1 1714 138 DYSLEXIA AS AN ADAPTATION TO CORTICO-LIMBIC STRESS SYSTEM REACTIVITY. A NEW SCHOOL OF THOUGHT IN EVOLUTIONARY DEVELOPMENTAL BIOLOGY, COMBINED WITH RESEARCH IN THE NEUROBIOLOGY OF STRESS, SUGGEST THAT EARLY EXPOSURE TO STRESSFUL CIRCUMSTANCES MAY BE A CAUSE OF DYSLEXIA. A BALANCE BETWEEN EPIGENETIC, STRESS-INDUCED AND COGNITIVE-GROWTH GENETIC PROGRAMS MODULATES THE BRAIN'S CELLULAR, REGIONAL, AND NETWORK HOMEOSTASIS. THIS BALANCE IS ESSENTIAL FOR ADAPTABILITY TO THE NORMATIVE RANGE OF EVERYDAY STRESS. HOWEVER, EVEN MILD CHRONIC STRESS EXPOSITION MAY OVERACTIVATE THE HYPOTHALMIC-PITUITARY-ADRENAL STRESS AXIS, UPSETTING THE HOMEOSTATIC BALANCE BETWEEN THESE PROGRAMS, AND EXPOSING THE BRAIN TO HARMFUL LEVELS OF STRESS HORMONES. A PROTECTIVE STRATEGY TO SUSTAINED DISEQUILIBRIUM PRECOCIOUSLY ADVANCES MATURATION AT THE COST OF NEUROPLASTICITY, WHICH BLUNTS STRESS AXIS REACTIVITY BUT ALSO COMPROMISES LEARNING POTENTIAL IN THE PREFRONTAL CORTEX AND NETWORKS ASSOCIATED WITH DYSLEXIA. STRESS EXCEEDING AN INDIVIDUAL'S RANGE OF RESILIENCE: (1) REDUCES LEVELS OF TFEB AND BDNF, GENE REGULATORY FACTORS PROLONGING MATURATION AND NEUROPLASTICITY; (2) INTERFERES WITH THE INSULAR CORTEX, AMYGDALA AND HIPPOCAMPUS IN COORDINATING AFFERENT VISCERAL SIGNALS WITH COGNITIVE PERFORMANCE; (3) OVER-RECRUITS THE BRAIN'S DEFAULT MODE NETWORK; AND (4) AMPLIFIES RELEASE FROM THE LOCUS COERULEUS/NOREPINEPHRINE SYSTEM WHICH IMPAIRS THE ENTRAINMENT OF OSCILLATIONS IN THE LOWER PHONOLOGICAL FREQUENCIES OF SPEECH. EVIDENCE SUPPORTING A STRESS-GROWTH IMBALANCE IS PRELIMINARY, BUT HOLDS PROMISE FOR RECONCEPTUALIZING THE NEUROBIOLOGY OF DYSLEXIA AND REDUCING ITS PREVALENCE. 2020 2 195 21 ACF CHROMATIN-REMODELING COMPLEX MEDIATES STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIOR. IMPROVED TREATMENT FOR MAJOR DEPRESSIVE DISORDER (MDD) REMAINS ELUSIVE BECAUSE OF THE LIMITED UNDERSTANDING OF ITS UNDERLYING BIOLOGICAL MECHANISMS. IT IS LIKELY THAT STRESS-INDUCED MALADAPTIVE TRANSCRIPTIONAL REGULATION IN LIMBIC NEURAL CIRCUITS CONTRIBUTES TO THE DEVELOPMENT OF MDD, POSSIBLY THROUGH EPIGENETIC FACTORS THAT REGULATE CHROMATIN STRUCTURE. WE ESTABLISH THAT PERSISTENT UPREGULATION OF THE ACF (ATP-UTILIZING CHROMATIN ASSEMBLY AND REMODELING FACTOR) ATP-DEPENDENT CHROMATIN-REMODELING COMPLEX, OCCURRING IN THE NUCLEUS ACCUMBENS OF STRESS-SUSCEPTIBLE MICE AND DEPRESSED HUMANS, IS NECESSARY FOR STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS. WE FOUND THAT ALTERED ACF BINDING AFTER CHRONIC STRESS WAS CORRELATED WITH ALTERED NUCLEOSOME POSITIONING, PARTICULARLY AROUND THE TRANSCRIPTION START SITES OF AFFECTED GENES. THESE ALTERATIONS IN ACF BINDING AND NUCLEOSOME POSITIONING WERE ASSOCIATED WITH REPRESSED EXPRESSION OF GENES IMPLICATED IN SUSCEPTIBILITY TO STRESS. TOGETHER, OUR FINDINGS IDENTIFY THE ACF CHROMATIN-REMODELING COMPLEX AS A CRITICAL COMPONENT IN THE DEVELOPMENT OF SUSCEPTIBILITY TO DEPRESSION AND IN REGULATING STRESS-RELATED BEHAVIORS. 2015 3 2808 29 FETAL PROGRAMMING OF HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS FUNCTION AND BEHAVIOR BY SYNTHETIC GLUCOCORTICOIDS. REDUCED FETAL GROWTH HAS BEEN CLOSELY ASSOCIATED WITH AN INCREASED RISK FOR THE DEVELOPMENT OF CHRONIC DISEASE IN LATER LIFE. ACCUMULATING EVIDENCE INDICATES THAT FETAL EXPOSURE TO EXCESS GLUCOCORTICOIDS REPRESENTS A CRITICAL MECHANISM UNDERLYING THIS ASSOCIATION. APPROXIMATELY 7% OF PREGNANT WOMEN ARE AT RISK OF PRETERM DELIVERY AND THESE WOMEN ARE ROUTINELY TREATED WITH SYNTHETIC GLUCOCORTICOIDS (SGC) BETWEEN 24 AND 34 OF WEEKS GESTATION TO IMPROVE NEONATAL OUTCOME. ANIMAL STUDIES HAVE DEMONSTRATED THAT MATERNALLY ADMINISTERED SGC CROSSES THE PLACENTA, AFFECTING FETAL HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) DEVELOPMENT, RESULTING IN CHANGES IN HPA AXIS FUNCTION THAT PERSIST THROUGHOUT LIFE. THESE CHANGES APPEAR TO BE MODULATED AT THE LEVEL OF GLUCOCORTICOID RECEPTORS (GR) AND MINERALOCORTICOID RECEPTORS (MR) IN THE BRAIN AND PITUITARY. AS THE HPA AXIS INTERACTS WITH MANY OTHER PHYSIOLOGICAL PATHWAYS, THE CHANGES IN ENDOCRINE FUNCTION ARE ALSO SEX-SPECIFIC AND AGE-DEPENDENT. ALTERATIONS IN