1 5873 150 SWEET SUCCESS, BITTER DEFEAT: A TASTE PHENOTYPE PREDICTS SOCIAL STATUS IN SELECTIVELY BRED RATS. FOR SOCIAL OMNIVORES SUCH AS RATS AND HUMANS, TASTE IS FAR MORE THAN A CHEMICAL SENSE ACTIVATED BY FOOD. BY VIRTUE OF EVOLUTIONARY AND EPIGENETIC ELABORATION, TASTE IS ASSOCIATED WITH NEGATIVE AFFECT, STRESS VULNERABILITY, RESPONSES TO PSYCHOACTIVE SUBSTANCES, PAIN, AND SOCIAL JUDGMENT. A CRUCIAL GAP IN THIS LITERATURE, WHICH SPANS BEHAVIOR GENETICS, AFFECTIVE AND SOCIAL NEUROSCIENCE, AND EMBODIED COGNITION, CONCERNS LINKS BETWEEN TASTE AND SOCIAL BEHAVIOR IN RATS. HERE WE SHOW THAT RATS SELECTIVELY BRED FOR LOW SACCHARIN INTAKE ARE SUBORDINATE TO HIGH-SACCHARIN-CONSUMING RATS WHEN THEY COMPETE IN WEIGHT-MATCHED DYADS FOR FOOD, A TASK USED TO MODEL DEPRESSION. STATISTICAL AND EXPERIMENTAL CONTROLS SUGGEST THAT DIFFERENTIAL RESOURCE UTILIZATION WITHIN DYADS IS NOT AN ARTIFACT OF INDIVIDUAL-LEVEL PROCESSES SUCH AS APPARATUS HABITUATION OR INGESTIVE MOTIVATION. TAIL SKIN TEMPERATURE MEASUREMENTS SHOWED THAT LOS RATS DISPLAY LARGER HYPERTHERMIC RESPONSES TO SOCIAL INTERACTION AFTER STATUS IS ESTABLISHED, EVIDENCE LINKING TASTE, SOCIAL STRESS, AUTONOMIC REACTIVITY, AND DEPRESSION-LIKE SYMPTOMS. BASED ON REGRESSION USING EARLY- AND LATE-COMPETITION PREDICTORS TO PREDICT DYADIC DISPARITY IN FINAL COMPETITION SCORES, WE TENTATIVELY SUGGEST THAT HIS RATS EMERGE AS DOMINANT BOTH BECAUSE OF AN "EARLY SURGE" ON THEIR PART AND BECAUSE LOS ACQUIESCE LATER. THESE FINDINGS SHOULD INVIGORATE THE COMPARATIVE STUDY OF INDIVIDUAL DIFFERENCES IN SOCIAL STATUS AND ITS RELATIONSHIP TO MENTAL AND PHYSICAL HEALTH.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2 6853  35 [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	

3 2999  38 GENETIC VARIATION, STRESS, AND PHYSIOLOGICAL STRESS RESPONSE IN ADULTS WITH FOOD ALLERGY OR CELIAC DISEASE. BACKGROUND: PERSISTENTLY HIGH CHRONIC STRESS CAN LEAD TO MALADAPTIVE PSYCHOLOGICAL, BEHAVIORAL, AND PHYSIOLOGICAL STRESS RESPONSES AND POOR MENTAL AND PHYSICAL HEALTH, HIGHLIGHTING THE IMPORTANCE OF IDENTIFYING INDIVIDUALS AT INCREASED RISK. CHRONIC HEALTH CONDITION DIAGNOSIS AND GENETICS ARE 2 CHARACTERISTICS THAT CAN INFLUENCE STRESS, STRESS RESPONSE, AND HEALTH OUTCOMES. PURPOSE: FOOD ALLERGY (FA) AND CELIAC DISEASE (CD) REQUIRE CONSTANT VIGILANCE IN DAILY LIFE AND CAN LEAD TO INCREASED STRESS. THE PURPOSE OF THIS EXPLORATORY ANALYSIS WAS TO EXAMINE THE ASSOCIATION OF VARIANTS IN SELECTED STRESS-RELATED GENES WITH STRESS EXPOSURES, STRESS, CLINICAL MEASURES OF PHYSIOLOGICAL STRESS RESPONSE, AND MENTAL HEALTH SYMPTOMS IN ADULTS WITH AND WITHOUT FA OR CD. METHODS: WE COMPARED STRESS EXPOSURES, SYMPTOMS OF PTSD, DEPRESSION, ANXIETY, AND STRESS, BMI, AND WAIST-HIP RATIO BETWEEN CASES AND CONTROLS. WE ANALYZED THE ASSOCIATION OF SNPS IN GENES WITH KNOWN OR HYPOTHESIZED ASSOCIATIONS WITH STRESS-RELATED MEASURES IN 124 CASES AND 124 MATCHED CONTROLS: CRHBP (RS7718461, RS10474485), CRHR1 (RS242940) AND OXTR (RS2268490). FOR THIS