1 1009 184 CHRONIC VOLUNTARY ETHANOL DRINKING IN CYNOMOLGUS MACAQUES ELICITS GENE EXPRESSION CHANGES IN PREFRONTAL CORTICAL AREA 46. BACKGROUND: GENOME-WIDE PROFILING TO EXAMINE BRAIN TRANSCRIPTIONAL FEATURES ASSOCIATED WITH EXCESSIVE ETHANOL (ETOH) CONSUMPTION HAS BEEN APPLIED TO A VARIETY OF SPECIES INCLUDING RODENTS, NONHUMAN PRIMATES (NHPS), AND HUMANS. HOWEVER, THESE DATA WERE OBTAINED FROM CROSS-SECTIONAL SAMPLES WHICH ARE PARTICULARLY VULNERABLE TO INDIVIDUAL VARIATION WHEN OBTAINED FROM SMALL OUTBRED POPULATIONS TYPICAL OF HUMAN AND NHP STUDIES. IN THE CURRENT STUDY, A NOVEL WITHIN-SUBJECT DESIGN WAS USED TO EXAMINE THE EFFECTS OF VOLUNTARY ETOH CONSUMPTION ON PREFRONTAL CORTEX (PFC) GENE EXPRESSION IN A NHP MODEL. METHODS: TWO COHORTS OF CYNOMOLGUS MACAQUES (N = 23) UNDERWENT A SCHEDULE-INDUCED POLYDIPSIA PROCEDURE TO ESTABLISH ETOH SELF-ADMINISTRATION FOLLOWED BY 6 MONTHS OF DAILY OPEN ACCESS TO ETOH (4% W/V) AND WATER. INDIVIDUAL DAILY ETOH INTAKES RANGED FROM AN AVERAGE OF 0.7 TO 3.7 G/KG/D. DORSAL LATERAL PFC AREA 46 (A46) BRAIN BIOPSIES WERE COLLECTED IN ETOH-NAIVE AND CONTROL MONKEYS; CONTRALATERAL A46 BIOPSIES WERE COLLECTED FROM THE SAME MONKEYS FOLLOWING THE 6 MONTHS OF FLUID CONSUMPTION. GENE EXPRESSION CHANGES WERE ASSESSED USING RNA-SEQ PAIRED ANALYSIS, WHICH ALLOWED FOR CORRECTION OF INDIVIDUAL BASELINE DIFFERENCES IN GENE EXPRESSION. RESULTS: A TOTAL OF 675 GENES WERE SIGNIFICANTLY DOWN-REGULATED FOLLOWING ETOH CONSUMPTION; THESE WERE FUNCTIONALLY ENRICHED FOR IMMUNE RESPONSE, CELL ADHESION, PLASMA MEMBRANE, AND EXTRACELLULAR MATRIX. A TOTAL OF 567 GENES THAT WERE UP-REGULATED FOLLOWING ETOH CONSUMPTION WERE ENRICHED IN MICRORNA TARGET SITES AND INCLUDED TARGET SITES ASSOCIATED WITH TOLL-LIKE RECEPTOR PATHWAYS. THE DIFFERENTIALLY EXPRESSED GENES WERE ALSO SIGNIFICANTLY ENRICHED IN TRANSCRIPTION FACTOR BINDING SITES. CONCLUSIONS: THE DATA PRESENTED HERE ARE THE FIRST TO USE A LONGITUDINAL BIOPSY STRATEGY TO EXAMINE HOW CHRONIC ETOH CONSUMPTION AFFECTS GENE EXPRESSION IN THE PRIMATE PFC. PROMINENT EFFECTS WERE SEEN IN BOTH CELL ADHESION AND NEUROIMMUNE PATHWAYS; THE LATTER CONTAINED BOTH PRO- AND ANTIINFLAMMATORY GENES. THE DATA ALSO INDICATE THAT CHANGES IN MIRNAS AND TRANSCRIPTION FACTORS MAY BE IMPORTANT EPIGENETIC REGULATORS OF ETOH CONSUMPTION. 2020 2 1200 32 CORTICOTROPIN RELEASING HORMONE AND IMAGING, RETHINKING THE STRESS AXIS. THE STRESS SYSTEM PROVIDES INTEGRATION OF BOTH NEUROCHEMICAL AND SOMATIC PHYSIOLOGIC FUNCTIONS WITHIN ORGANISMS AS AN ADAPTIVE MECHANISM TO CHANGING ENVIRONMENTAL CONDITIONS THROUGHOUT EVOLUTION. IN MAMMALS AND PRIMATES THE COMPLEXITY AND SOPHISTICATION OF THESE SYSTEMS HAVE SURPASSED OTHER SPECIES IN TRIAGING NEUROCHEMICAL AND PHYSIOLOGIC SIGNALING TO MAXIMIZE CHANCES OF SURVIVAL. CORTICOTROPIN RELEASING HORMONE (CRH) AND ITS RELATED PEPTIDES AND RECEPTORS