BEHAVIOR, PARTICULARLY LOCOMOTION, IN ANIMALS EXPOSED TO SGC IN UTERO HAVE ALSO BEEN DEMONSTRATED. CONSISTENT WITH THE FINDING IN ANIMAL MODELS, EMERGING HUMAN DATA ARE INDICATING ATTENTION DEFICIT-HYPERACTIVITY DISORDER (ADHD)-LIKE SYMPTOMS IN CHILDREN EXPOSED TO REPEATED COURSES OF SGC IN UTERO. THIS BEHAVIORAL PHENOTYPE IS LIKELY LINKED TO ALTERATIONS IN DOPAMINE (DA) SIGNALING, SUGGESTING THAT SGC ARE ABLE TO PERMANENTLY MODIFY OR 'PROGRAM' THIS SYSTEM. FINALLY, IT IS EMERGING THAT CHANGES IN HPA AXIS FUNCTION AND BEHAVIOR FOLLOWING ANTENATAL EXPOSURE TO SGC ARE TRANSGENERATIONAL AND LIKELY INVOLVE EPIGENETIC MECHANISMS. A COMPREHENSIVE UNDERSTANDING OF THE ACUTE AND LONG-TERM IMPACT OF SGC EXPOSURE IN UTERO IS NECESSARY TO BEGIN TO DEVELOP RECOMMENDATIONS AND TREATMENT OPTIONS FOR PREGNANT WOMEN AT RISK OF PRETERM DELIVERY. 2008 4 2246 27 EPIGENETIC MODULATION OF INFLAMMATION AND SYNAPTIC PLASTICITY PROMOTES RESILIENCE AGAINST STRESS IN MICE. MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH ABNORMALITIES IN THE BRAIN AND THE IMMUNE SYSTEM. CHRONIC STRESS IN ANIMALS SHOWED THAT EPIGENETIC AND INFLAMMATORY MECHANISMS PLAY IMPORTANT ROLES IN MEDIATING RESILIENCE AND SUSCEPTIBILITY TO DEPRESSION. HERE, THROUGH A HIGH-THROUGHPUT SCREENING, WE IDENTIFY TWO PHYTOCHEMICALS, DIHYDROCAFFEIC ACID (DHCA) AND MALVIDIN-3'-O-GLUCOSIDE (MAL-GLUC) THAT ARE EFFECTIVE IN PROMOTING RESILIENCE AGAINST STRESS BY MODULATING BRAIN SYNAPTIC PLASTICITY AND PERIPHERAL INFLAMMATION. DHCA/MAL-GLUC ALSO SIGNIFICANTLY REDUCES DEPRESSION-LIKE PHENOTYPES IN A MOUSE MODEL OF INCREASED SYSTEMIC INFLAMMATION INDUCED BY TRANSPLANTATION OF HEMATOPOIETIC PROGENITOR CELLS FROM STRESS-SUSCEPTIBLE MICE. DHCA REDUCES PRO-INFLAMMATORY INTERLEUKIN 6 (IL-6) GENERATIONS BY INHIBITING DNA METHYLATION AT THE CPG-RICH IL-6 SEQUENCES INTRONS 1 AND 3, WHILE MAL-GLUC MODULATES SYNAPTIC PLASTICITY BY INCREASING HISTONE ACETYLATION OF THE REGULATORY SEQUENCES OF THE RAC1 GENE. PERIPHERAL INFLAMMATION AND SYNAPTIC MALADAPTATION ARE IN LINE WITH NEWLY HYPOTHESIZED CLINICAL INTERVENTION TARGETS FOR DEPRESSION THAT ARE NOT ADDRESSED BY CURRENTLY AVAILABLE ANTIDEPRESSANTS. 2018 5 677 30 BRAIN CIRCUITS AT RISK IN PSYCHIATRIC DISEASES AND PHARMACOLOGICAL PATHWAYS. THE MULTIPLE BRAIN CIRCUITS INVOLVED IN PSYCHIATRIC DISEASES MAY APPEAR DAUNTING, BUT WE PREFER TO CONCENTRATE ON A SELECT FEW, WITH A PARTICULAR SENSITIVITY TO STRESS AND NEURODEVELOPMENTAL ISSUES, WITH A CLEAR PHARMACOTHERAPY. THIS REVIEW IS STRUCTURED AROUND 1. THE KEY CIRCUITS, THEIR ROLE IN HEALTH AND DISEASE, AND THE NEUROTRANSMITTERS MAINTAINING THEM, 2. THE INFLUENCE OF UPBRINGING, STRESS, CHRONOBIOLOGY, INFLAMMATION AND INFECTION, 3. THE GENETIC AND EPIGENETIC INFLUENCE ON THESE CIRCUITS, PARTICULARLY REGARDING COPY NUMBER VARIANTS AND NEURONAL PLASTICITY, 4. THE USE AND ABUSE OF PHARMACOLOGICAL AGENTS WITH THE PARTICULAR RISKS OF STRESS AND CHRONOBIOLOGY AT CRITICAL PERIODS. A MAJOR EMPHASIS IS PLACED ON THE LINKS BETWEEN HIPPOCAMPUS, PREFRONTAL CORTEX AND AMYGDALA/PERIAQUEDUCTAL GREY WHICH CONTROL SPECIFIC ASPECTS OF COGNITION, MOOD, PAIN AND EVEN VIOLENCE. SOME OF THE RESEARCH FINDINGS WERE FROM THE INNOVATIVE MEDICINE INITIATIVE (IMI) NEWMEDS, A 22MEURO ACADEMIC/INDUSTRIAL CONSORTIUM ON THE BRAIN CIRCUITS CRITICAL FOR PSYCHIATRIC DISEASE. 2021 6 1162 28 CONTRASTING EFFECTS OF ACUTE AND CHRONIC STRESS ON THE TRANSCRIPTOME, EPIGENOME, AND IMMUNE RESPONSE OF ATLANTIC SALMON. STRESS EXPERIENCED DURING EARLY LIFE MAY HAVE LASTING EFFECTS ON THE IMMUNE SYSTEM, WITH IMPACTS ON HEALTH AND DISEASE DEPENDENT ON THE NATURE AND DURATION OF THE STRESSOR. THE EPIGENOME IS ESPECIALLY SENSITIVE TO ENVIRONMENTAL STIMULI DURING EARLY LIFE AND REPRESENTS A POTENTIAL MECHANISM THROUGH WHICH STRESS MAY CAUSE LONG-LASTING HEALTH EFFECTS. HOWEVER, THE EXTENT TO WHICH THE EPIGENOME RESPONDS DIFFERENTLY TO CHRONIC VS ACUTE STRESSORS IS UNCLEAR, ESPECIALLY FOR NON-MAMMALIAN SPECIES. WE EXAMINED THE EFFECTS OF ACUTE STRESS (COLD-SHOCK DURING EMBRYOGENESIS) AND CHRONIC STRESS (ABSENCE OF TANK ENRICHMENT DURING LARVAL-STAGE) ON GLOBAL GENE EXPRESSION (USING RNA-SEQ) AND DNA