1 3760 99 INTEGRATED SINGLE CELL ANALYSIS SHOWS CHRONIC ALCOHOL DRINKING DISRUPTS MONOCYTE DIFFERENTIATION IN THE BONE MARROW. CHRONIC HEAVY ALCOHOL DRINKING (CHD) REWIRES MONOCYTES AND MACROPHAGES TOWARD HEIGHTENED INFLAMMATORY STATES WITH COMPROMISED ANTIMICROBIAL DEFENSES THAT PERSIST AFTER 1-MONTH ABSTINENCE. TO DETERMINE WHETHER THESE CHANGES ARE MEDIATED THROUGH ALTERATIONS IN THE BONE MARROW NICHE, WE PROFILED MONOCYTES AND HEMATOPOIETIC STEM CELL PROGENITORS (HSCPS) FROM CHD RHESUS MACAQUES USING A COMBINATION OF FUNCTIONAL ASSAYS AND SINGLE CELL GENOMICS. CHD RESULTED IN TRANSCRIPTIONAL PROFILES CONSISTENT WITH INCREASED ACTIVATION AND INFLAMMATION WITHIN BONE MARROW RESIDENT MONOCYTES AND MACROPHAGES. FURTHERMORE, CHD RESULTED IN TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH INCREASED OXIDATIVE AND CELLULAR STRESS IN HSCP. DIFFERENTIATION OF HSCP IN VITRO REVEALED SKEWING TOWARD MONOCYTES EXPRESSING "NEUTROPHIL-LIKE" MARKERS WITH GREATER INFLAMMATORY RESPONSES TO BACTERIAL AGONISTS. FURTHER ANALYSES OF HSCPS SHOWED BROAD EPIGENETIC CHANGES THAT WERE IN LINE WITH EXACERBATED INFLAMMATORY RESPONSES WITHIN MONOCYTES AND THEIR PROGENITORS. IN SUMMARY, CHD ALTERS HSCPS IN THE BONE MARROW LEADING TO THE PRODUCTION OF MONOCYTES POISED TO GENERATE DYSREGULATED HYPER-INFLAMMATORY RESPONSES. 2023 2 231 23 ADAPTIVE CARDIORESPIRATORY CHANGES TO CHRONIC CONTINUOUS AND INTERMITTENT HYPOXIA. THIS CHAPTER REVIEWS CARDIORESPIRATORY ADAPTATIONS TO CHRONIC HYPOXIA (CH) EXPERIENCED AT HIGH ALTITUDE AND CARDIORESPIRATORY PATHOLOGIES ELICITED BY CHRONIC INTERMITTENT HYPOXIA (CIH) OCCURRING WITH OBSTRUCTIVE SLEEP APNEA (OSA). SHORT-TERM CH INCREASES BREATHING (VENTILATORY ACCLIMATIZATION TO HYPOXIA) AND BLOOD PRESSURE (BP) THROUGH CAROTID BODY (CB) CHEMO REFLEX. HYPERPLASIA OF GLOMUS CELLS, ALTERATIONS IN ION CHANNELS, AND RECRUITMENT OF ADDITIONAL EXCITATORY MOLECULES ARE IMPLICATED IN THE HEIGHTENED CB CHEMO REFLEX BY CH. TRANSCRIPTIONAL ACTIVATION OF HYPOXIA-INDUCIBLE FACTORS (HIF-1 AND 2) IS A MAJOR MOLECULAR MECHANISM UNDERLYING RESPIRATORY ADAPTATIONS TO SHORT-TERM CH. HIGH-ALTITUDE NATIVES EXPERIENCING LONG-TERM CH EXHIBIT BLUNTED HYPOXIC VENTILATORY RESPONSE (HVR) AND REDUCED BP DUE TO DESENSITIZATION OF CB RESPONSE TO HYPOXIA AND IMPAIRED PROCESSING OF CB SENSORY INFORMATION AT THE CENTRAL NERVOUS SYSTEM. VENTILATORY CHANGES EVOKED BY LONG-TERM CH ARE NOT READILY REVERSED AFTER RETURN TO SEA LEVEL. OSA PATIENTS AND RODENTS SUBJECTED TO CIH EXHIBIT HEIGHTENED CB CHEMO REFLEX, INCREASED HYPOXIC VENTILATORY RESPONSE, AND HYPERTENSION. INCREASED GENERATION OF REACTIVE OXYGEN SPECIES (ROS) IS A MAJOR CELLULAR MECHANISM UNDERLYING CIH-INDUCED ENHANCED CB CHEMO REFLEX AND THE ENSUING CARDIORESPIRATORY PATHOLOGIES. ROS GENERATION BY CIH IS MEDIATED BY NONTRANSCRIPTIONAL, DISRUPTED HIF-1 AND HIF-2-DEPENDENT TRANSCRIPTIONS AS WELL AS EPIGENETIC MECHANISMS. 2022 3 3759 74 INTEGRATED SINGLE CELL ANALYSIS SHOWS CHRONIC ALCOHOL DRINKING DISRUPTS MONOCYTE DIFFERENTIATION IN THE BONE MARROW NICHE. CHRONIC ALCOHOL DRINKING REWIRES CIRCULATING MONOCYTES AND TISSUE-RESIDENT MACROPHAGES TOWARDS HEIGHTENED INFLAMMATORY STATES WITH COMPROMISED ANTI-MICROBIAL DEFENSES. AS THESE EFFECTS REMAIN CONSISTENT IN SHORT-LIVED MONOCYTES AFTER A 1-MONTH ABSTINENCE PERIOD IT IS UNCLEAR WHETHER THESE CHANGES ARE RESTRICTED TO THE PERIPHERY OR MEDIATED THROUGH ALTERATIONS IN THE PROGENITOR NICHE. TO TEST THIS HYPOTHESIS, WE PROFILED MONOCYTES/MACROPHAGES AND HEMATOPOIETIC STEM CELL PROGENITORS (HSCP) OF THE BONE MARROW COMPARTMENT FROM RHESUS MACAQUES AFTER 12 MONTHS OF ETHANOL CONSUMPTION USING A COMBINATION OF FUNCTIONAL ASSAYS AND SINGLE CELL GENOMICS. BONE MARROW-RESIDENT MONOCYTES/MACROPHAGES FROM ETHANOL-CONSUMING ANIMALS EXHIBITED HEIGHTENED INFLAMMATION. DIFFERENTIATION OF HSCP IN VITRO REVEALED SKEWING TOWARDS MONOCYTES EXPRESSING NEUTROPHIL-LIKE MARKERS WITH HEIGHTENED INFLAMMATORY RESPONSES TO BACTERIAL AGONISTS. SINGLE CELL TRANSCRIPTIONAL ANALYSIS OF HSCPS SHOWED REDUCED PROLIFERATION BUT INCREASED INFLAMMATORY MARKERS IN MATURE MYELOID PROGENITORS. WE OBSERVED TRANSCRIPTIONAL SIGNATURES ASSOCIATED WITH INCREASED OXIDATIVE AND CELLULAR STRESS AS WELL AS OXIDATIVE PHOSPHORYLATION IN IMMATURE AND MATURE MYELOID PROGENITORS. SINGLE CELL ANALYSIS OF THE CHROMATIN LANDSCAPE SHOWED ALTERED DRIVERS OF DIFFERENTIATION IN MONOCYTES AND PROGENITORS. COLLECTIVELY, THESE DATA INDICATE THAT CHRONIC ETHANOL DRINKING RESULTS IN REMODELING OF THE TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPES OF THE BONE MARROW COMPARTMENT LEADING TO ALTERED FUNCTIONS IN THE PERIPHERY. 