EXPLORATORY STUDY, P-VALUES </= 0.10 WERE CONSIDERED SUGGESTIVE. RESULTS: FOR CASES AND CONTROLS, RS7718461 WAS ASSOCIATED WITH STRESS SYMPTOMS, RS2268490 WITH SYMPTOMS OF STRESS AND PTSD, AND RS242940 WITH SYMPTOMS OF STRESS, PTSD, ANXIETY, AND DEPRESSION. FURTHER ANALYSES FOUND THAT STRESS-RELATED OUTCOMES IN INDIVIDUALS WITH FA OR CD MAY BE INFLUENCED BY SNP GENOTYPE. CONCLUSIONS: GIVEN THESE SUGGESTIVE FINDINGS, LARGER PROSPECTIVE STUDIES SHOULD EXAMINE SIMILAR RELATIONSHIPS IN INDIVIDUALS WITH OTHER CHRONIC HEALTH CONDITIONS, INCORPORATING FACTORS SUCH AS ENVIRONMENTAL EXPOSURES, INDIVIDUAL EXPERIENCES, AND EPIGENETIC MODIFICATIONS.	2023	
                                                                                                                                                                                                                                   
4 2471  28 EPIGENETIC TRANSGENERATIONAL INHERITANCE OF ALTERED STRESS RESPONSES. ANCESTRAL ENVIRONMENTAL EXPOSURES HAVE PREVIOUSLY BEEN SHOWN TO PROMOTE EPIGENETIC TRANSGENERATIONAL INHERITANCE AND INFLUENCE ALL ASPECTS OF AN INDIVIDUAL'S LIFE HISTORY. IN ADDITION, PROXIMATE LIFE EVENTS SUCH AS CHRONIC STRESS HAVE DOCUMENTED EFFECTS ON THE DEVELOPMENT OF PHYSIOLOGICAL, NEURAL, AND BEHAVIORAL PHENOTYPES IN ADULTHOOD. WE USED A SYSTEMS BIOLOGY APPROACH TO INVESTIGATE IN MALE RATS THE INTERACTION OF THE ANCESTRAL MODIFICATIONS CARRIED TRANSGENERATIONALLY IN THE GERM LINE AND THE PROXIMATE MODIFICATIONS INVOLVING CHRONIC RESTRAINT STRESS DURING ADOLESCENCE. WE FIND THAT A SINGLE EXPOSURE TO A COMMON-USE FUNGICIDE (VINCLOZOLIN) THREE GENERATIONS REMOVED ALTERS THE PHYSIOLOGY, BEHAVIOR, METABOLIC ACTIVITY, AND TRANSCRIPTOME IN DISCRETE BRAIN NUCLEI IN DESCENDANT MALES, CAUSING THEM TO RESPOND DIFFERENTLY TO CHRONIC RESTRAINT STRESS. THIS ALTERATION OF BASELINE BRAIN DEVELOPMENT PROMOTES A CHANGE IN NEURAL GENOMIC ACTIVITY THAT CORRELATES WITH CHANGES IN PHYSIOLOGY AND BEHAVIOR, REVEALING THE INTERACTION OF GENETICS, ENVIRONMENT, AND EPIGENETIC TRANSGENERATIONAL INHERITANCE IN THE SHAPING OF THE ADULT PHENOTYPE. THIS IS AN IMPORTANT DEMONSTRATION IN AN ANIMAL THAT ANCESTRAL EXPOSURE TO AN ENVIRONMENTAL COMPOUND MODIFIES HOW DESCENDANTS OF THESE PROGENITOR INDIVIDUALS PERCEIVE AND RESPOND TO A STRESS CHALLENGE EXPERIENCED DURING THEIR OWN LIFE HISTORY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5 2808  27 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	
                                                                                                                                                                    