METHYLATION (USING RRBS) IN THE GILLS OF ATLANTIC SALMON (SALMO SALAR) FOUR MONTHS AFTER HATCHING. CHRONIC STRESS INDUCED PRONOUNCED TRANSCRIPTIONAL DIFFERENCES, WHILE ACUTE STRESS CAUSED FEW LASTING TRANSCRIPTIONAL EFFECTS. HOWEVER, BOTH ACUTE AND CHRONIC STRESS CAUSED LASTING AND CONTRASTING CHANGES IN THE METHYLOME. CRUCIALLY, WE FOUND THAT ACUTE STRESS ENHANCED TRANSCRIPTIONAL IMMUNE RESPONSE TO A PATHOGENIC CHALLENGE (BACTERIAL LIPOPOLYSACCHARIDE, LPS), WHILE CHRONIC STRESS SUPPRESSED IT. WE IDENTIFIED STRESS-INDUCED CHANGES IN PROMOTER AND GENE-BODY METHYLATION THAT WERE ASSOCIATED WITH ALTERED EXPRESSION FOR A SMALL PROPORTION OF IMMUNE-RELATED GENES, AND EVIDENCE OF WIDER EPIGENETIC REGULATION WITHIN SIGNALLING PATHWAYS INVOLVED IN IMMUNE RESPONSE. OUR RESULTS SUGGEST THAT STRESS CAN AFFECT IMMUNO-COMPETENCE THROUGH EPIGENETIC MECHANISMS, AND HIGHLIGHT THE MARKEDLY DIFFERENT EFFECTS OF CHRONIC LARVAL AND ACUTE EMBRYONIC STRESS. THIS KNOWLEDGE COULD BE USED TO HARNESS THE STIMULATORY EFFECTS OF ACUTE STRESS ON IMMUNITY, PAVING THE WAY FOR IMPROVED STRESS AND DISEASE MANAGEMENT THROUGH EPIGENETIC CONDITIONING. 2018 7 4999 30 PERINATAL PROGRAMMING OF CIRCADIAN CLOCK-STRESS CROSSTALK. AN INTACT COMMUNICATION BETWEEN CIRCADIAN CLOCKS AND THE STRESS SYSTEM IS IMPORTANT FOR MAINTAINING PHYSIOLOGICAL HOMEOSTASIS UNDER RESTING CONDITIONS AND IN RESPONSE TO EXTERNAL STIMULI. THERE IS ACCUMULATING EVIDENCE FOR A RECIPROCAL INTERACTION BETWEEN BOTH-FROM THE SYSTEMIC TO THE MOLECULAR LEVEL. DISRUPTION OF THIS INTERACTION BY EXTERNAL FACTORS SUCH AS SHIFTWORK, JETLAG, OR CHRONIC STRESS INCREASES THE RISK OF DEVELOPING METABOLIC, IMMUNE, OR MOOD DISORDERS. FROM EXPERIMENTS IN RODENTS, WE KNOW THAT BOTH SYSTEMS MATURATE DURING THE PERINATAL PERIOD. DURING THAT TIME, EXOGENOUS FACTORS SUCH AS STRESS OR ALTERATIONS IN THE EXTERNAL PHOTOPERIOD MAY CRITICALLY AFFECT-OR PROGRAM-PHYSIOLOGICAL FUNCTIONS LATER IN LIFE. THIS DEVELOPMENTAL PROGRAMMING PROCESS HAS BEEN ATTRIBUTED TO MATERNAL STRESS SIGNALS REACHING THE EMBRYO, WHICH LASTINGLY CHANGE GENE EXPRESSION THROUGH THE INDUCTION OF EPIGENETIC MECHANISMS. DESPITE THE WELL-KNOWN FUNCTION OF THE ADULT CIRCADIAN SYSTEM IN TEMPORAL COORDINATION OF PHYSIOLOGY AND BEHAVIOR, THE ROLE OF MATERNAL AND EMBRYONIC CIRCADIAN CLOCKS DURING PREGNANCY AND POSTNATAL DEVELOPMENT IS STILL POORLY DEFINED. A BETTER UNDERSTANDING OF THE CIRCADIAN-STRESS CROSSTALK AT DIFFERENT PERIODS OF DEVELOPMENT MAY HELP TO IMPROVE STRESS RESISTANCE AND DEVISE PREVENTIVE AND THERAPEUTIC STRATEGIES AGAINST CHRONIC STRESS-ASSOCIATED DISORDERS. 2018 8 2886 20 GABA-AALPHA5 MIGHT BE INVOLVED IN LEARNING-MEMORY DYSFUNCTION IN THE OFFSPRINGS OF CHRONIC ETHANOL-TREATED RATS VIA GABA-AALPHA5 HISTONE H3K9 ACETYLATION. RECENTLY, NUMEROUS STUDIES HAVE BEEN FOCUSED ON THE RELATIONSHIP BETWEEN GABA-A RECEPTORS AND ALCOHOL-INDUCED SPATIAL LEARNING AND MEMORY DEFICITS. GABA-AALPHA5, A SUBUNIT OF GABA-A RECEPTORS, IS CONSIDERED TO PLAY AN IMPORTANT ROLE IN ALCOHOL-INDUCED COGNITIVE IMPAIRMENT, HOWEVER, THE MECHANISM REMAINS OBSCURE. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF GABA-AALPHA5 INCREASED IN RATS TREATED WITH CHRONIC ETHANOL VIA HISTONE H3K9 ACETYLATION. FURTHERMORE, THIS EPIGENETIC MODIFICATION COULD BE INHERITED BY THE NEXT GENERATIONS, WHICH EVENTUALLY EXHIBIT SIMILAR SPATIAL LEARNING AND MEMORY DEFICITS IN THE OFFSPRINGS. IN SUMMARY, OUR RESULTS SUGGESTED THAT GABA-AALPHA5 MIGHT BE INVOLVED IN CHRONIC ETHANOL TREATMENT-INDUCED LEARNING-MEMORY DYSFUNCTION AND FOR THE FIRST TIME PROVED THAT LEARNING-MEMORY DYSFUNCTION COULD BE INHERITED BY THE OFFSPRINGS VIA HISTONE H3K9 ACETYLATION. HOPEFULLY, IN THE NEAR FUTURE, GABA-AALPHA5 INHIBITORS WOULD BE AN EFFECTIVE WAY TO TREAT ALCOHOL-INDUCED COGNITION IMPAIRMENT. 