2023 4 5315 26 PSYCHOLOGICAL STRESS IN CHILDHOOD AND SUSCEPTIBILITY TO THE CHRONIC DISEASES OF AGING: MOVING TOWARD A MODEL OF BEHAVIORAL AND BIOLOGICAL MECHANISMS. AMONG PEOPLE EXPOSED TO MAJOR PSYCHOLOGICAL STRESSORS IN EARLY LIFE, THERE ARE ELEVATED RATES OF MORBIDITY AND MORTALITY FROM CHRONIC DISEASES OF AGING. THE MOST COMPELLING DATA COME FROM STUDIES OF CHILDREN RAISED IN POVERTY OR MALTREATED BY THEIR PARENTS, WHO SHOW HEIGHTENED VULNERABILITY TO VASCULAR DISEASE, AUTOIMMUNE DISORDERS, AND PREMATURE MORTALITY. THESE FINDINGS RAISE CHALLENGING THEORETICAL QUESTIONS. HOW DOES CHILDHOOD STRESS GET UNDER THE SKIN, AT THE MOLECULAR LEVEL, TO AFFECT RISK FOR LATER DISEASES? AND HOW DOES IT INCUBATE THERE, GIVING RISE TO DISEASES SEVERAL DECADES LATER? HERE WE PRESENT A BIOLOGICAL EMBEDDING MODEL, WHICH ATTEMPTS TO ADDRESS THESE QUESTIONS BY SYNTHESIZING KNOWLEDGE ACROSS SEVERAL BEHAVIORAL AND BIOMEDICAL LITERATURES. THIS MODEL MAINTAINS THAT CHILDHOOD STRESS GETS "PROGRAMMED" INTO MACROPHAGES THROUGH EPIGENETIC MARKINGS, POSTTRANSLATIONAL MODIFICATIONS, AND TISSUE REMODELING. AS A CONSEQUENCE THESE CELLS ARE ENDOWED WITH PROINFLAMMATORY TENDENCIES, MANIFEST IN EXAGGERATED CYTOKINE RESPONSES TO CHALLENGE AND DECREASED SENSITIVITY TO INHIBITORY HORMONAL SIGNALS. THE MODEL GOES ON TO PROPOSE THAT OVER THE LIFE COURSE, THESE PROINFLAMMATORY TENDENCIES ARE EXACERBATED BY BEHAVIORAL PROCLIVITIES AND HORMONAL DYSREGULATION, THEMSELVES THE PRODUCTS OF EXPOSURE TO EARLY STRESS. BEHAVIORALLY, THE MODEL POSITS THAT CHILDHOOD STRESS GIVES RISE TO EXCESSIVE THREAT VIGILANCE, MISTRUST OF OTHERS, POOR SOCIAL RELATIONSHIPS, IMPAIRED SELF-REGULATION, AND UNHEALTHY LIFESTYLE CHOICES. HORMONALLY, EARLY STRESS CONFERS ALTERED PATTERNS OF ENDOCRINE AND AUTONOMIC DISCHARGE. THIS MILIEU AMPLIFIES THE PROINFLAMMATORY ENVIRONMENT ALREADY INSTANTIATED BY MACROPHAGES. ACTING IN CONCERT WITH OTHER EXPOSURES AND GENETIC LIABILITIES, THE RESULTING INFLAMMATION DRIVES FORWARD PATHOGENIC MECHANISMS THAT ULTIMATELY FOSTER CHRONIC DISEASE. 2011 5 2671 39 ETHANOL CONSUMPTION INDUCES NONSPECIFIC INFLAMMATION AND FUNCTIONAL DEFECTS IN ALVEOLAR MACROPHAGES. CHRONIC ALCOHOL DRINKING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO VIRAL AND BACTERIAL RESPIRATORY PATHOGENS. IN THIS STUDY, WE USE A RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION TO STUDY THE EFFECTS OF LONG-TERM ALCOHOL DRINKING ON THE IMMUNOLOGICAL LANDSCAPE OF THE LUNG. WE REPORT A HEIGHTENED INFLAMMATORY STATE IN ALVEOLAR MACROPHAGES (AMS) OBTAINED FROM ETHANOL (ETOH)-DRINKING ANIMALS THAT IS ACCOMPANIED BY INCREASED CHROMATIN ACCESSIBILITY IN INTERGENIC REGIONS THAT REGULATE INFLAMMATORY GENES AND CONTAIN BINDING MOTIFS FOR TRANSCRIPTION FACTORS AP-1, IRF8, AND NFKB P-65. IN LINE WITH THESE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT THE BASAL STATE, AMS FROM ETOH-DRINKING ANIMALS GENERATE ELEVATED INFLAMMATORY MEDIATOR RESPONSES TO LIPOPOLYSACCHARIDES AND RESPIRATORY SYNCYTIAL VIRUS. HOWEVER, THE TRANSCRIPTIONAL ANALYSIS REVEALED AN INEFFICIENT INDUCTION OF INTERFERON-STIMULATED GENES WITH ETOH IN RESPONSE TO THE RESPIRATORY SYNCYTIAL VIRUS, SUGGESTING DISRUPTION OF ANTIMICROBIAL DEFENSES. CORRESPONDINGLY, AMS FROM ETOH-DRINKING ANIMALS EXHIBITED TRANSCRIPTIONAL SHIFTS INDICATIVE OF INCREASED OXIDATIVE STRESS AND OXIDATIVE PHOSPHORYLATION, WHICH WAS COUPLED WITH HIGHER CYTOSOLIC REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL POTENTIAL. THIS HEIGHTENED OXIDATIVE STRESS STATE WAS ACCOMPANIED BY DECREASED ABILITY TO PHAGOCYTOSE BACTERIA. BULK RNA AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING DATA FURTHER REVEALED REDUCED EXPRESSION AND CHROMATIN ACCESSIBILITY OF LOCI ASSOCIATED WITH TISSUE REPAIR AND MAINTENANCE WITH CHRONIC ETOH DRINKING. SIMILARLY, ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA REVEALED SHIFTS IN CELL STATES FROM TISSUE MAINTENANCE TO INFLAMMATORY RESPONSES WITH ETOH. COLLECTIVELY, THESE DATA PROVIDE NOVEL INSIGHT INTO MECHANISMS BY WHICH CHRONIC ETOH DRINKING INCREASES SUSCEPTIBILITY TO INFECTION IN PATIENTS WITH ALCOHOL USE DISORDERS. 