6 1639  34 DOES EPIGENETIC 'MEMORY' OF EARLY-LIFE STRESS PREDISPOSE TO CHRONIC PAIN IN LATER LIFE? A POTENTIAL ROLE FOR THE STRESS REGULATOR FKBP5. ANIMAL BEHAVIOURS ARE AFFECTED NOT ONLY BY INHERITED GENES BUT ALSO BY ENVIRONMENTAL EXPERIENCES. FOR EXAMPLE, IN BOTH RATS AND HUMANS, STRESSFUL EARLY-LIFE EVENTS SUCH AS BEING REARED BY AN INATTENTIVE MOTHER CAN LEAVE A LASTING TRACE AND AFFECT LATER STRESS RESPONSE IN ADULT LIFE. THIS IS OWING TO A CHEMICAL TRACE LEFT ON THE CHROMATIN ATTRIBUTED TO SO-CALLED EPIGENETIC MECHANISMS. SUCH AN EPIGENETIC TRACE OFTEN HAS CONSEQUENCES, SOMETIMES LONG-LASTING, ON THE FUNCTIONING OF OUR GENES, THEREBY ALLOWING INDIVIDUALS TO RAPIDLY ADAPT TO A NEW ENVIRONMENT. ONE GENE UNDER SUCH EPIGENETIC CONTROL IS FKBP5, THE GENE THAT ENCODES THE PROTEIN FKPB51, A CRUCIAL REGULATOR OF THE STRESS AXIS AND A SIGNIFICANT DRIVER OF CHRONIC PAIN STATES. IN THIS ARTICLE, WE WILL DISCUSS THE POSSIBILITY THAT EXPOSURE TO STRESS COULD DRIVE THE SUSCEPTIBLY TO CHRONIC PAIN VIA EPIGENETIC MODIFICATIONS OF GENES WITHIN THE STRESS AXIS SUCH AS FKBP5. THE POSSIBILITY THAT SUCH MODIFICATIONS, AND THEREFORE, THE SUSCEPTIBILITY TO CHRONIC PAIN, COULD BE TRANSMITTED ACROSS GENERATIONS IN MAMMALS AND WHETHER SUCH MECHANISMS MAY BE EVOLUTIONARILY CONSERVED ACROSS PHYLA WILL ALSO BE DEBATED. THIS ARTICLE IS PART OF THE THEO MURPHY MEETING ISSUE 'EVOLUTION OF MECHANISMS AND BEHAVIOUR IMPORTANT FOR PAIN'.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7 1823  31 EFFECTS OF EARLY-LIFE STRESS AND HDAC INHIBITION ON MATERNAL BEHAVIOR IN MICE. DESPITE THE WELL-ESTABLISHED FACT THAT MATERNAL CARE PLAYS A PIVOTAL ROLE IN THE OFFSPRING DEVELOPMENT, LITTLE IS KNOWN ABOUT THE EFFECTS OF DISRUPTION OF MATERNAL CARE EARLY IN LIFE ON THE DEVELOPMENT OF THIS BEHAVIOR IN THE OFFSPRING. USING BRIEF REPEATED MATERNAL SEPARATION (45 MIN/DAY ON POSTNATAL DAYS 3-6), WHICH REPRESENTS A MODEL OF EARLY LIFE STRESS, WE FOUND BEHAVIORAL CHANGES IN ADULT FEMALE MICE OFFSPRING. THE DECREASE IN HOME CAGE EXPLORATORY BEHAVIOR (BOTH PUP-DIRECTED AND NONPUP-DIRECTED) WAS REVEALED LATER IN ADULTHOOD WITHOUT CHANGES IN MATERNAL CARE LEVEL. MATERNAL SEPARATION COUPLED WITH PAIN EXPOSURE CAUSED BY SUBCUTANEOUS SALINE INJECTION PROCEDURE HAD A CUMULATIVE RESULTING EFFECT, WHICH WAS MANIFESTED IN THE DECREASED LEVEL OF NURSING ASSOCIATED WITH LICKING-GROOMING IN ADULT FEMALES. THE BEHAVIORAL CHANGES FOUND IN ADULT FEMALE OFFSPRING COULD BE TRIGGERED BY IDENTIFIED CHANGES IN THE BEHAVIOR OF THEIR MOTHERS, WHILE ALTERATIONS OF THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN WERE NOT DETECTED. HISTONE DEACETYLASE INHIBITOR SODIUM VALPROATE WAS USED IN ORDER TO STUDY THE POSSIBILITY OF PREVENTING THE EFFECTS OF EARLY LIFE STRESS THROUGH INVOLVEMENT OF EPIGENETIC MECHANISMS. DESPITE THE INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN CAUSED BY VALPROATE, ITS BEHAVIORAL EFFECTS WERE BARELY DETECTABLE. THESE EFFECTS WERE REFLECTED IN PREVENTION OF THE REDUCTION OF NURSING ASSOCIATED WITH LICKING-GROOMING INDUCED BY MATERNAL SEPARATION, ACCOMPANIED BY PAIN EXPOSURE. THE DATA ARE DISCUSSED IN TERMS OF THE POSSIBLE APPLICATION TO THE STUDIES OF MECHANISMS UNDERLYING LONG-TERM EFFECTS OF HUMAN EARLY LIFE TRAUMA. (PSYCINFO DATABASE RECORD (C) 2019 APA, ALL RIGHTS RESERVED).	2019	
                                                                                                                                                                                                                                                                                                   