2019 9 5832 27 STRESS-INDUCED EPIGENETIC CHANGES IN HIPPOCAMPAL MKP-1 PROMOTE PERSISTENT DEPRESSIVE BEHAVIORS. CHRONIC STRESS INDUCES PERSISTENT DEPRESSIVE BEHAVIORS. STRESS-INDUCED TRANSCRIPTIONAL ALTERATION OVER THE HOMEOSTATIC RANGE IN STRESS HORMONE-SENSITIVE BRAIN REGIONS IS BELIEVED TO UNDERLIE LONG-LASTING DEPRESSIVE BEHAVIORS. HOWEVER, THE DETAILED MECHANISMS BY WHICH CHRONIC STRESS CAUSES THOSE ADAPTIVE CHANGES ARE NOT CLEARLY UNDERSTOOD. IN THE PRESENT STUDY, WE INVESTIGATED WHETHER EPIGENETIC CHANGES REGULATE STRESS-INDUCED DEPRESSIVE BEHAVIORS. WE FOUND THAT CHRONIC STRESS IN MICE DOWNREGULATES THE EPIGENETIC FACTORS HDAC2 AND SUV39H1 IN THE HIPPOCAMPUS. A SERIES OF FOLLOW-UP ANALYSES INCLUDING CHIP ASSAY AND SIRNA-MEDIATED FUNCTIONAL ANALYSES REVEAL THAT GLUCOCORTICOIDS RELEASED BY STRESS CUMULATIVELY INCREASE MKP-1 EXPRESSION IN THE HIPPOCAMPUS, AND INCREASED MKP-1 THEN DEBILITATES P-CREB AND PPARGAMMA, WHICH IN TURN SUPPRESS THE EPIGENETIC FACTORS HDAC2 AND SUV39H1. FURTHERMORE, HDAC2 AND SUV39H1 NORMALLY SUPPRESS THE TRANSCRIPTION OF THE MKP-1, AND THEREFORE THE REDUCED EXPRESSION OF HDAC2 AND SUV39H1 INCREASES MKP-1 EXPRESSION. ACCORDINGLY, REPEATED STRESS PROGRESSIVELY STRENGTHENS A VICIOUS CYCLE OF THE MKP-1 SIGNALING CASCADE THAT FACILITATES DEPRESSIVE BEHAVIORS. THESE RESULTS SUGGEST THAT THE HIPPOCAMPAL STRESS ADAPTATION SYSTEM COMPRISING HDAC2/SUV39H1-REGULATED MKP-1 SIGNALING NETWORK DETERMINES THE VULNERABILITY TO CHRONIC STRESS AND THE MAINTENANCE OF DEPRESSIVE BEHAVIORS. 2019 10 4627 24 NEUROENDOCRINOLOGICAL AND EPIGENETIC MECHANISMS SUBSERVING AUTONOMIC IMBALANCE AND HPA DYSFUNCTION IN THE METABOLIC SYNDROME. IMPACT OF ENVIRONMENTAL STRESS UPON PATHOPHYSIOLOGY OF THE METABOLIC SYNDROME (METS) HAS BEEN SUBSTANTIATED BY EPIDEMIOLOGICAL, PSYCHOPHYSIOLOGICAL, AND ENDOCRINOLOGICAL STUDIES. THIS REVIEW DISCUSSES RECENT ADVANCES IN THE UNDERSTANDING OF CAUSATIVE ROLES OF NUTRITIONAL FACTORS, SYMPATHOMEDULLO-ADRENAL (SMA) AND HYPOTHALAMIC-PITUITARY ADRENOCORTICAL (HPA) AXES, AND ADIPOSE TISSUE CHRONIC LOW-GRADE INFLAMMATION PROCESSES IN METS. DISTURBANCES IN THE NEUROENDOCRINE SYSTEMS FOR LEPTIN, MELANOCORTIN, AND NEUROPEPTIDE Y (NPY)/AGOUTI-RELATED PROTEIN SYSTEMS HAVE BEEN FOUND RESULTING DIRECTLY IN METS-LIKE CONDITIONS. THE REVIEW IDENTIFIES CANDIDATE RISK GENES FROM FACTORS SHOWN CRITICAL FOR THE FUNCTIONING OF EACH OF THESE NEUROENDOCRINE SIGNALING CASCADES. IN ITS META-ANALYTIC PART, RECENT STUDIES IN EPIGENETIC MODIFICATION (HISTONE METHYLATION, ACETYLATION, PHOSPHORYLATION, UBIQUITINATION) AND POSTTRANSCRIPTIONAL GENE REGULATION BY MICRORNAS ARE EVALUATED. SEVERAL STUDIES SUGGEST MODIFICATION MECHANISMS OF EARLY LIFE STRESS (ELS) AND DIET-INDUCED OBESITY (DIO) PROGRAMMING IN THE HYPOTHALAMIC REGIONS WITH POPULATIONS OF POMC-EXPRESSING NEURONS. EPIGENETIC MODIFICATIONS WERE FOUND IN CORTISOL (HERE HSD11B1 EXPRESSION), MELANOCORTIN, LEPTIN, NPY, AND ADIPONECTIN GENES. WITH RESPECT TO ADIPOSITY GENES, EPIGENETIC MODIFICATIONS WERE DOCUMENTED FOR FAT MASS GENE CLUSTER APOA1/C3/A4/A5, AND THE LIPOLYSIS GENE LIPE. WITH REGARD TO INFLAMMATORY, IMMUNE AND SUBCELLULAR METABOLISM, PPARG, NKBF1, TNFA, TCF7C2, AND THOSE GENES EXPRESSING CYTOCHROME P450 FAMILY ENZYMES INVOLVED IN STEROIDOGENESIS AND IN HEPATIC LIPOPROTEINS WERE DOCUMENTED FOR EPIGENETIC MODIFICATIONS. 2016 11 3002 27 GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS FOR TREATMENT OF MAJOR DEPRESSION: THE 5-HT1A RECEPTOR GENE AS A PARADIGM. MAJOR DEPRESSION AND ANXIETY ARE HIGHLY PREVALENT AND INVOLVE CHRONIC DYSREGULATION OF SEROTONIN, BUT THEY REMAIN POORLY UNDERSTOOD. HERE, WE REVIEW NOVEL TRANSCRIPTIONAL (GENETIC, EPIGENETIC) AND POSTTRANSCRIPTIONAL (MICRORNA, ALTERNATIVE SPLICING) MECHANISMS IMPLICATED IN MENTAL ILLNESS, FOCUSING ON A KEY SEROTONIN-RELATED REGULATOR, THE SEROTONIN 1A (5-HT1A) RECEPTOR. FUNCTIONAL SINGLE-NUCLEOTIDE POLYMORPHISMS AND STRESS-INDUCED DNA METHYLATION OF THE 5-HT1A PROMOTER CONVERGE TO DIFFERENTIALLY ALTER PRE- AND POSTSYNAPTIC 5-HT1A RECEPTOR EXPRESSION ASSOCIATED WITH MAJOR DEPRESSION AND REDUCED THERAPEUTIC RESPONSE TO SEROTONERGIC ANTIDEPRESSANTS. MAJOR DEPRESSION IS ALSO ASSOCIATED WITH ALTERED LEVELS OF SPLICE FACTORS AND MICRORNA, POSTTRANSCRIPTIONAL MECHANISMS THAT REGULATE RNA STABILITY. THE HUMAN 5-HT1A 3'-UNTRANSLATED REGION IS ALTERNATIVELY SPLICED, REMOVING MICRORNA SITES AND INCREASING 5-HT1A EXPRESSION, WHICH IS REDUCED IN MAJOR DEPRESSION AND MAY BE GENOTYPE-DEPENDENT. THUS, THE 5-HT1A RECEPTOR GENE ILLUSTRATES THE CONVERGENCE OF GENETIC, EPIGENETIC AND POSTTRANSCRIPTIONAL MECHANISMS IN GENE EXPRESSION, NEURODEVELOPMENT AND NEUROPLASTICITY, AND MAJOR DEPRESSION. UNDERSTANDING GENE REGULATORY MECHANISMS COULD ENHANCE THE DETECTION, CATEGORIZATION AND PERSONALIZED TREATMENT OF MAJOR DEPRESSION. 