2022 6 3735 17 INNATE IMMUNE MEMORY: IMPLICATIONS FOR DEVELOPMENT OF PEDIATRIC IMMUNOMODULATORY AGENTS AND ADJUVANTED VACCINES. UNIQUE FEATURES OF IMMUNITY EARLY IN LIFE INCLUDE A DISTINCT IMMUNE SYSTEM PARTICULARLY RELIANT ON INNATE IMMUNITY, WITH WEAK T HELPER (TH)1-POLARIZING IMMUNE RESPONSES, AND IMPAIRED RESPONSES TO CERTAIN VACCINES LEADING TO A HEIGHTENED SUSCEPTIBILITY TO INFECTION. TO THESE IMPORTANT ASPECTS, WE NOW ADD AN INCREASINGLY APPRECIATED CONCEPT THAT THE INNATE IMMUNE SYSTEM DISPLAYS EPIGENETIC MEMORY OF AN EARLIER INFECTION OR VACCINATION, A PHENOMENON THAT HAS BEEN NAMED "TRAINED IMMUNITY." EXPOSURE OF NEONATAL LEUKOCYTES IN VITRO OR NEONATAL ANIMALS OR HUMANS IN VIVO TO SPECIFIC INNATE IMMUNE STIMULI RESULTS IN AN ALTERED INNATE IMMUNE SET POINT. GIVEN THE PARTICULAR IMPORTANCE OF INNATE IMMUNITY EARLY IN LIFE, TRAINED IMMUNITY TO EARLY LIFE INFECTION AND/OR IMMUNIZATION MAY PLAY AN IMPORTANT ROLE IN MODULATING BOTH ACUTE AND CHRONIC DISEASES. 2014 7 803 23 CENTRAL CONTROL OF VISCERAL PAIN AND URINARY TRACT FUNCTION. AFFERENT INPUT FROM ADELTA AND C-FIBRES INNERVATING THE URINARY BLADDER ARE PROCESSED DIFFERENTLY BY THE BRAIN, AND HAVE DIFFERENT ROLES IN SIGNALING BLADDER SENSATION. ADELTA FIBRES THAT SIGNAL BLADDER FILLING ACTIVATE A SPINO-BULBO-SPINAL LOOP, WHICH RELAYS IN THE MIDBRAIN PERIAQUEDUCTAL GREY (PAG) AND PONTINE MICTURITION CENTRE (PMC). THE EXCITABILITY OF THIS CIRCUITRY IS REGULATED BY TONIC GABAERGIC INHIBITORY PROCESSES. IN HUMANS AND SOCIALISED ANIMALS MICTURITION IS NORMALLY UNDER VOLITIONAL CONTROL AND INFLUENCED BY A HOST OF PSYCHOSOCIAL FACTORS. HIGHER NERVOUS DECISION-MAKING IN A SOCIAL CONTEXT TO 'GO NOW' OR 'DO NOT GO' PROBABLY RESIDES IN FRONTAL CORTICAL AREAS, WHICH ACT AS A CENTRAL CONTROL SWITCH FOR MICTURITION. EXPOSURE TO PSYCHOSOCIAL STRESS CAN HAVE PROFOUNDLY DISRUPTIVE INFLUENCE ON THE PROCESS AND LEAD TO MALADAPTIVE CHANGES IN THE BLADDER. DURING SLEEPING THE VOIDING REFLEX THRESHOLD APPEARS TO BE RESET TO A HIGHER LEVEL TO PROMOTE URINARY CONTINENCE. UNDER PHYSIOLOGICAL CONDITIONS C-FIBRE BLADDER AFFERENTS ARE NORMALLY SILENT BUT ARE ACTIVATED IN INFLAMMATORY BLADDER STATES AND BY INTENSE DISTENDING PRESSURE. FOLLOWING PROLONGED STIMULATION VISCERAL NOCICEPTORS SENSITISE, LEADING TO A LOWERED THRESHOLD AND HEIGHTENED SENSITIVITY. IN ADDITION, SENSITIZATION MAY OCCUR WITHIN THE CENTRAL PAIN PROCESSING CIRCUITRY, WHICH OUTLASTS THE ORIGINAL NOCICEPTIVE INSULT. VISCERAL NOCICEPTION MAY ALSO BE INFLUENCED BY GENETIC AND ENVIRONMENTAL INFLUENCES. A PERIOD OF CHRONIC STRESS CAN PRODUCE INCREASED SENSITIVITY TO VISCERAL PAIN THAT LASTS FOR MONTHS. ADVERSE EARLY LIFE EVENTS CAN PRODUCE EVEN LONGER LASTING EPIGENETIC CHANGES, WHICH INCREASE THE INDIVIDUAL'S SUSCEPTIBILITY TO DEVELOPING VISCERAL PAIN STATES IN ADULTHOOD. 2016 8 3092 18 GENOMIC AND EPIGENOMIC MECHANISMS OF GLUCOCORTICOIDS IN THE BRAIN. FOLLOWING THE DISCOVERY OF GLUCOCORTICOID RECEPTORS IN THE HIPPOCAMPUS AND OTHER BRAIN REGIONS, RESEARCH HAS FOCUSED ON UNDERSTANDING THE EFFECTS OF GLUCOCORTICOIDS IN THE BRAIN AND THEIR ROLE IN REGULATING EMOTION AND COGNITION. GLUCOCORTICOIDS ARE ESSENTIAL FOR ADAPTATION TO STRESSORS (ALLOSTASIS) AND IN MALADAPTATION RESULTING FROM ALLOSTATIC LOAD AND OVERLOAD. ALLOSTATIC OVERLOAD, WHICH CAN OCCUR DURING CHRONIC STRESS, CAN RESHAPE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS THROUGH EPIGENETIC MODIFICATION OF GENES IN THE HIPPOCAMPUS, HYPOTHALAMUS AND OTHER STRESS-RESPONSIVE BRAIN REGIONS. GLUCOCORTICOIDS EXERT THEIR EFFECTS ON THE BRAIN THROUGH GENOMIC MECHANISMS THAT INVOLVE BOTH GLUCOCORTICOID RECEPTORS AND MINERALOCORTICOID RECEPTORS DIRECTLY BINDING TO DNA, AS WELL AS BY NON-GENOMIC MECHANISMS. FURTHERMORE, GLUCOCORTICOIDS SYNERGIZE BOTH GENOMICALLY AND NON-GENOMICALLY WITH NEUROTRANSMITTERS, NEUROTROPHIC FACTORS, SEX HORMONES AND OTHER STRESS MEDIATORS TO SHAPE AN ORGANISM'S PRESENT AND FUTURE RESPONSES TO A STRESSFUL ENVIRONMENT. HERE, WE DISCUSS THE MECHANISMS OF GLUCOCORTICOID ACTION IN THE BRAIN AND REVIEW HOW GLUCOCORTICOIDS INTERACT WITH STRESS MEDIATORS IN THE CONTEXT OF ALLOSTASIS, ALLOSTATIC LOAD AND STRESS-INDUCED NEUROPLASTICITY. 