HAVE BEEN IDENTIFIED OVER THE LAST THREE DECADES AND ARE FUNDAMENTAL MOLECULAR INITIATORS OF THE STRESS RESPONSE. THEY ARE CRUCIAL IN THE TOP DOWN REGULATORY CASCADE OVER A MYRIAD OF NEUROCHEMICAL, NEUROENDOCRINE AND SYMPATHETIC NERVOUS SYSTEM EVENTS. FROM NEUROSCIENCE, WE'VE SEEN THAT STRESS ACTIVATION IMPACTS BEHAVIOR, ENDOCRINE AND SOMATIC PHYSIOLOGY AND INFLUENCES NEUROCHEMICAL EVENTS THAT ONE CAN CAPTURE IN REAL TIME WITH CURRENT IMAGING TECHNOLOGIES. TO DELINEATE THESE EFFECTS ONE CAN DEMONSTRATE HOW THE CRH NEURONAL NETWORKS INFILTRATE CRITICAL COGNITIVE, EMOTIVE AND AUTONOMIC REGIONS OF THE CENTRAL NERVOUS SYSTEM (CNS) WITH SOMATIC EFFECTS. ABUNDANT PRECLINICAL AND CLINICAL STUDIES SHOW INTER-REGULATORY ACTIONS OF CRH WITH MULTIPLE NEUROTRANSMITTERS/PEPTIDES. STRESS, BOTH ACUTE AND CHRONIC HAS EPIGENETIC EFFECTS WHICH MAGNIFY GENETIC SUSCEPTIBILITIES TO ALTER NEUROCHEMISTRY; STRESS SYSTEM ACTIVATION CAN ADD CRITICAL VARIABLES IN DESIGN AND INTERPRETATION OF BASIC AND CLINICAL NEUROSCIENCE AND RELATED RESEARCH. THIS REVIEW WILL ATTEMPT TO PROVIDE AN OVERVIEW OF THE SPECTRUM OF KNOWN FUNCTIONS AND SPECULATIVE ACTIONS OF CRH AND STRESS RESPONSES IN LIGHT OF IMAGING TECHNOLOGY AND ITS INTERPRETATION. METABOLIC AND NEURORECEPTOR POSITRON EMISSION/SINGLE PHOTON TOMOGRAPHY (PET/SPECT), FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI), ANATOMIC MRI, DIFFUSION TENSOR IMAGING (DTI), AND PROTON MAGNETIC RESONANCE SPECTROSCOPY (PMRS) ARE TECHNOLOGIES THAT CAN DELINEATE BASIC MECHANISMS OF NEUROPHYSIOLOGY AND PHARMACOLOGY. STRESS MODULATES THE MYRIAD OF NEUROCHEMICAL AND NETWORKS WITHIN AND CONTROLLED THROUGH THE CENTRAL AND PERIPHERAL NERVOUS SYSTEM AND THE EFFECTS OF STRESS ACTIVATION ON IMAGING WILL BE HIGHLIGHTED. 2015 3 6540 48 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 4 6545 30 TRANSCRIPTOMIC AND EPIGENETIC CHANGES IN THE HYPOTHALAMUS ARE INVOLVED IN AN INCREASED SUSCEPTIBILITY TO A HIGH-FAT-SUCROSE DIET IN PRENATALLY STRESSED FEMALE RATS. DISTURBANCES IN THE PRENATAL PERIOD ARE LINKED TO METABOLIC DISORDERS IN ADULTHOOD, IMPLYING THE HYPOTHALAMIC SYSTEMS OF APPETITE AND ENERGY BALANCE REGULATION. IN ORDER TO ANALYZE THE CENTRAL EFFECTS OF A HIGH-FAT-SUCROSE (HFS) DIET IN PRENATALLY STRESSED (PNS) FEMALE ADULT RATS, WISTAR DAMS WERE EXPOSED TO CHRONIC-MILD-STRESS DURING THE THIRD WEEK OF GESTATION AND WERE THEN COMPARED WITH UNSTRESSED CONTROLS. ADULT FEMALE OFFSPRING WERE FED A CHOW OR HFS DIET FOR 10 WEEKS. CHANGES IN BODY WEIGHT, ADIPOSITY AS WELL AS EXPRESSION AND METHYLATION LEVELS OF SELECTED HYPOTHALAMIC GENES WERE ANALYZED. PNS INDUCED LOWER BIRTHWEIGHT AND BODY LENGTH WITH NO CHANGES IN BODY FAT MASS. AFTER THE HFS DIET, THE EXPECTED OVERWEIGHT MODEL WAS OBSERVED ACCOMPANIED BY HIGHER ADIPOSITY AND INSULIN RESISTANCE, WHICH WAS WORSENED BY PNS. THE STRESS MODEL INDUCED HIGHER