2019 12 989 28 CHRONIC SOCIAL DEFEAT STRESS DIFFERENTIALLY REGULATES THE EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE. OBJECTIVES: ALTHOUGH STRESS IS CONSIDERED A PRIMARY RISK FACTOR FOR NEUROPSYCHIATRIC DISORDERS, A MAJORITY OF INDIVIDUALS ARE RESILIENT TO THE EFFECTS OF STRESS EXPOSURE AND SUCCESSFULLY ADAPT TO ADVERSE LIFE EVENTS, WHILE OTHERS, THE SO-CALLED SUSCEPTIBLE INDIVIDUALS, MAY HAVE PROBLEMS TO PROPERLY ADAPT TO ENVIRONMENTAL CHANGES. HOWEVER, THE MECHANISMS UNDERLYING THESE DIFFERENT RESPONSES TO STRESS EXPOSURE ARE POORLY UNDERSTOOD.METHODS: ADULT MALE C57BL/6J MICE WERE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS PROTOCOL AND LEVELS OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES WERE ANALYSED BY REAL-TIME PCR IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) OF SUSCEPTIBLE AND RESILIENT MICE.RESULTS: WE FOUND A SELECTIVE REDUCTION OF BDNF-6 TRANSCRIPT IN THE HPC AND AN INCREASE OF BDNF-4 TRANSCRIPT IN THE PFC OF SUSCEPTIBLE MICE. MOREOVER, SUSCEPTIBLE MICE SHOWED A SELECTIVE REDUCTION OF THE G9A MRNA LEVELS IN THE HPC, WHILE HDAC-5 AND DNMT3A MRNA LEVELS WERE SPECIFICALLY REDUCED IN THE PFC.CONCLUSIONS: OVERALL, OUR RESULTS, SHOWING A DIFFERENT EXPRESSION OF BDNF TRANSCRIPTS AND EPIGENETIC MODIFYING ENZYMES IN SUSCEPTIBLE AND RESILIENT MICE, SUGGEST THAT STRESS RESILIENCE IS NOT SIMPLY A LACK OF ACTIVATION OF STRESS-RELATED PATHWAYS, BUT IS RELATED TO THE ACTIVATION OF ADDITIONAL DIFFERENT SPECIFIC MECHANISMS. 2019 13 3093 29 GENOMIC AND EPIGENOMIC RESPONSES TO CHRONIC STRESS INVOLVE MIRNA-MEDIATED PROGRAMMING. STRESS REPRESENTS A CRITICAL INFLUENCE ON MOTOR SYSTEM FUNCTION AND HAS BEEN SHOWN TO IMPAIR MOVEMENT PERFORMANCE. WE HYPOTHESIZED THAT STRESS-INDUCED MOTOR IMPAIRMENTS ARE DUE TO BRAIN-SPECIFIC CHANGES IN MIRNA AND PROTEIN-ENCODING GENE EXPRESSION. HERE WE SHOW A CAUSAL LINK BETWEEN STRESS-INDUCED MOTOR IMPAIRMENT AND ASSOCIATED GENETIC AND EPIGENETIC RESPONSES IN RELEVANT CENTRAL MOTOR AREAS IN A RAT MODEL. EXPOSURE TO TWO WEEKS OF MILD RESTRAINT STRESS ALTERED THE EXPRESSION OF 39 GENES AND NINE MIRNAS IN THE CEREBELLUM. IN LINE WITH PERSISTENT BEHAVIOURAL IMPAIRMENTS, SOME CHANGES IN GENE AND MIRNA EXPRESSION WERE RESISTANT TO RECOVERY FROM STRESS. INTERESTINGLY, STRESS UP-REGULATED THE EXPRESSION OF ADIPOQ AND PROLACTIN RECEPTOR MRNAS IN THE CEREBELLUM. STRESS ALSO ALTERED THE EXPRESSION OF PRLR, MIR-186, AND MIR-709 IN HIPPOCAMPUS AND PREFRONTAL CORTEX. IN ADDITION, OUR FINDINGS DEMONSTRATE THAT MIR-186 TARGETS THE GENE EPS15. FURTHERMORE, WE FOUND AN AGE-DEPENDENT INCREASE IN EPHRINB3 AND GABAA4 RECEPTORS. THESE DATA SHOW THAT EVEN MILD STRESS RESULTS IN SUBSTANTIAL GENOMIC AND EPIGENOMIC CHANGES INVOLVING MIRNA EXPRESSION AND ASSOCIATED GENE TARGETS IN THE MOTOR SYSTEM. THESE FINDINGS SUGGEST A CENTRAL ROLE OF MIRNA-REGULATED GENE EXPRESSION IN THE STRESS RESPONSE AND IN ASSOCIATED NEUROLOGICAL FUNCTION. 2012 14 6853 44 [NEUROBIOLOGY OF EARLY LIFE TRAUMATIC STRESS AND TRAUMA: PROLONGED NEUROENDOCRINE DYSREGULATION AS A NEURODEVELOPMENTAL RISK FACTOR]. EARLY LIFE STRESSORS DISPLAY A HIGH UNIVERSAL PREVALENCE AND CONSTITUTE A MAJOR PUBLIC HEALTH PROBLEM WITH TWO THIRDS OF YOUTH BEING EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS AND REPRESENTS A DEVELOPMENTAL RISK FACTOR MEDIATING RISK FOR DISEASE. EARLY-LIFE STRESS (ELS) AND CHILDHOOD TRAUMA (CT) CAN BOTH HAVE AN IMPACT ON SENSITIVE NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING LEADING TO CHRONIC HYPER- OR HYPO-ACTIVATION OF THE STRESS SYSTEM. IN ADDITION, ALTERATIONS IN EMOTIONAL AND AUTONOMIC REACTIVITY, CIRCADIAN RHYTHM DISRUPTION, FUNCTIONAL AND STRUCTURAL CHANGES IN THE BRAIN, AS WELL AS IMMUNE AND METABOLIC DYSREGULATION HAVE BEEN LATELY IDENTIFIED AS IMPORTANT RISK FACTORS FOR A CHRONICALLY IMPAIRED HOMEOSTATIC BALANCE