2017 9 2264 25 EPIGENETIC PROGRAMMING BY STRESS AND GLUCOCORTICOIDS ALONG THE HUMAN LIFESPAN. PSYCHOSOCIAL STRESS TRIGGERS A SET OF BEHAVIORAL, NEURAL, HORMONAL, AND MOLECULAR RESPONSES THAT CAN BE A DRIVING FORCE FOR SURVIVAL WHEN ADAPTIVE AND TIME-LIMITED, BUT MAY ALSO CONTRIBUTE TO A HOST OF DISEASE STATES IF DYSREGULATED OR CHRONIC. THE BENEFICIAL OR DETRIMENTAL EFFECTS OF STRESS ARE LARGELY MEDIATED BY THE HYPOTHALAMIC-PITUITARY AXIS, A HIGHLY CONSERVED NEUROHORMONAL CASCADE THAT CULMINATES IN SYSTEMIC SECRETION OF GLUCOCORTICOIDS. GLUCOCORTICOIDS ACTIVATE THE GLUCOCORTICOID RECEPTOR, A UBIQUITOUS NUCLEAR RECEPTOR THAT NOT ONLY CAUSES WIDESPREAD CHANGES IN TRANSCRIPTIONAL PROGRAMS, BUT ALSO INDUCES LASTING EPIGENETIC MODIFICATIONS IN MANY TARGET TISSUES. WHILE THE EPIGENOME REMAINS SENSITIVE TO STRESSORS THROUGHOUT LIFE, WE PROPOSE TWO KEY PRINCIPLES THAT MAY GOVERN THE EPIGENETICS OF STRESS AND GLUCOCORTICOIDS ALONG THE LIFESPAN: FIRST, THE PRESENCE OF DISTINCT LIFE PERIODS, DURING WHICH THE EPIGENOME SHOWS HEIGHTENED PLASTICITY TO STRESS EXPOSURE, SUCH AS IN EARLY DEVELOPMENT AND AT ADVANCED AGE; AND, SECOND, THE POTENTIAL OF STRESS-INDUCED EPIGENETIC CHANGES TO ACCUMULATE THROUGHOUT LIFE BOTH IN SELECT CHROMATIN REGIONS AND AT THE GENOME-WIDE LEVEL. THESE PRINCIPLES HAVE IMPORTANT CLINICAL AND TRANSLATIONAL IMPLICATIONS, AND THEY SHOW STRIKING PARALLELS WITH THE EXISTENCE OF SENSITIVE DEVELOPMENTAL PERIODS AND THE CUMULATIVE IMPACT OF STRESSFUL EXPERIENCES ON THE DEVELOPMENT OF STRESS-RELATED PHENOTYPES. WE HOPE THAT THIS CONCEPTUAL MECHANISTIC FRAMEWORK WILL STIMULATE FRUITFUL RESEARCH THAT AIMS AT UNRAVELING THE MOLECULAR PATHWAYS THROUGH WHICH OUR LIFE STORIES SCULPT GENOMIC FUNCTION TO CONTRIBUTE TO COMPLEX BEHAVIORAL AND SOMATIC PHENOTYPES. 2017 10 235 18 ADDING FUEL TO THE FIRE: THE IMPACT OF STRESS ON THE AGEING BRAIN. BOTH AGEING AND CHRONIC STRESS ARE ASSOCIATED WITH ALTERED BRAIN PLASTICITY, DYSREGULATION OF THE IMMUNE SYSTEM, AND AN INCREASED RISK OF DEVELOPING BRAIN DISORDERS; ALL OF WHICH HAVE CONSEQUENCES FOR COGNITIVE AND EMOTIONAL PROCESSING. HERE WE EXAMINE THE SIMILARITIES BETWEEN BEHAVIOURAL CHANGES DURING AGEING AND STRESS ALTERED BEHAVIOURS (ANXIETY, DEPRESSIVE-LIKE BEHAVIOUR, COGNITION, AND SOCIABILITY) IN RODENTS AND HUMANS. THE MOLECULAR MECHANISMS HYPOTHESISED TO MEDIATE AGE-RELATED CHANGES IN BRAIN FUNCTION INCLUDING DYSFUNCTION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, DYSREGULATION OF NEUROTRANSMISSION AND NEUROTROPHIC FACTOR SIGNALLING, INCREASED INFLAMMATORY STATE, GENETIC AND EPIGENETIC CHANGES, OXIDATIVE STRESS, METABOLIC CHANGES, AND CHANGES IN THE MICROBIOTA-GUT-BRAIN AXIS ARE DISCUSSED. FINALLY, WE EXPLORE HOW THE ALREADY STRESSED AGED BRAIN PSYCHOLOGICALLY AND PHYSIOLOGICALLY RESPONDS TO EXTERNAL STRESSORS. 2015 11 6540 39 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE. 2021 12 2013 27 EPIGENETIC BASIS OF THE DARK SIDE OF ALCOHOL ADDICTION. ALCOHOLISM IS A COMPLEX BRAIN DISEASE CHARACTERIZED BY THREE DISTINCT STAGES OF THE ADDICTION CYCLE THAT MANIFEST AS NEUROADAPTIVE CHANGES IN THE BRAIN. ONE SUCH STAGE OF THE ADDICTION CYCLE IS ALCOHOL WITHDRAWAL AND THE NEGATIVE AFFECTIVE STATES THAT PROMOTE DRINKING AND MAINTAIN ADDICTION. REPEATED ALCOHOL USE, GENETIC PREDISPOSITION TO ALCOHOLISM AND ANXIETY, AND ALCOHOL EXPOSURE DURING CRUCIAL DEVELOPMENTAL PERIODS ALL CONTRIBUTE TO THE DEVELOPMENT OF ALCOHOL-INDUCED WITHDRAWAL AND NEGATIVE AFFECTIVE SYMPTOMS. EPIGENETIC MODIFICATIONS WITHIN THE AMYGDALA HAVE PROVIDED A MOLECULAR BASIS OF THESE NEGATIVE AFFECTIVE SYMPTOMS, ALSO KNOWN AS THE DARK SIDE OF ADDICTION. HERE, WE PROPOSE THAT ALLOSTATIC CHANGE WITHIN THE EPIGENOME IN THE AMYGDALA IS A PRIME MECHANISM OF THE BIOLOGICAL BASIS OF NEGATIVE AFFECTIVE STATES RESULTING FROM, AND CONTRIBUTING TO, ALCOHOLISM. ACUTE ALCOHOL EXPOSURE PRODUCES AN ANXIOLYTIC RESPONSE WHICH IS ASSOCIATED WITH THE OPENING OF CHROMATIN DUE TO INCREASED HISTONE ACETYLATION, INCREASED CREB BINDING PROTEIN (CBP) LEVELS, AND HISTONE DEACETYLASE (HDAC) INHIBITION. AFTER CHRONIC ETHANOL EXPOSURE, THESE CHANGES RETURN TO BASELINE ALONG WITH ANXIETY-LIKE BEHAVIORS. HOWEVER, DURING WITHDRAWAL, HISTONE ACETYLATION DECREASES DUE TO INCREASED HDAC ACTIVITY AND DECREASED CBP LEVELS IN THE AMYGDALA CIRCUITRY LEADING TO THE DEVELOPMENT OF ANXIETY-LIKE BEHAVIORS. ADDITIONALLY, INNATELY HIGHER EXPRESSION OF THE HDAC2 ISOFORM LEADS TO A DEFICIT IN GLOBAL AND GENE-SPECIFIC HISTONE ACETYLATION IN THE AMYGDALA THAT IS ASSOCIATED WITH A DECREASE IN THE EXPRESSION OF SEVERAL SYNAPTIC PLASTICITY-ASSOCIATED GENES AND MAINTAINING HEIGHTENED ANXIETY-LIKE BEHAVIOR AND EXCESSIVE ALCOHOL INTAKE. ADOLESCENT ALCOHOL EXPOSURE ALSO LEADS TO HIGHER EXPRESSION OF HDAC2 AND A DEFICIT IN HISTONE ACETYLATION LEADING TO DECREASED EXPRESSION OF SYNAPTIC PLASTICITY-ASSOCIATED GENES AND HIGH ANXIETY AND DRINKING BEHAVIOR IN ADULTHOOD. ALL THESE STUDIES INDICATE THAT THE EPIGENOME CAN UNDERGO ALLOSTATIC REPROGRAMMING IN THE AMYGDALOID CIRCUITRY DURING VARIOUS STAGES OF ALCOHOL EXPOSURE. FURTHERMORE, OPENING THE CHROMATIN BY INHIBITING HDACS USING PHARMACOLOGICAL OR GENETIC MANIPULATIONS CAN LEAD TO THE ATTENUATION OF ANXIETY AS WELL AS ALCOHOL INTAKE. CHROMATIN REMODELING PROVIDES A CLEAR BIOLOGICAL BASIS FOR THE NEGATIVE AFFECTIVE STATES SEEN DURING ALCOHOL ADDICTION AND PRESENTS OPPORTUNITIES FOR NOVEL DRUG DEVELOPMENT AND TREATMENT OPTIONS. THIS ARTICLE IS PART OF THE SPECIAL ISSUE ENTITLED "ALCOHOLISM". 2017 13 6502 16 TRAINED IMMUNITY: LONG-TERM ADAPTATION IN INNATE IMMUNE RESPONSES. ADAPTIVE IMMUNE RESPONSES ARE CHARACTERIZED BY ANTIGEN SPECIFICITY AND INDUCTION OF LIFELONG IMMUNOLOGIC MEMORY. RECENTLY, IT HAS BEEN REPORTED THAT INNATE IMMUNE CELLS CAN ALSO BUILD IMMUNE MEMORY CHARACTERISTICS-A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY DESCRIBES THE PERSISTENT HYPERRESPONSIVE PHENOTYPE THAT INNATE IMMUNE CELLS CAN DEVELOP AFTER BRIEF STIMULATION. PATHOGENIC STIMULI SUCH AS MICROORGANISMS, AND ALSO ENDOGENOUS MOLECULES INCLUDING URIC ACID, OXIDIZED LDL (LOW-DENSITY LIPOPROTEIN), AND CATECHOLAMINES, ARE CAPABLE OF INDUCING MEMORY IN MONOCYTES AND MACROPHAGES. WHILE TRAINED IMMUNITY PROVIDES FAVORABLE CROSS-PROTECTION IN THE CONTEXT OF INFECTIOUS DISEASES, THE HEIGHTENED IMMUNE RESPONSE CAN BE MALADAPTIVE IN DISEASES DRIVEN BY CHRONIC SYSTEMIC INFLAMMATION, SUCH AS ATHEROSCLEROSIS. TRAINED IMMUNITY IS MAINTAINED BY DISTINCT EPIGENETIC AND METABOLIC MECHANISMS AND PERSISTS FOR AT LEAST SEVERAL MONTHS IN VIVO DUE TO REPROGRAMMING OF MYELOID PROGENITOR CELLS. ADDITIONALLY, CERTAIN NONIMMUNE CELLS ARE ALSO FOUND TO EXHIBIT TRAINED IMMUNITY CHARACTERISTICS. THUS, TRAINED IMMUNITY PRESENTS AN EXCITING FRAMEWORK TO DEVELOP NEW APPROACHES TO VACCINATION AND ALSO NOVEL PHARMACOLOGICAL TARGETS IN THE TREATMENT OF INFLAMMATORY DISEASES. 2021 14 3151 24 GLUCOCORTICOIDS, EPIGENETIC CONTROL AND STRESS RESILIENCE. GLUCOCORTICOID HORMONES PLAY A PIVOTAL ROLE IN THE RESPONSE TO STRESSFUL CHALLENGES. THE SURGE IN GLUCOCORTICOID HORMONE SECRETION AFTER STRESS NEEDS TO BE TIGHTLY CONTROLLED WITH CHARACTERISTICS LIKE PEAK HEIGHT, CURVATURE AND DURATION DEPENDING ON THE NATURE AND SEVERITY OF THE CHALLENGE. THIS IS IMPORTANT AS CHRONIC HYPER- OR HYPO-RESPONSES ARE DETRIMENTAL TO HEALTH DUE TO INCREASING THE RISK FOR DEVELOPING A STRESS-RELATED MENTAL DISORDER. PROPER GLUCOCORTICOID RESPONSES TO STRESS ARE CRITICAL FOR ADAPTATION. THEREFORE, THE TIGHT CONTROL OF BASELINE AND STRESS-EVOKED GLUCOCORTICOID SECRETION ARE IMPORTANT CONSTITUENTS OF AN ORGANISM'S RESILIENCE. HERE, WE ADDRESS A NUMBER OF MECHANISMS THAT ILLUSTRATE THE MULTITUDE AND COMPLEXITY OF MEASURES SAFEGUARDING THE CONTROL OF GLUCOCORTICOID FUNCTION. THESE MECHANISMS INCLUDE THE CONTROL OF MINERALOCORTICOID (MR) AND GLUCOCORTICOID RECEPTOR (GR) OCCUPANCY AND CONCENTRATION, THE DYNAMIC CONTROL OF FREE GLUCOCORTICOID HORMONE AVAILABILITY BY CORTICOSTEROID-BINDING GLOBULIN (CBG), AND THE CONTROL EXERTED BY GLUCOCORTICOIDS AT THE SIGNALING, EPIGENETIC AND GENOMIC LEVEL ON GENE TRANSCRIPTIONAL RESPONSES TO STRESS. WE REVIEW THE BENEFICIAL EFFECTS OF REGULAR EXERCISE ON HPA AXIS AND SLEEP PHYSIOLOGY, AND COGNITIVE AND ANXIETY-RELATED BEHAVIOR. FURTHERMORE, WE DESCRIBE THAT, POSSIBLY THROUGH CHANGES IN THE GABAERGIC SYSTEM, EXERCISE REDUCES THE IMPACT OF STRESS ON A SIGNALING PATHWAY SPECIFICALLY IN THE DENTATE GYRUS THAT IS STRONGLY IMPLICATED IN THE BEHAVIORAL RESPONSE TO THAT STRESSOR. THESE OBSERVATIONS UNDERLINE THE IMPACT OF LIFE STYLE ON STRESS RESILIENCE. FINALLY, WE ADDRESS HOW SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AFFECTING GLUCOCORTICOID ACTION CAN COMPROMISE STRESS RESILIENCE, WHICH BECOMES MOST APPARENT UNDER CONDITIONS OF CHILDHOOD ABUSE. 