ENERGY INTAKE IN ADULTHOOD. HYPOTHALAMIC GENE EXPRESSION ANALYSIS REVEALED THAT THE HFS DIET DECREASED SLC6A3 (DOPAMINE ACTIVE TRANSPORTER), NPY (NEUROPEPTIDE Y) AND IR (INSULIN RECEPTOR) AND INCREASED POMC (PRO-OPIOMELANOCORTIN). HYPOTHALAMIC DNA METHYLATION LEVELS IN THE PROMOTER REGION OF SLC6A3 REVEALED THAT SLC6A3 WAS HYPERMETHYLATED BY THE HFS DIET IN CPG SITE -53 BP TO THE TRANSCRIPTION START SITE. HFS DIET ALSO HYPERMETHYLATED CPG SITE -167 BP OF THE POMC PROMOTER ONLY IN NONSTRESSED ANIMALS. NO CORRELATIONS WERE FOUND BETWEEN GENE EXPRESSION AND DNA METHYLATION LEVELS. THESE RESULTS IMPLY THAT EARLY-LIFE STRESS IN FEMALES INCREASED PREDISPOSITION TO DIET-INDUCED OBESITY IN ADULTHOOD. 2012 5 1715 35 DYSLIPIDEMIC DIET-INDUCED MONOCYTE "PRIMING" AND DYSFUNCTION IN NON-HUMAN PRIMATES IS TRIGGERED BY ELEVATED PLASMA CHOLESTEROL AND ACCOMPANIED BY ALTERED HISTONE ACETYLATION. MONOCYTES AND THE RECRUITMENT OF MONOCYTE-DERIVED MACROPHAGES INTO SITES OF INFLAMMATION PLAY A KEY ROLE IN ATHEROGENESIS AND OTHER CHRONIC INFLAMMATORY DISEASES LINKED TO CARDIOMETABOLIC SYNDROME AND OBESITY. PREVIOUS STUDIES FROM OUR GROUP HAVE SHOWN THAT METABOLIC STRESS PROMOTES MONOCYTE PRIMING, I.E., ENHANCED ADHESION AND ACCELERATED CHEMOTAXIS OF MONOCYTES IN RESPONSE TO CHEMOKINES, BOTH IN VITRO AND IN DYSLIPIDEMIC LDLR(-/-) MICE. WE ALSO SHOWED THAT METABOLIC STRESS-INDUCED MONOCYTE DYSFUNCTION IS, AT LEAST TO A LARGE EXTENT CAUSED BY THE S-GLUTATHIONYLATION, INACTIVATION, AND SUBSEQUENT DEGRADATION OF MITOGEN-ACTIVATED PROTEIN KINASE PHOSPHATASE 1. HERE, WE ANALYZED THE EFFECTS OF A WESTERN-STYLE, DYSLIPIDEMIC DIET (DD), WHICH WAS COMPOSED OF HIGH LEVELS OF SATURATED FAT, CHOLESTEROL, AND SIMPLE SUGARS, ON MONOCYTE (DYS)FUNCTION IN NON-HUMAN PRIMATES (NHPS). WE FOUND THAT SIMILAR TO MICE, A DD ENHANCES MONOCYTE CHEMOTAXIS IN NHP WITHIN 4 WEEKS, OCCURRING CONCORDANTLY WITH THE ONSET OF HYPERCHOLESTEROLEMIA BUT PRIOR TO CHANGES IN TRIGLYCERIDES, BLOOD GLUCOSE, MONOCYTOSIS, OR CHANGES IN MONOCYTE SUBSET COMPOSITION. IN ADDITION, WE IDENTIFIED TRANSITORY DECREASES IN THE ACETYLATION OF HISTONE H3 AT THE LYSINE RESIDUES 18 AND 23 IN METABOLICALLY PRIMED MONOCYTES, AND WE FOUND THAT MONOCYTE PRIMING WAS CORRELATED WITH THE ACETYLATION OF HISTONE H3 AT LYSINE 27 AFTER AN 8-WEEK DD REGIMEN. OUR DATA SHOW THAT METABOLIC STRESS PROMOTES MONOCYTE PRIMING AND HYPER-CHEMOTACTIC RESPONSES IN NHP. THE HISTONE MODIFICATIONS ACCOMPANYING MONOCYTE PRIMING IN PRIMATES SUGGEST A REPROGRAMMING OF THE EPIGENETIC LANDSCAPE, WHICH MAY LEAD TO DYSREGULATED RESPONSES AND FUNCTIONALITIES IN MACROPHAGES DERIVED FROM PRIMED MONOCYTES THAT ARE RECRUITED TO SITES OF INFLAMMATION. 