AFTER ELS/CT. FURTHERMORE, HUMAN GENETIC BACKGROUND AND EPIGENETIC MODIFICATIONS THROUGH STRESS-RELATED GENE EXPRESSION COULD INTERACT WITH THESE ALTERATIONS AND EXPLAIN INTER-INDIVIDUAL VARIATION IN VULNERABILITY OR RESILIENCE TO STRESS. THIS NARRATIVE REVIEW PRESENTS RELEVANT EVIDENCE FROM MAINLY HUMAN RESEARCH ON THE MOST ACKNOWLEDGED NEUROBIOLOGICAL ALLOSTATIC PATHWAYS EXERTING ENDURING ADVERSE EFFECTS OF ELS/CT EVEN DECADES LATER. FUTURE STUDIES SHOULD PROSPECTIVELY INVESTIGATE POTENTIAL CONFOUNDERS, THEIR TEMPORAL SEQUENCE AND COMBINED EFFECTS AT THE BIOLOGICAL LEVEL, WHILE CONSIDERING THE POTENTIALLY DELAYED TIME-FRAME FOR THE EXPRESSION OF THEIR EFFECTS. FINALLY, SCREENING STRATEGIES FOR ELS/CT AND TRAUMA NEED TO BE IMPROVED. INFORMATION ABOUT ELS/CT HISTORY AND THE NUMBER OF ADVERSE EXPERIENCES COULD HELP TO BETTER IDENTIFY THE INDIVIDUAL RISK FOR DISEASE DEVELOPMENT, PREDICT INDIVIDUAL TREATMENT RESPONSE AND DESIGN PREVENTION STRATEGIES TO REDUCE THE NEGATIVE EFFECTS OF ELS/CT. 2023 15 660 27 BLOOD LEVELS OF T-CELL RECEPTOR EXCISION CIRCLES (TRECS) PROVIDE AN INDEX OF EXPOSURE TO TRAUMATIC STRESS IN MICE AND HUMANS. EXPOSURE TO STRESS TRIGGERS BIOLOGICAL CHANGES THROUGHOUT THE BODY. ACCUMULATING EVIDENCE INDICATES THAT ALTERATIONS IN IMMUNE SYSTEM FUNCTION ARE ASSOCIATED WITH THE DEVELOPMENT OF STRESS-ASSOCIATED ILLNESSES SUCH AS MAJOR DEPRESSIVE DISORDER AND POST-TRAUMATIC STRESS DISORDER, INCREASING INTEREST IN IDENTIFYING IMMUNE MARKERS THAT PROVIDE INSIGHT INTO MENTAL HEALTH. RECOMBINATION EVENTS DURING T-CELL RECEPTOR REARRANGEMENT AND T-CELL MATURATION IN THE THYMUS PRODUCE CIRCULAR DNA FRAGMENTS CALLED T-CELL RECEPTOR EXCISION CIRCLES (TRECS) THAT CAN BE UTILIZED AS INDICATORS OF THYMIC FUNCTION AND NUMBERS OF NEWLY EMIGRATING T-CELLS. GIVEN DATA SUGGESTING THAT STRESS AFFECTS THYMUS FUNCTION, WE EXAMINED WHETHER BLOOD LEVELS OF TRECS MIGHT SERVE AS A QUANTITATIVE PERIPHERAL INDEX OF CUMULATIVE STRESS EXPOSURE AND ITS PHYSIOLOGICAL CORRELATES. WE HYPOTHESIZED THAT CHRONIC STRESS EXPOSURE WOULD COMPROMISE THYMUS FUNCTION AND PRODUCE CORRESPONDING DECREASES IN LEVELS OF TRECS. IN MALE MICE, EXPOSURE TO CHRONIC SOCIAL DEFEAT STRESS (CSDS) PRODUCED THYMIC INVOLUTION, ADRENAL HYPERTROPHY, AND DECREASED LEVELS OF TRECS IN BLOOD. EXTENDING THESE STUDIES TO HUMANS REVEALED ROBUST INVERSE CORRELATIONS BETWEEN LEVELS OF CIRCULATING TRECS AND CHILDHOOD EMOTIONAL AND PHYSICAL ABUSE. CELL-TYPE SPECIFIC ANALYSES ALSO REVEALED ASSOCIATIONS BETWEEN TREC LEVELS AND BLOOD CELL COMPOSITION, AS WELL AS CELL-TYPE SPECIFIC METHYLATION CHANGES IN CD4T + AND CD8T + CELLS. ADDITIONALLY, TREC LEVELS CORRELATED WITH EPIGENETIC AGE ACCELERATION, A COMMON BIOMARKER OF STRESS EXPOSURE. OUR FINDINGS DEMONSTRATE ALIGNMENT BETWEEN FINDINGS IN MICE AND HUMANS AND SUGGEST THAT BLOOD-BORNE TRECS ARE A TRANSLATIONALLY-RELEVANT BIOMARKER THAT CORRELATES WITH, AND PROVIDES INSIGHT INTO, THE CUMULATIVE PHYSIOLOGICAL AND IMMUNE-RELATED IMPACTS OF STRESS EXPOSURE IN MAMMALS. 2022 16 6895 21 [SYSTEMIC CONTROL OF THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF LONG-LASTING CONSEQUENCES OF STRESS]. BASED ON M.E. LOBASHEV'S VIEWS OF THE SYSTEMIC CONTROL OF GENETIC AND CYTOGENEITC PROCESSES AND A SUBSTANTIAL EFFECT OF EXCITABILITY ON PLASTIC CHANGES IN THE CENTRAL NERVOUS SYSTEM (CNS), THE EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS (PEPS) ON THE MOLECULAR, CELL, AND EPIGENETIC MECHANISMS OF INJURY MEMORY WAS STUDIED IN RAT STRAINS BRED FOR A CERTAIN EXCITABILITY OF THE NERVOUS SYSTEM. PEPS WAS FOR THE FIRST TIME FOUND TO CAUSE LONG-LASTING (2 MONTHS) MORPHOLOGICAL ALTERATIONS OF THE CA3 REGION OF THE HIPPOCAMPUS AND TO MODIFY THE GENOME ACTIVITY OF ITS PYRAMIDAL NEURONS. THE TWO PHENOMENA WERE POTENTIATED BY A GENETICALLY DETERMINED LOW FUNCTIONAL STATE OF THE CNS. THE POST-STRESS REGULATION OF THE GENOME FUNCTION IN HIPPOCAMPAL NEURONS WAS MEDIATED BY CHANGES IN HETEROCHROMATIN CONFORMATION, ACTIVATION OF METHYL-CPG-BINDING PROTEIN (MECP2) SYNTHESIS, AND SUBSEQUENT CHANGES IN ACETYLATION OF HISTONE H4. GENETICALLY DETERMINED HIGH EXCITABILITY OF THE NERVOUS SYSTEM PROVED TO BE A RISK FACTOR THAT AFFECTS THE SPECIFICS AND TIME COURSE OF THE OBSERVED MOLECULAR, CELL, AND GENETIC TRANSFORMATIONS OF NEURONS. THE RESULTS PROVIDE FOR A BETTER UNDERSTANDING OF THE EPIGENETIC MECHANISMS OF INJURY MEMORY, WHICH FORMS A PATHOGENETIC BASIS FOR POSTTRAUMATIC STRESS DISORDER AND OTHER HUMAN PSYCHOGENIC CONDITIONS CHARACTERIZED BY A PROLONGED DURATION. 