2015 15 6267 23 THE NEUROENDOCRINOLOGY OF STRESS: A NEVER ENDING STORY. EVOLUTIONARY SUCCESS DEPENDS ON OUR ABILITY TO ADAPT TO CHANGING CIRCUMSTANCES. THE NEUROENDOCRINE RESPONSE TO STRESS IS AN EXCELLENT EXAMPLE OF A PLASTIC SYSTEM THAT RESPONDS TO THREATS TO HOMEOSTASIS AND ALTERS ITS OUTPUT TO MEET CURRENT AND EXPECTED FUTURE DEMANDS. AT THE LEVEL OF THE HYPOTHALAMUS, THE CORTICOTROPH SECRETAGOGUES CORTICOTROPHIN-RELEASING HORMONE (CRH) AND ARGININE VASOPRESSIN (AVP) RESPOND RAPIDLY TO AN ACUTE STRESSOR BUT, FOLLOWING CHRONIC STRESS, THEY ADAPT WITH A REDUCTION OF CRH BUT A MAJOR INCREASE IN AVP. THE RELEASE OF CRH AND AVP ACTIVATES PRO-OPIOMELANOCORTIN IN ANTERIOR PITUITARY CORTICOTROPH CELLS AND THE RELEASE OF ADRENOCORTICOTROPHIC HORMONE INTO PERIPHERAL BLOOD FROM WHERE IT TARGETS RECEPTORS IN THE ADRENAL CORTEX TO RELEASE GLUCOCORTICOID HORMONES. THESE HORMONES (I.E. CORTICOSTERONE IN THE RAT AND CORTISOL IN MAN) ARE RELEASED IN A PULSATILE ULTRADIAN PATTERN WHICH DEFINES THE NORMAL CIRCADIAN RHYTHM. THE FREQUENCY OF THE PULSES IS INCREASED UNDER STATES OF CHRONIC STRESS, AND IN RATS WITH GENETICALLY DETERMINED HYPER-RESPONSIVENESS OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. INTERESTINGLY, NEONATAL INFLUENCES CAN ALSO PROGRAMME ALTERATIONS IN ULTRADIAN RHYTHMICITY, IMPLICATING EPIGENETIC FACTORS IN ITS REGULATION. AT THE LEVEL OF TISSUE RECEPTORS, THE ALTERATION IN PATTERN OF GLUCOCORTICOID ULTRADIAN RHYTHM HAS DIFFERENTIAL EFFECTS ON MINERALOCORTICOID RECEPTOR AND GLUCOCORTICOID RECEPTOR (GR) BINDING TO DNA AND OFFERS A MECHANISM FOR TISSUE SPECIFIC RESPONSES TO ALTERED GLUCOCORTICOID DYNAMICS. THE EFFECTS OF NEONATAL EXPERIENCE ARE NOT ONLY SEEN AT THE LEVEL OF CRH AND GR REGULATION, BUT ALSO ARE EVIDENT IN BEHAVIOURAL RESPONSES TO STRESS AND IN THE RESPONSIVENESS OF BRAIN STEM SEROTONERGIC PATHWAYS, AS MEASURED BY TRYPTOPHAN HYDROXYLASE MRNA IN THE BRAIN STEM. 2008 16 6376 25 THE ROLE OF NEUTROPHILS IN TRAINED IMMUNITY. THE PRINCIPLE OF TRAINED IMMUNITY REPRESENTS INNATE IMMUNE MEMORY DUE TO SUSTAINED, MAINLY EPIGENETIC, CHANGES TRIGGERED BY ENDOGENOUS OR EXOGENOUS STIMULI IN BONE MARROW (BM) PROGENITORS (CENTRAL TRAINED IMMUNITY) AND THEIR INNATE IMMUNE CELL PROGENY, THEREBY TRIGGERING ELEVATED RESPONSIVENESS AGAINST SECONDARY STIMULI. BM PROGENITORS CAN RESPOND TO MICROBIAL AND STERILE SIGNALS, THEREBY POSSIBLY ACQUIRING TRAINED IMMUNITY-MEDIATED LONG-LASTING ALTERATIONS THAT MAY SHAPE THE FATE AND FUNCTION OF THEIR PROGENY, FOR EXAMPLE, NEUTROPHILS. NEUTROPHILS, THE MOST ABUNDANT INNATE IMMUNE CELL POPULATION, ARE PRODUCED IN THE BM FROM COMMITTED PROGENITOR CELLS IN A PROCESS DESIGNATED GRANULOPOIESIS. NEUTROPHILS ARE THE FIRST RESPONDERS AGAINST INFECTIOUS OR INFLAMMATORY CHALLENGES AND HAVE VERSATILE FUNCTIONS IN IMMUNITY. TOGETHER WITH OTHER INNATE IMMUNE CELLS, NEUTROPHILS ARE EFFECTORS OF PERIPHERAL TRAINED IMMUNITY. HOWEVER, GIVEN THE SHORT LIFETIME OF NEUTROPHILS, THEIR ABILITY TO ACQUIRE IMMUNOLOGICAL MEMORY MAY LIE IN THE CENTRAL TRAINING OF THEIR BM PROGENITORS RESULTING IN GENERATION OF REPROGRAMMED, THAT IS, "TRAINED", NEUTROPHILS. ALTHOUGH TRAINED IMMUNITY MAY HAVE BENEFICIAL EFFECTS IN INFECTION OR CANCER, IT MAY ALSO MEDIATE DETRIMENTAL OUTCOMES IN CHRONIC INFLAMMATION. HERE, WE REVIEW THE EMERGING RESEARCH AREA OF TRAINED IMMUNITY WITH A PARTICULAR EMPHASIS ON THE ROLE OF NEUTROPHILS AND GRANULOPOIESIS. 