2017 6 5815 35 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 7 6267 33 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 8 3973 34 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 9 4948 41 PATERNAL STRESS EXPOSURE ALTERS SPERM MICRORNA CONTENT AND REPROGRAMS OFFSPRING HPA STRESS AXIS REGULATION. NEUROPSYCHIATRIC DISEASE FREQUENTLY PRESENTS WITH AN UNDERLYING HYPOREACTIVITY OR HYPERREACTIVITY OF THE HPA STRESS AXIS, SUGGESTING AN EXCEPTIONAL VULNERABILITY OF THIS CIRCUITRY TO EXTERNAL PERTURBATIONS. PARENTAL LIFETIME EXPOSURES TO ENVIRONMENTAL CHALLENGES ARE ASSOCIATED WITH INCREASED OFFSPRING NEUROPSYCHIATRIC DISEASE RISK, AND LIKELY CONTRIBUTE TO STRESS DYSREGULATION. WHILE MATERNAL INFLUENCES HAVE BEEN EXTENSIVELY EXAMINED, MUCH LESS IS KNOWN REGARDING THE SPECIFIC ROLE OF PATERNAL FACTORS. TO INVESTIGATE THE POTENTIAL MECHANISMS BY WHICH PATERNAL STRESS MAY CONTRIBUTE TO OFFSPRING HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS DYSREGULATION, WE EXPOSED MICE TO 6 WEEKS OF CHRONIC STRESS BEFORE BREEDING. AS EPIDEMIOLOGICAL STUDIES SUPPORT VARIATION IN PATERNAL GERM CELL SUSCEPTIBILITY TO REPROGRAMMING ACROSS THE LIFESPAN, MALE STRESS EXPOSURE OCCURRED EITHER THROUGHOUT PUBERTY OR IN ADULTHOOD. REMARKABLY, OFFSPRING OF SIRES FROM BOTH PATERNAL STRESS GROUPS DISPLAYED SIGNIFICANTLY REDUCED HPA STRESS AXIS RESPONSIVITY. GENE SET ENRICHMENT ANALYSES IN OFFSPRING STRESS REGULATING BRAIN REGIONS, THE PARAVENTRICULAR NUCLEUS (PVN) AND THE BED NUCLEUS OF STRIA TERMINALIS, REVEALED GLOBAL PATTERN CHANGES IN TRANSCRIPTION SUGGESTIVE OF EPIGENETIC REPROGRAMMING AND CONSISTENT WITH ALTERED OFFSPRING STRESS RESPONSIVITY, INCLUDING INCREASED EXPRESSION OF GLUCOCORTICOID-RESPONSIVE GENES IN THE PVN. IN EXAMINING POTENTIAL EPIGENETIC MECHANISMS OF GERM CELL TRANSMISSION, WE FOUND ROBUST CHANGES IN SPERM MICRORNA (MIR) CONTENT, WHERE NINE SPECIFIC MIRS WERE SIGNIFICANTLY INCREASED IN BOTH PATERNAL STRESS GROUPS. OVERALL, THESE RESULTS DEMONSTRATE THAT PATERNAL EXPERIENCE ACROSS THE LIFESPAN CAN INDUCE GERM CELL EPIGENETIC REPROGRAMMING AND IMPACT OFFSPRING HPA STRESS AXIS REGULATION, AND MAY THEREFORE OFFER NOVEL INSIGHT INTO FACTORS INFLUENCING NEUROPSYCHIATRIC DISEASE RISK. 2013 10 3463 30 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 11 4075 38 MATERNAL HIGH-FAT DIET IMPAIRS LEPTIN SIGNALING AND UP-REGULATES TYPE-1 CANNABINOID RECEPTOR WITH SEX-SPECIFIC EPIGENETIC CHANGES IN THE HYPOTHALAMUS OF NEWBORN RATS. MATERNAL NUTRITIONAL IMBALANCES TRIGGER DEVELOPMENTAL ADAPTATIONS INVOLVING EARLY EPIGENETIC MECHANISMS ASSOCIATED WITH ADULT CHRONIC DISEASE. MATERNAL HIGH-FAT (HF) DIET PROMOTES OBESITY AND HYPOTHALAMIC LEPTIN RESISTANCE IN MALE RAT OFFSPRING AT WEANING AND ADULTHOOD. LEPTIN RESISTANCE IS ASSOCIATED WITH OVER ACTIVATION OF THE ENDOCANNABINOID SYSTEM (ECS). THE ECS MAINLY CONSISTS OF ENDOCANNABINOIDS DERIVED FROM N-6 FATTY ACIDS AND CANNABINOID RECEPTORS (CB1 CODED BY CNR1 AND CB2 CODED BY CNR2). THE CB1 ACTIVATION IN HYPOTHALAMUS STIMULATES FEEDING AND APPETITE