2009 17 3708 20 INFLUENCE OF PHARMACOLOGICAL AND EPIGENETIC FACTORS TO SUPPRESS NEUROTROPHIC FACTORS AND ENHANCE NEURAL PLASTICITY IN STRESS AND MOOD DISORDERS. STRESS-INDUCED MAJOR DEPRESSION AND MOOD DISORDERS ARE CHARACTERIZED BY BEHAVIOURAL ABNORMALITIES AND PSYCHIATRIC ILLNESS, LEADING TO DISABILITY AND IMMATURE MORTALITY WORLDWIDE. NEUROBIOLOGICAL MECHANISMS OF STRESS AND MOOD DISORDERS ARE DISCUSSED CONSIDERING RECENT FINDINGS, AND CHALLENGES TO ENHANCE PHARMACOLOGICAL EFFECTS OF ANTIDEPRESSANT, AND MOOD STABILIZERS. PHARMACOLOGICAL ENHANCEMENT OF KETAMINE AND SCOPOLAMINE REGULATES DEPRESSION AT THE MOLECULAR LEVEL, INCREASING SYNAPTIC PLASTICITY IN PREFRONTAL REGIONS. BLOOD-DERIVED NEUROTROPHIC FACTORS FACILITATE MOOD-DEFICIT SYMPTOMS. EPIGENETIC FACTORS MAINTAIN STRESS-RESILIENCE IN HIPPOCAMPAL REGION. REGULATION OF NEUROTROPHIC FACTORS BLOCKADES STRESS, AND ENHANCES NEURONAL SURVIVAL THOUGH IT PARALYZES LIMBIC REGIONS. MOLECULAR AGENTS AND NEUROTROPHIC FACTORS ALSO CONTROL BEHAVIORAL AND SYNAPTIC PLASTICITY IN ADDICTION AND STRESS DISORDERS. FUTURE RESEARCH ON NEURONAL DYNAMICS AND CELLULAR ACTIONS CAN BE DIRECTED TO OBTAIN THE ETIOLOGY OF SYNAPTIC DYSREGULATION IN MOOD DISORDER AND STRESS. FOR THE FIRST TIME, THE CURRENT REVIEW CONTRIBUTES TO THE LITERATURE OF SYNAPTIC PLASTICITY REPRESENTING THE ROLE OF EPIGENETIC MECHANISMS AND GLUCOCORTICOID RECEPTORS TO PREDICT DEPRESSION AND ANXIETY IN CLINICAL CONDITIONS. 2019 18 2597 26 EPIGENETICS OF SUBCELLULAR STRUCTURE FUNCTIONING IN THE ORIGIN OF RISK OR RESILIENCE TO COMORBIDITY OF NEUROPSYCHIATRIC AND CARDIOMETABOLIC DISORDERS. MECHANISMS CONTROLLING MITOCHONDRIAL FUNCTION, PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM (ER) AND NUCLEAR PROCESSES SUCH AS TELOMERE LENGTH AND DNA REPAIR MAY BE SUBJECT TO EPIGENETIC CUES THAT RELATE THE GENOMIC EXPRESSION AND ENVIRONMENTAL EXPOSURES IN EARLY STAGES OF LIFE. THEY MAY ALSO BE INVOLVED IN THE COMORBID APPEARANCE OF CARDIOMETABOLIC (CMD) AND NEUROPSYCHIATRIC DISORDERS (NPD) DURING ADULTHOOD. MITOCHONDRIAL FUNCTION AND PROTEIN FOLDING IN THE ENDOPLASMIC RETICULUM ARE ASSOCIATED WITH OXIDATIVE STRESS AND ELEVATED INTRACELLULAR CALCIUM LEVELS AND MAY ALSO UNDERLIE THE VULNERABILITY FOR COMORBID CMD AND NPD. MITOCHONDRIA PROVIDE KEY METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD+), ATP, ALPHA-KETOGLUTARATE AND ACETYL COENZYME A THAT ARE REQUIRED FOR MANY TRANSCRIPTIONAL AND EPIGENETIC PROCESSES. THEY ARE ALSO A SOURCE OF FREE RADICALS. ON THE OTHER HAND, EPIGENETIC MARKERS IN NUCLEAR DNA DETERMINE MITOCHONDRIAL BIOGENESIS. THE ER IS THE SUBCELLULAR ORGANELLE IN WHICH SECRETORY PROTEINS ARE FOLDED. MANY ENVIRONMENTAL FACTORS STOP THE ABILITY OF CELLS TO PROPERLY FOLD PROTEINS AND MODIFY POST-TRANSLATIONALLY SECRETORY AND TRANSMEMBRANE PROTEINS LEADING TO ENDOPLASMIC RETICULUM STRESS AND OXIDATIVE STRESS. ER FUNCTIONING MAY BE EPIGENETICALLY DETERMINED. CHRONIC ER STRESS IS EMERGING AS A KEY CONTRIBUTOR TO A GROWING LIST OF HUMAN DISEASES, INCLUDING CMD AND NPD. TELOMERE LOSS CAUSES CHROMOSOMAL FUSION, ACTIVATION OF THE CONTROL OF DNA DAMAGE-RESPONSES, UNSTABLE GENOME AND ALTERED STEM CELL FUNCTION, WHICH MAY UNDERLIE THE COMORBIDITY OF CMD AND NPD. THE LENGTH OF TELOMERES IS RELATED TO OXIDATIVE STRESS AND MAY BE EPIGENETICALLY PROGRAMMED. PATHWAYS INVOLVED IN DNA REPAIR MAY BE EPIGENETICALLY PROGRAMMED AND MAY CONTRIBUTE TO DISEASES. IN THIS PAPER, WE DESCRIBE SUBCELLULAR MECHANISMS THAT ARE DETERMINED BY EPIGENETIC MARKERS AND THEIR POSSIBLE RELATION TO THE DEVELOPMENT OF INCREASED SUSCEPTIBILITY TO DEVELOP CMD AND NPD. 2018 19 5705 21 SINGLE-CELL TRANSCRIPTIONAL CHANGES IN HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR-EXPRESSING NEURONS AFTER EARLY-LIFE ADVERSITY INFORM ENDURING