2023 17 5833 27 STRESS-INDUCED MECHANISMS IN MENTAL ILLNESS: A ROLE FOR GLUCOCORTICOID SIGNALLING. STRESS REPRESENTS THE MAIN ENVIRONMENTAL RISK FACTOR FOR MENTAL ILLNESS. EXPOSURE TO STRESSFUL EVENTS, PARTICULARLY EARLY IN LIFE, HAS BEEN ASSOCIATED WITH INCREASED INCIDENCE AND SUSCEPTIBILITY OF MAJOR DEPRESSIVE DISORDERS AS WELL AS OF OTHER PSYCHIATRIC ILLNESSES. AMONG THE KEY PLAYERS IN THESE EVENTS ARE GLUCOCORTICOID RECEPTORS. DYSFUNCTIONAL GLUCOCORTICOID SIGNALLING MAY INDEED CONTRIBUTE TO PSYCHOPATHOLOGY THROUGH A NUMBER OF MECHANISMS THAT REGULATE THE RESPONSE TO ACUTE OR CHRONIC STRESS AND THAT AFFECT THE FUNCTION OF GENES AND SYSTEMS KNOWN TO BE RELEVANT FOR MOOD DISORDERS. INDEED, EXPOSURE TO CHRONIC STRESS EARLY IN LIFE AS WELL AS IN ADULTHOOD HAS BEEN SHOWN TO REDUCE THE EXPRESSION OF GLUCOCORTICOID RECEPTORS (GR), ALSO THROUGH EPIGENETIC MECHANISMS, AND TO UP-REGULATE THE EXPRESSION OF THE CO-CHAPERONE GENE FKBP5, WHICH RESTRAINS GR ACTIVITY BY LIMITING THE TRANSLOCATION OF THE RECEPTOR COMPLEX TO THE NUCLEUS. ANOTHER MECHANISM THAT CONTRIBUTES TO CHANGES IN GR RESPONSIVENESS IS THE STATE OF RECEPTOR PHOSPHORYLATION THAT CONTROLS ACTIVATION, SUBCELLULAR LOCALIZATION AS WELL AS ITS TRANSCRIPTIONAL ACTIVITY. MOREOVER, GR PHOSPHORYLATION MAY REPRESENT AN IMPORTANT MECHANISM FOR THE CROSS TALK BETWEEN NEUROTROPHIC SIGNALLING AND GR-DEPENDENT TRANSCRIPTION, BRIDGING TWO IMPORTANT PLAYERS FOR MOOD DISORDERS. ONE GENE THAT LIES DOWNSTREAM FROM GR AND MAY CONTRIBUTE TO STRESS-RELATED CHANGES IS SERUM GLUCOCORTICOID KINASE-1 (SGK1). WE HAVE DEMONSTRATED THAT THE EXPRESSION OF SGK1 IS SIGNIFICANTLY INCREASED AFTER EXPOSURE TO CHRONIC STRESS IN RODENTS AS WELL AS IN THE BLOOD OF DRUG-FREE DEPRESSED PATIENTS. WE HAVE ALSO SHOWN THAT SGK1 UP-REGULATION MAY ULTIMATELY REDUCE HIPPOCAMPAL NEUROGENESIS AND CONTRIBUTE TO THE STRUCTURAL ABNORMALITIES THAT HAVE BEEN REPORTED TO OCCUR IN DEPRESSED PATIENTS. IN SUMMARY, GR SIGNALLING MAY REPRESENT A POINT OF CONVERGENCE AS WELL AS OF DIVERGENCE FOR DEFECTS ASSOCIATED WITH PATHOLOGIC CONDITIONS CHARACTERIZED BY HEIGHTENED VULNERABILITY TO STRESS. THE CHARACTERIZATION OF THESE ABNORMALITIES IS CRUCIAL TO IDENTIFY NOVEL TARGETS FOR THERAPEUTIC INTERVENTION THAT MAY COUNTERACT MORE EFFECTIVELY STRESS-INDUCED NEUROBIOLOGICAL ABNORMALITIES. 2016 18 3463 21 HYPOTHALAMIC-PITUITARY-ADRENAL AND HYPOTHALAMIC-PITUITARY-GONADAL AXES: SEX DIFFERENCES IN REGULATION OF STRESS RESPONSIVITY. GONADAL HORMONES PLAY A KEY ROLE IN THE ESTABLISHMENT, ACTIVATION, AND REGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. BY INFLUENCING THE RESPONSE AND SENSITIVITY TO RELEASING FACTORS, NEUROTRANSMITTERS, AND HORMONES, GONADAL STEROIDS HELP ORCHESTRATE THE GAIN OF THE HPA AXIS TO FINE-TUNE THE LEVELS OF STRESS HORMONES IN THE GENERAL CIRCULATION. FROM EARLY LIFE TO ADULTHOOD, GONADAL STEROIDS CAN DIFFERENTIALLY AFFECT THE HPA AXIS, RESULTING IN SEX DIFFERENCES IN THE RESPONSIVITY OF THIS AXIS. THE HPA AXIS INFLUENCES MANY PHYSIOLOGICAL FUNCTIONS MAKING AN ORGANISM'S RESPONSE TO CHANGES IN THE ENVIRONMENT APPROPRIATE FOR ITS REPRODUCTIVE STATUS. ALTHOUGH THE ACUTE HPA RESPONSE TO STRESSORS IS A BENEFICIAL RESPONSE, CONSTANT ACTIVATION OF THIS CIRCUITRY BY CHRONIC OR TRAUMATIC STRESSFUL EPISODES MAY LEAD TO A DYSREGULATION OF THE HPA AXIS AND CAUSE PATHOLOGY. COMPARED TO MALES, FEMALE MICE AND RATS SHOW A MORE ROBUST HPA AXIS RESPONSE, AS A RESULT OF CIRCULATING ESTRADIOL LEVELS WHICH ELEVATE STRESS HORMONE LEVELS DURING NON-THREATENING SITUATIONS, AND DURING AND AFTER STRESSORS. FLUCTUATING LEVELS OF GONADAL STEROIDS IN FEMALES ACROSS THE ESTROUS CYCLE ARE A MAJOR FACTOR CONTRIBUTING TO SEX DIFFERENCES IN THE ROBUSTNESS OF HPA ACTIVITY IN FEMALES COMPARED TO MALES. MOREOVER, GONADAL STEROIDS MAY ALSO CONTRIBUTE TO EPIGENETIC AND ORGANIZATIONAL INFLUENCES ON THE HPA AXIS EVEN BEFORE PUBERTY. CORRESPONDINGLY, CROSSTALK BETWEEN THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AND HPA AXES COULD LEAD TO ABNORMALITIES OF STRESS RESPONSES. IN HUMANS, A DYSREGULATED STRESS RESPONSE IS ONE OF THE MOST COMMON SYMPTOMS SEEN ACROSS MANY NEUROPSYCHIATRIC DISORDERS, AND AS A RESULT, SUCH INTERACTIONS MAY EXACERBATE PERIPHERAL PATHOLOGIES. IN THIS REVIEW, WE DISCUSS THE HPA AND HPG AXES AND REVIEW HOW GONADAL STEROIDS INTERACT WITH THE HPA AXIS TO REGULATE THE STRESS CIRCUITRY DURING ALL STAGES IN LIFE. 2017 19 5815 24 STRESS AND GLUCOCORTICOID RECEPTOR TRANSCRIPTIONAL PROGRAMMING IN TIME AND SPACE: IMPLICATIONS FOR THE BRAIN-GUT AXIS. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ENHANCED ABDOMINAL PAIN AND ALTERED INTESTINAL BARRIER FUNCTION THAT MAY RESULT FROM A PERTURBATION IN THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS. THE GLUCOCORTICOID RECEPTOR (GR) EXPLOITS DIVERSE MECHANISMS TO ACTIVATE OR SUPPRESS CONGENERIC GENE EXPRESSION, WITH REGULATORY VARIATION ASSOCIATED WITH STRESS-RELATED DISORDERS IN PSYCHIATRY AND GASTROENTEROLOGY. PURPOSE: DURING ACUTE AND CHRONIC STRESS, CORTICOTROPIN-RELEASING HORMONE DRIVES SECRETION OF ADRENOCORTICOTROPIC HORMONE FROM THE PITUITARY, ULTIMATELY LEADING TO THE RELEASE OF CORTISOL (HUMAN) AND CORTICOSTERONE (RODENT) FROM THE ADRENAL GLANDS. CORTISOL BINDS WITH THE GR IN THE CYTOSOL, TRANSLOCATES TO THE NUCLEUS, AND ACTIVATES THE NR3C1 (NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 [GR]) GENE. THIS REVIEW FOCUSES ON THE RAPIDLY DEVELOPING OBSERVATIONS THAT CORTISOL IS RESPONSIBLE FOR DRIVING CIRCADIAN AND ULTRADIAN BURSTS OF TRANSCRIPTIONAL ACTIVITY IN THE CLOCK (CLOCK CIRCADIAN REGULATOR) AND PER (PERIOD CIRCADIAN CLOCK 1) GENE FAMILIES, AND THIS RHYTHM IS DISRUPTED IN MAJOR DEPRESSIVE DISORDER, BIPOLAR DISORDER, AND STRESS-RELATED GASTROINTESTINAL AND IMMUNE DISORDERS. GLUCOCORTICOID RECEPTOR REGULATES DIFFERENT SETS OF TRANSCRIPTS IN A TISSUE-SPECIFIC MANNER, THROUGH PULSATILE WAVES OF GENE EXPRESSION THAT INCLUDES OCCUPANCY OF GLUCOCORTICOID RESPONSE ELEMENTS LOCATED WITHIN CONSTITUTIVELY OPEN SPATIAL DOMAINS IN CHROMATIN. EMERGING EVIDENCE SUPPORTS A POTENTIALLY PIVOTAL ROLE FOR EPIGENETIC REGULATION OF HOW GR INTERACTS WITH OTHER CHROMATIN REGULATORS TO CONTROL THE EXPRESSION OF ITS TARGET GENES. DYSREGULATION OF THE CENTRAL AND PERIPHERAL GR REGULOME HAS POTENTIALLY SIGNIFICANT CONSEQUENCES FOR STRESS-RELATED DISORDERS AFFECTING THE BRAIN-GUT AXIS. 2016 20 6520 41 TRANSCRIPTIONAL AND EPIGENETIC REGULATION OF MONOCYTE AND MACROPHAGE DYSFUNCTION BY CHRONIC ALCOHOL CONSUMPTION. DRINKING ALCOHOL, EVEN IN MODERATION, CAN AFFECT THE IMMUNE SYSTEM. STUDIES HAVE SHOWN DISPROPORTIONATE EFFECTS OF ALCOHOL ON CIRCULATING AND TISSUE-RESIDENT MYELOID CELLS (GRANULOCYTES, MONOCYTES, MACROPHAGES, DENDRITIC CELLS). THESE CELLS ORCHESTRATE THE BODY'S FIRST LINE OF DEFENSE AGAINST MICROBIAL CHALLENGES AS WELL AS MAINTAIN TISSUE HOMEOSTASIS AND REPAIR. ALCOHOL'S EFFECTS ON THESE CELLS ARE DEPENDENT ON EXPOSURE PATTERN, WITH ACUTE DRINKING DAMPENING BUT CHRONIC DRINKING ENHANCING PRODUCTION OF INFLAMMATORY MEDIATORS. ALTHOUGH CHRONIC DRINKING IS ASSOCIATED WITH HEIGHTENED SYSTEMIC INFLAMMATION, STUDIES ON TISSUE RESIDENT MACROPHAGE POPULATIONS IN SEVERAL ORGANS INCLUDING THE SPLEEN, LIVER, BRAIN, AND LUNG HAVE ALSO SHOWN COMPROMISED FUNCTIONAL AND METABOLIC CAPACITIES OF THESE CELLS. MANY OF THESE EFFECTS ARE THOUGHT TO BE MEDIATED BY OXIDATIVE STRESS CAUSED BY ALCOHOL AND ITS METABOLITES WHICH CAN DIRECTLY IMPACT THE CELLULAR EPIGENETIC LANDSCAPES. IN ADDITION, SINCE MYELOID CELLS ARE RELATIVELY SHORT-LIVED IN CIRCULATION AND ARE UNDER CONSTANT REPOPULATION FROM THE BONE MARROW COMPARTMENT, ALCOHOL'S EFFECTS ON BONE MARROW PROGENITORS AND HEMATOPOIESIS ARE IMPORTANT FOR UNDERSTANDING THE IMPACT OF ALCOHOL SYSTEMICALLY ON THESE MYELOID POPULATIONS. ALCOHOL-INDUCED DISRUPTION OF PROGENITOR, CIRCULATING, AND TISSUE RESIDENT MYELOID POPULATIONS CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PATIENTS WITH ALCOHOL USE DISORDERS TO VIRAL AND BACTERIAL INFECTIONS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE IMPACT OF CHRONIC ALCOHOL CONSUMPTION ON THE FUNCTION OF MONOCYTES AND MACROPHAGES IN HOST DEFENSE, TISSUE REPAIR AND INFLAMMATION. WE THEN SUMMARIZE OUR CURRENT UNDERSTANDING OF THE MECHANISMS UNDERLYING ALCOHOL-INDUCED DISRUPTION AND EXAMINE CHANGES IN TRANSCRIPTOME AND EPIGENOME OF MONOCYTES AND MCROPHAGES. OVERALL, CHRONIC ALCOHOL CONSUMPTION LEADS TO HYPER-INFLAMMATION CONCOMITANT WITH DECREASED MICROBIAL AND WOUND HEALING RESPONSES BY MONOCYTES/MACROPHAGES DUE TO A REWIRING OF THE EPIGENTIC AND TRANSCRIPTIONAL LANDSCAPE. HOWEVER, IN ADVANCED ALCOHOLIC LIVER DISEASE, MYELOID CELLS BECOME IMMUNOSUPPRESSED AS A RESPONSE TO THE SURROUNDING HYPER-INFLAMMATORY MILIEU. THEREFORE, THE EFFECT OF CHRONIC ALCOHOL ON THE INFLAMMATORY RESPONSE DEPENDS ON DISEASE STATE AND THE IMMUNE CELL POPULATION. 2022