FOR FAT WHILE CB2 ACTIVATION SEEMS TO PLAY AN IMMUNOMODULATORY ROLE. WE DEMONSTRATED THAT MATERNAL HF DIET INCREASES HYPOTHALAMIC CB1 IN MALE OFFSPRING WHILE INCREASES CB2 IN FEMALE OFFSPRING AT BIRTH, PRIOR TO OBESITY DEVELOPMENT. HOWEVER, THE MOLECULAR MECHANISMS BEHIND THESE CHANGES REMAIN UNEXPLORED. WE HYPOTHESIZED THAT MATERNAL HF DIET WOULD DOWN-REGULATE LEPTIN SIGNALING AND UP-REGULATE CNR1 MRNA LEVELS IN THE HYPOTHALAMUS OF THE OFFSPRING AT BIRTH, ASSOCIATED WITH SEX-SPECIFIC CHANGES IN EPIGENETIC MARKERS AND SEX STEROID SIGNALING. TO TEST OUR HYPOTHESIS, WE USED PROGENITOR FEMALE RATS THAT RECEIVED CONTROL DIET (C, 9% FAT) OR ISOCALORIC HIGH-FAT DIET (HF, 28% FAT) FROM 8 WEEKS BEFORE MATING UNTIL DELIVERY. BLOOD, HYPOTHALAMUS AND CARCASS FROM C AND HF MALE AND FEMALE OFFSPRING WERE COLLECTED FOR BIOCHEMICAL AND MOLECULAR ANALYSES AT BIRTH. MATERNAL HF DIET DOWN-REGULATED THE TRANSCRIPTIONAL FACTOR STAT3 IN THE HYPOTHALAMUS OF MALE AND FEMALE OFFSPRING, BUT INDUCED HYPOLEPTINEMIA ONLY IN MALES AND DECREASED PHOSPHORYLATED STAT3 ONLY IN FEMALE OFFSPRING. BECAUSE LEPTIN ACTS THROUGH STAT3 PATHWAY TO INHIBIT CENTRAL ECS, OUR RESULTS SUGGEST THAT LEPTIN PATHWAY IMPAIRMENT MIGHT CONTRIBUTE TO INCREASED LEVELS OF CRN1 MRNA IN HYPOTHALAMUS OF BOTH SEX OFFSPRING. BESIDES, MATERNAL HF DIET INCREASED THE HISTONE ACETYLATION PERCENTAGE OF CNR1 PROMOTER IN MALE OFFSPRING AND INCREASED THE ANDROGEN RECEPTOR BINDING TO THE CNR1 PROMOTER, WHICH CAN CONTRIBUTE TO HIGHER EXPRESSION OF CNR1 IN NEWBORN HF OFFSPRING. MATERNAL HF DIET INCREASED PLASMA N6 TO N3 FATTY ACID RATIO IN MALE OFFSPRING, WHICH IS AN IMPORTANT RISK FACTOR TO METABOLIC DISEASES AND MIGHT INDICATE AN OVER ACTIVATION OF ENDOCANNABINOID SIGNALING. THUS, ALTHOUGH MATERNAL HF DIET PROGRAMS A SIMILAR PHENOTYPE IN ADULT OFFSPRING OF BOTH SEXES (OBESITY, HYPERPHAGIA AND HIGHER PREFERENCE FOR FAT), HERE WE SHOWED THAT MOLECULAR MECHANISMS INVOLVING LEPTIN SIGNALING, ECS, EPIGENETIC MARKERS AND SEX HORMONE SIGNALING WERE MODIFIED PRIOR TO OBESITY DEVELOPMENT AND CAN DIFFER BETWEEN NEWBORN MALE AND FEMALE OFFSPRING. THESE OBSERVATIONS MAY PROVIDE MOLECULAR INSIGHTS INTO SEX-SPECIFIC TARGETS FOR ANTI-OBESITY THERAPIES. 2019 12 4608 34 NEONATAL ANESTHESIA AND DYSREGULATION OF THE EPIGENOMEDAGGER. EACH YEAR, MILLIONS OF INFANTS AND CHILDREN ARE ANESTHETIZED FOR MEDICAL AND SURGICAL PROCEDURES. YET, A SUBSTANTIAL BODY OF PRECLINICAL EVIDENCE SUGGESTS THAT ANESTHETICS ARE NEUROTOXINS THAT CAUSE RAPID AND WIDESPREAD APOPTOTIC CELL DEATH IN THE BRAINS OF INFANT RODENTS AND NONHUMAN PRIMATES. THESE ANIMALS HAVE PERSISTENT IMPAIRMENTS IN COGNITION AND BEHAVIOR MANY WEEKS OR MONTHS AFTER ANESTHESIA EXPOSURE, LEADING US TO HYPOTHESIZE THAT ANESTHETICS DO MORE THAN SIMPLY KILL BRAIN CELLS. INDEED, ANESTHETICS CAUSE CHRONIC NEUROPATHOLOGY IN NEURONS THAT SURVIVE THE