ALTERATIONS IN VULNERABILITIES TO STRESS. BACKGROUND: MENTAL HEALTH AND VULNERABILITIES TO NEUROPSYCHIATRIC DISORDERS INVOLVE THE INTERPLAY OF GENES AND ENVIRONMENT, PARTICULARLY DURING SENSITIVE DEVELOPMENTAL PERIODS. EARLY-LIFE ADVERSITY (ELA) AND STRESS PROMOTE VULNERABILITIES TO STRESS-RELATED AFFECTIVE DISORDERS, YET IT IS UNKNOWN HOW TRANSIENT ELA DICTATES LIFELONG NEUROENDOCRINE AND BEHAVIORAL REACTIONS TO STRESS. THE POPULATION OF HYPOTHALAMIC CORTICOTROPIN-RELEASING FACTOR (CRF)-EXPRESSING NEURONS THAT REGULATE STRESS RESPONSES IS A PROMISING CANDIDATE TO MEDIATE THE LONG-LASTING INFLUENCES OF ELA ON STRESS-RELATED BEHAVIORAL AND HORMONAL RESPONSES VIA ENDURING TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS. METHODS: CAPITALIZING ON A WELL-CHARACTERIZED MODEL OF ELA, WE EXAMINED ELA-INDUCED CHANGES IN GENE EXPRESSION PROFILES OF CRF-EXPRESSING NEURONS IN THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS OF DEVELOPING MALE MICE. WE USED SINGLE-CELL RNA SEQUENCING ON ISOLATED CRF-EXPRESSING NEURONS. WE DETERMINED THE ENDURING FUNCTIONAL CONSEQUENCES OF TRANSCRIPTIONAL CHANGES ON STRESS REACTIVITY IN ADULT ELA MICE, INCLUDING HORMONAL RESPONSES TO ACUTE STRESS, ADRENAL WEIGHTS AS A MEASURE OF CHRONIC STRESS, AND BEHAVIORS IN THE LOOMING SHADOW THREAT TASK. RESULTS: SINGLE-CELL TRANSCRIPTOMICS IDENTIFIED DISTINCT AND NOVEL CRF-EXPRESSING NEURONAL POPULATIONS, CHARACTERIZED BY BOTH THEIR GENE EXPRESSION REPERTOIRE AND THEIR NEUROTRANSMITTER PROFILES. ELA-PROVOKED EXPRESSION CHANGES WERE SELECTIVE TO SPECIFIC SUBPOPULATIONS AND AFFECTED GENES INVOLVED IN NEURONAL DIFFERENTIATION, SYNAPSE FORMATION, ENERGY METABOLISM, AND CELLULAR RESPONSES TO STRESS AND INJURY. IMPORTANTLY, THESE EXPRESSION CHANGES WERE IMPACTFUL, APPARENT FROM ADRENAL HYPERTROPHY AND AUGMENTED BEHAVIORAL RESPONSES TO STRESS IN ADULTHOOD. CONCLUSIONS: WE UNCOVER A NOVEL REPERTOIRE OF STRESS-REGULATING CRF CELL TYPES DIFFERENTIALLY AFFECTED BY ELA AND RESULTING IN AUGMENTED STRESS VULNERABILITY, WITH RELEVANCE TO THE ORIGINS OF STRESS-RELATED AFFECTIVE DISORDERS. 2023 20 5374 32 RECENT ADVANCES IN UNDERSTANDING/MANAGEMENT OF PREMENSTRUAL DYSPHORIC DISORDER/PREMENSTRUAL SYNDROME. PREMENSTRUAL SYNDROME (PMS) AND PREMENSTRUAL DYSPHORIC DISORDER (PMDD) ARE COMMON DISORDERS OF THE LUTEAL PHASE OF THE MENSTRUAL CYCLE AND ARE CHARACTERIZED BY MODERATE TO SEVERE PHYSICAL, AFFECTIVE, OR BEHAVIORAL SYMPTOMS THAT IMPAIR DAILY ACTIVITIES AND QUALITY OF LIFE. PMS AND PMDD HAVE RECENTLY RAISED GREAT INTEREST IN THE RESEARCH COMMUNITY FOR THEIR CONSIDERABLE GLOBAL PREVALENCE. THE ETIOLOGY OF PMS/PMDD IS COMPLEX. OVARIAN REPRODUCTIVE STEROIDS (ESTRADIOL AND PROGESTERONE) ARE CONSIDERED PATHOGENETIC EFFECTORS, BUT THE KEY FEATURE SEEMS TO BE AN ALTERED SENSITIVITY OF THE GABAERGIC CENTRAL INHIBITORY SYSTEM TO ALLOPREGNANOLONE, A NEUROSTEROID DERIVED FROM PROGESTERONE PRODUCED AFTER OVULATION. ALSO, A REDUCED AVAILABILITY OF SEROTONIN SEEMS TO BE INVOLVED. NEW INSIGHTS POINT TO A ROLE FOR GENETIC AND EPIGENETIC MODIFICATIONS OF HORMONAL AND NEUROTRANSMITTER PATHWAYS, AND INFLAMMATION IS THE POTENTIAL LINK BETWEEN PERIPHERAL AND NEUROLOGICAL INTEGRATED RESPONSES TO STRESSORS. THUS, NEW THERAPEUTIC APPROACHES TO PMS/PMDD INCLUDE INHIBITION OF PROGESTERONE RECEPTORS IN THE BRAIN (I.E., WITH ULIPRISTAL ACETATE), REDUCED CONVERSION OF PROGESTERONE TO ITS METABOLITE ALLOPREGNANOLONE WITH DUTASTERIDE, AND POSSIBLE MODULATION OF THE ACTION OF ALLOPREGNANOLONE ON THE BRAIN GABAERGIC SYSTEM WITH SEPRANOLONE. FURTHER RESEARCH IS NEEDED TO BETTER UNDERSTAND THE INTERACTION BETWEEN PERIPHERAL INFLAMMATORY MOLECULES (CYTOKINES, INTERLEUKINS, C-REACTIVE PROTEIN, AND REACTIVE OXYGEN SPECIES) AND THE BRAIN NEUROTRANSMITTER SYSTEMS IN WOMEN WITH PMS/PMDD. IF CONFIRMED, NEUROINFLAMMATION COULD LEAD BOTH TO DEVELOP TARGETED ANTI-INFLAMMATORY THERAPIES AND TO DEFINE PREVENTION STRATEGIES FOR THE ASSOCIATED CHRONIC INFLAMMATORY RISK IN PMS/PMDD. FINALLY, THE OBSERVED ASSOCIATION BETWEEN PREMENSTRUAL DISORDERS AND PSYCHOLOGICAL DISEASES MAY GUIDE PROMPT AND ADEQUATE INTERVENTIONS TO ACHIEVE A BETTER QUALITY OF LIFE. 2022