EPIGENETIC MOLECULES ACTED VIA GLOBALLY OR SELECTIVELY INFLUENCING THE EXPRESSION OF DISEASE-RELATED GENES. COMPARED TO AD, THE ASSOCIATION OF LEAD EXPOSURE WITH OTHER NEUROLOGICAL DISORDERS WERE PRIMARILY SUPPORTED BY EPIDEMIOLOGICAL SURVEY, WITH FEWER REPORTS CONNECTING EPIGENETIC REGULATORS WITH LEAD-INDUCED PATHOGENESIS. SOME PHARMACEUTICALS, SUCH AS HDAC (HISTONE DEACETYLASE) INHIBITORS AND DNA METHYLATION INHIBITORS, WERE DEVELOPED TO DEAL WITH CNS DISEASE BY TARGETING EPIGENETIC COMPONENTS. STILL, UNDERSTANDINGS ARE INSUFFICIENT REGARDING THE CAUSE-CONSEQUENCE RELATIONS OF EPIGENETIC FACTORS AND NEUROLOGICAL ILLNESS. THEREFORE, CLEAR EVIDENCE SHOULD BE PROVIDED IN FUTURE INVESTIGATIONS TO ADDRESS DETAILED ROLES OF NOVEL EPIGENETIC FACTORS IN LEAD-INDUCED NEUROLOGICAL DISORDERS, AND EFFORTS OF DEVELOPING SPECIFIC EPIGENETIC THERAPEUTICS SHOULD BE APPRAISED. 2020 20 2596 30 EPIGENETICS OF STRESS ADAPTATIONS IN THE BRAIN. RECENT FINDINGS IN EPIGENETICS SHED NEW LIGHT ON THE REGULATION OF GENE EXPRESSION IN THE CENTRAL NERVOUS SYSTEM (CNS) DURING STRESS. THE MOST FREQUENTLY STUDIED EPIGENETIC MECHANISMS ARE DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNA ACTIVITY. THESE MECHANISMS STABLY DETERMINE CELL PHENOTYPE BUT CAN ALSO BE RESPONSIBLE FOR DYNAMIC MOLECULAR ADAPTATIONS OF THE CNS TO STRESSORS. THE LIMBIC-HYPOTHALAMIC-PITUITARY-ADRENAL AXIS (LHPA) IS THE PRIMARY CIRCUIT THAT INITIATES, REGULATES AND TERMINATES A STRESS RESPONSE. THE SAME BRAIN AREAS THAT CONTROL STRESS ALSO REACT TO STRESS DYNAMICALLY AND WITH LONG-TERM CONSEQUENCES. ONE OF THE BIOLOGICAL PROCESSES EVOKING POTENT ADAPTIVE CHANGES IN THE CNS SUCH AS CHANGES IN BEHAVIOR, GENE ACTIVITY OR SYNAPTIC PLASTICITY IN THE HIPPOCAMPUS IS PSYCHOGENIC STRESS. THIS REVIEW SUMMARIZES THE CURRENT DATA REGARDING THE EPIGENETIC BASIS OF MOLECULAR ADAPTATIONS IN THE BRAIN INCLUDING GENOME-WIDE EPIGENETIC CHANGES OF DNA METHYLATION AND PARTICULAR GENES INVOLVED IN EPIGENETIC RESPONSES THAT PARTICIPATE IN THE BRAIN RESPONSE TO CHRONIC PSYCHOGENIC STRESSORS. IT IS CONCLUDED THAT SPECIFIC EPIGENETIC MECHANISMS IN THE CNS ARE INVOLVED IN THE STRESS RESPONSE. 2013