INSULT, WHICH THEN INTERFERES WITH MAJOR ASPECTS OF BRAIN DEVELOPMENT, SYNAPTIC PLASTICITY, AND NEURONAL FUNCTION. UNDERSTANDING THE PHENOMENON OF ANESTHESIA-INDUCED DEVELOPMENTAL NEUROTOXICITY IS OF CRITICAL PUBLIC HEALTH IMPORTANCE BECAUSE CLINICAL STUDIES NOW REPORT THAT ANESTHESIA IN HUMAN INFANCY IS ASSOCIATED WITH COGNITIVE AND BEHAVIORAL DEFICITS. IN OUR SEARCH FOR MECHANISTIC EXPLANATIONS FOR WHY A YOUNG AND PLIABLE BRAIN CANNOT FULLY RECOVER FROM A RELATIVELY BRIEF PERIOD OF ANESTHESIA, WE HAVE ACCUMULATED EVIDENCE THAT NEONATAL ANESTHESIA CAN DYSREGULATE EPIGENETIC TAGS THAT INFLUENCE GENE TRANSCRIPTION SUCH AS HISTONE ACETYLATION AND DNA METHYLATION. IN THIS REVIEW, WE BRIEFLY SUMMARIZE THE PHENOMENON OF ANESTHESIA-INDUCED DEVELOPMENTAL NEUROTOXICITY. WE THEN DISCUSS CHRONIC NEUROPATHOLOGY CAUSED BY NEONATAL ANESTHESIA, INCLUDING DISTURBANCES IN COGNITION, SOCIO-AFFECTIVE BEHAVIOR, NEURONAL MORPHOLOGY, AND SYNAPTIC PLASTICITY. FINALLY, WE PRESENT EVIDENCE OF ANESTHESIA-INDUCED GENETIC AND EPIGENETIC DYSREGULATION WITHIN THE DEVELOPING BRAIN THAT MAY BE TRANSMITTED INTERGENERATIONALLY TO ANESTHESIA-NAIVE OFFSPRING. 2021 13 3179 35 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED. 2016 14 1761 35 EARLY STRESS EVOKES AGE-DEPENDENT BIPHASIC CHANGES IN HIPPOCAMPAL NEUROGENESIS, BDNF EXPRESSION, AND COGNITION. BACKGROUND: ADULT-ONSET STRESSORS EXERT OPPOSING EFFECTS ON HIPPOCAMPAL NEUROGENESIS AND COGNITION, WITH ENHANCEMENT OBSERVED FOLLOWING MILD STRESS AND DYSFUNCTION FOLLOWING SEVERE CHRONIC STRESS. WHILE EARLY LIFE STRESS EVOKES PERSISTENT CHANGES IN ANXIETY, IT IS UNKNOWN WHETHER EARLY STRESS DIFFERENTIALLY REGULATES HIPPOCAMPAL NEUROGENESIS, TROPHIC FACTOR EXPRESSION, AND COGNITION ACROSS THE LIFE SPAN. METHODS: HIPPOCAMPAL-DEPENDENT COGNITIVE BEHAVIOR, NEUROGENESIS, AND EPIGENETIC REGULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION WAS EXAMINED AT DISTINCT TIME POINTS ACROSS THE LIFE SPAN IN RATS SUBJECTED TO THE EARLY STRESS OF MATERNAL SEPARATION (ES) AND CONTROL GROUPS. WE ALSO EXAMINED THE INFLUENCE OF CHRONIC ANTIDEPRESSANT TREATMENT ON THE NEUROGENIC, NEUROTROPHIC, AND COGNITIVE CHANGES IN MIDDLE-AGED ES ANIMALS. RESULTS: ANIMALS SUBJECTED TO EARLY STRESS OF MATERNAL SEPARATION EXAMINED DURING POSTNATAL LIFE AND YOUNG ADULTHOOD EXHIBITED ENHANCED HIPPOCAMPAL NEUROGENESIS, DECREASED REPRESSIVE HISTONE METHYLATION AT THE BDNF IV PROMOTER ALONG WITH ENHANCED BDNF LEVELS, AND IMPROVED PERFORMANCE ON THE STRESS-ASSOCIATED MORRIS WATER MAZE. STRIKINGLY, OPPOSING CHANGES IN HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC REGULATION OF BDNF IV EXPRESSION, CONCOMITANT WITH IMPAIRMENTS ON HIPPOCAMPAL-DEPENDENT COGNITIVE TASKS, WERE OBSERVED IN MIDDLE-AGED ES ANIMALS. CHRONIC ANTIDEPRESSANT TREATMENT WITH AMITRIPTYLINE ATTENUATED THE MALADAPTIVE NEUROGENIC, EPIGENETIC, TRANSCRIPTIONAL, AND COGNITIVE EFFECTS IN MIDDLE-AGED ES ANIMALS. CONCLUSIONS: OUR STUDY PROVIDES NOVEL INSIGHTS INTO THE SHORT- AND LONG-TERM CONSEQUENCES OF ES, DEMONSTRATING BOTH BIPHASIC AND UNIQUE, AGE-DEPENDENT CHANGES AT THE MOLECULAR, EPIGENETIC, NEUROGENIC, AND BEHAVIORAL LEVELS. THESE RESULTS INDICATE THAT EARLY STRESS MAY TRANSIENTLY ENDOW ANIMALS WITH A POTENTIAL ADAPTIVE ADVANTAGE IN STRESSFUL ENVIRONMENTS BUT ACROSS A LIFE SPAN IS ASSOCIATED WITH LONG-TERM DELETERIOUS EFFECTS. 2013 15 4944 29 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 16 5200 36 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES. 2016 17 5662 23 SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE. CHRONIC STRESS IS ENCOUNTERED IN OUR EVERYDAY LIFE AND IS THOUGHT TO CONTRIBUTE TO A NUMBER OF DISEASES. MANY OF THESE STRESS-RELATED DISORDERS DISPLAY A SEX BIAS. BECAUSE GLUCOCORTICOID HORMONES ARE THE MAIN BIOLOGICAL MEDIATOR OF CHRONIC STRESS, RESEARCHERS HAVE BEEN INTERESTED IN UNDERSTANDING THE SEXUAL DIMORPHISM IN GLUCOCORTICOID STRESS RESPONSE TO BETTER EXPLAIN THE SEX BIAS IN STRESS-RELATED DISEASES. ALTHOUGH NOT YET DEMONSTRATED FOR GLUCOCORTICOID REGULATION, SEX CHROMOSOMES DO INFLUENCE SEX-SPECIFIC BIOLOGY AS SOON AS CONCEPTION. THEN A TRANSIENT RISE IN TESTOSTERONE START TO SHAPE THE MALE BRAIN DURING THE PRENATAL PERIOD DIFFERENTLY TO THE FEMALE BRAIN. THESE ORGANIZATIONAL EFFECTS ARE COMPLETED JUST BEFORE PUBERTY. THE CEREBRAL REGIONS IMPLICATED IN GLUCOCORTICOID REGULATION AT REST AND AFTER STRESS ARE THEREBY IMPACTED IN A SEX-SPECIFIC MANNER. AFTER PUBERTY, THE HIGH LEVELS OF ALL GONADAL HORMONES WILL INTERACT WITH GLUCOCORTICOID HORMONES IN SPECIFIC CROSSTALK THROUGH THEIR RESPECTIVE NUCLEAR RECEPTORS. IN ADDITION, STRESS OCCURRING EARLY IN LIFE, IN PARTICULAR DURING THE PRENATAL PERIOD AND IN ADOLESCENCE WILL PRIME IN THE LONG-TERM GLUCOCORTICOID STRESS RESPONSE THROUGH EPIGENETIC MECHANISMS, AGAIN IN A SEX-SPECIFIC MANNER. ALTOGETHER, VARIOUS MOLECULAR MECHANISMS EXPLAIN SEX-SPECIFIC GLUCOCORTICOID STRESS RESPONSES THAT DO NOT EXCLUDE IMPORTANT GENDER EFFECTS IN HUMANS. 2021 18 4082 31 MATERNAL MODIFIERS OF THE INFANT GUT MICROBIOTA: METABOLIC CONSEQUENCES. TRANSMISSION OF METABOLIC DISEASES FROM MOTHER TO CHILD IS MULTIFACTORIAL AND INCLUDES GENETIC, EPIGENETIC AND ENVIRONMENTAL INFLUENCES. EVIDENCE IN RODENTS, HUMANS AND NON-HUMAN PRIMATES SUPPORT THE SCIENTIFIC PREMISE THAT EXPOSURE TO MATERNAL OBESITY OR HIGH-FAT DIET DURING PREGNANCY CREATES A LONG-LASTING METABOLIC SIGNATURE ON THE INFANT INNATE IMMUNE SYSTEM AND THE JUVENILE MICROBIOTA, WHICH PREDISPOSES THE OFFSPRING TO OBESITY AND METABOLIC DISEASES. IN NEONATES, GASTROINTESTINAL MICROBES INTRODUCED THROUGH THE MOTHER ARE NOTED FOR THEIR ABILITY TO SERVE AS DIRECT INDUCERS/REGULATORS OF THE INFANT IMMUNE SYSTEM. NEONATES HAVE A LIMITED CAPACITY TO INITIATE AN IMMUNE RESPONSE. THUS, DISRUPTION OF MICROBIAL COLONIZATION DURING THE EARLY NEONATAL PERIOD RESULTS IN DISRUPTED POSTNATAL IMMUNE RESPONSES THAT HIGHLIGHT THE NEONATAL PERIOD AS A CRITICAL DEVELOPMENTAL WINDOW. ALTHOUGH THE MECHANISMS ARE POORLY UNDERSTOOD, INCREASING EVIDENCE SUGGESTS THAT MATERNAL OBESITY OR POOR DIET INFLUENCES THE DEVELOPMENT AND MODULATION OF THE INFANT LIVER AND OTHER END ORGANS THROUGH DIRECT COMMUNICATION VIA THE PORTAL SYSTEM, METABOLITE PRODUCTION, ALTERATIONS IN GUT BARRIER INTEGRITY AND THE HEMATOPOIETIC IMMUNE CELL AXIS. THIS REVIEW WILL FOCUS ON HOW MATERNAL OBESITY AND DIETARY INTAKE INFLUENCE THE COMPOSITION OF THE INFANT GUT MICROBIOTA AND HOW AN IMBALANCE OR MALADAPTATION IN THE MICROBIOTA, INCLUDING CHANGES IN EARLY PIONEERING MICROBES, MIGHT CONTRIBUTE TO THE PROGRAMMING OF OFFSPRING METABOLISM WITH SPECIAL EMPHASIS ON MECHANISMS THAT PROMOTE CHRONIC INFLAMMATION IN THE LIVER. COMPREHENSION OF THESE PATHWAYS AND MECHANISMS WILL ELUCIDATE OUR UNDERSTANDING OF DEVELOPMENTAL PROGRAMMING AND MAY EXPAND THE AVENUE OF OPPORTUNITIES FOR NOVEL THERAPEUTICS. 2017 19 23 33 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015 20 4064 33 MATERNAL AND EARLY-LIFE CIRCADIAN DISRUPTION HAVE LONG-LASTING NEGATIVE CONSEQUENCES ON OFFSPRING DEVELOPMENT AND ADULT BEHAVIOR IN MICE. MODERN LIFE INVOLVES CHRONIC CIRCADIAN DISRUPTION THROUGH ARTIFICIAL LIGHT AND THESE DISRUPTIONS ARE ASSOCIATED WITH NUMEROUS MENTAL AND PHYSICAL HEALTH MALADIES. BECAUSE THE DEVELOPING NERVOUS SYSTEM IS PARTICULARLY VULNERABLE TO PERTURBATION, WE HYPOTHESIZED THAT EARLY-LIFE CIRCADIAN DISRUPTION WOULD NEGATIVELY IMPACT OFFSPRING DEVELOPMENT AND ADULT FUNCTION. PREGNANT MICE WERE SUBJECTED TO CHRONIC CIRCADIAN DISRUPTION FROM THE TIME OF UTERINE IMPLANTATION THROUGH WEANING. TO DISSOCIATE IN UTERO FROM POSTNATAL EFFECTS, A SUBSET OF LITTERS WAS CROSS-FOSTERED AT BIRTH FROM DISRUPTED DAMS TO CONTROL DAMS AND VICE VERSA. POSTNATAL CIRCADIAN DISRUPTION WAS ASSOCIATED WITH REDUCED ADULT BODY MASS, SOCIAL AVOIDANCE, AND HYPERACTIVITY. IN UTERO DISRUPTION RESULTED IN MORE PRONOUNCED SOCIAL AVOIDANCE AND HYPERACTIVITY, PHENOTYPES NOT ABROGATED BY CROSS-FOSTERING TO CONTROL MOTHERS. TO EXAMINE WHETHER CIRCADIAN DISRUPTION AFFECTS DEVELOPMENT BY ACTING AS AN EARLY LIFE STRESSOR, WE EXAMINED BIRTHWEIGHT, LITTER SIZE, MATERNAL CANNIBALISM, AND EPIGENETIC MODIFICATIONS. NONE OF THESE VARIABLES DIFFERED BETWEEN CONTROL AND DISRUPTED DAMS, OR RESEMBLED PATTERNS SEEN FOLLOWING EARLY-LIFE STRESS. OUR FINDINGS INDICATE THAT DEVELOPMENTAL CHRONIC CIRCADIAN DISRUPTION PERMANENTLY AFFECTS SOMATIC AND BEHAVIORAL DEVELOPMENT IN A STAGE-OF-LIFE-DEPENDENT MANNER, INDEPENDENT OF EARLY LIFE STRESS MECHANISMS, UNDERSCORING THE IMPORTANCE OF TEMPORAL STRUCTURE DURING DEVELOPMENT, BOTH IN UTERO AND EARLY POSTNATAL LIFE. 2017