8 1647  31 DOES THE STRESS OF LABORATORY LIFE AND EXPERIMENTATION ON ANIMALS ADVERSELY AFFECT RESEARCH DATA? A CRITICAL REVIEW. RECURRENT ACUTE AND/OR CHRONIC STRESS CAN AFFECT ALL VERTEBRATE SPECIES, AND CAN HAVE SERIOUS CONSEQUENCES. IT IS INCREASINGLY AND WIDELY APPRECIATED THAT LABORATORY ANIMALS EXPERIENCE SIGNIFICANT AND REPEATED STRESS, WHICH IS UNAVOIDABLE AND IS CAUSED BY MANY ASPECTS OF LABORATORY LIFE, SUCH AS CAPTIVITY, TRANSPORT, NOISE, HANDLING, RESTRAINT AND OTHER PROCEDURES, AS WELL AS THE EXPERIMENTAL PROCEDURES APPLIED TO THEM. SUCH STRESS IS DIFFICULT TO MITIGATE, AND LACK OF SIGNIFICANT DESENSITISATION/HABITUATION CAN RESULT IN CONSIDERABLE PSYCHOLOGICAL AND PHYSIOLOGICAL WELFARE PROBLEMS, WHICH ARE MEDIATED BY THE ACTIVATION OF VARIOUS NEUROENDOCRINE NETWORKS THAT HAVE NUMEROUS AND PERVASIVE EFFECTS. PSYCHOLOGICAL DAMAGE CAN BE REFLECTED IN STEREOTYPICAL BEHAVIOURS, INCLUDING REPETITIVE PACING AND CIRCLING, AND EVEN SELF-HARM. PHYSICAL CONSEQUENCES INCLUDE ADVERSE EFFECTS ON IMMUNE FUNCTION, INFLAMMATORY RESPONSES, METABOLISM, AND DISEASE SUSCEPTIBILITY AND PROGRESSION. FURTHER, SOME OF THESE EFFECTS ARE EPIGENETIC, AND ARE THEREFORE POTENTIALLY TRANSGENERATIONAL: THE BIOLOGY OF ANIMALS WHOSE PARENTS/GRANDPARENTS WERE WILD-CAUGHT AND/OR HAVE EXPERIENCED CHRONIC STRESS IN LABORATORIES COULD BE ALTERED, AS COMPARED TO FREE-LIVING INDIVIDUALS. IT IS ARGUED THAT THESE EFFECTS MUST HAVE CONSEQUENCES FOR THE RELIABILITY OF EXPERIMENTAL DATA AND THEIR EXTRAPOLATION TO HUMANS, AND THIS MAY NOT BE RECOGNISED SUFFICIENTLY AMONG THOSE WHO USE ANIMALS IN EXPERIMENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  678  31 BRAIN DEVELOPMENT UNDER STRESS: HYPOTHESES OF GLUCOCORTICOID ACTIONS REVISITED. ONE OF THE CONUNDRUMS IN TODAY'S STRESS RESEARCH IS WHY SOME INDIVIDUALS FLOURISH AND OTHERS PERISH UNDER SIMILAR STRESSFUL CONDITIONS. IT IS RECOGNIZED THAT THIS INDIVIDUAL VARIABILITY IN ADAPTATION TO STRESS DEPENDS ON THE OUTCOME OF THE INTERACTION OF GENETIC AND COGNITIVE/EMOTIONAL INPUTS IN WHICH GLUCOCORTICOID HORMONES AND RECEPTORS PLAY A CRUCIAL ROLE. HENCE ONE APPROACH TOWARDS UNDERSTANDING INDIVIDUAL VARIATION IN STRESS COPING IS HOW GLUCOCORTICOID ACTIONS CAN CHANGE FROM PROTECTIVE TO HARMFUL. TO ADDRESS THIS QUESTION WE FOCUS ON FOUR HYPOTHESES THAT ARE CONNECTED AND NOT MUTUAL EXCLUSIVE. FIRST, THE CLASSICAL GLUCOCORTICOID CASCADE HYPOTHESIS, IN WHICH THE INABILITY TO COPE WITH CHRONIC STRESS CAUSES A VICIOUS CYCLE OF EXCESS GLUCOCORTICOID AND DOWNREGULATION OF GLUCOCORTICOID RECEPTORS (GR) IN THE HIPPOCAMPUS TRIGGERING A FEED-FORWARD CASCADE OF DEGENERATION AND DISEASE. SECOND, THE BALANCE HYPOTHESIS, WHICH TAKES ALSO THE LIMBIC MINERALOCORTICOID RECEPTORS (MR) INTO ACCOUNT AND PROPOSES THAT AN INTEGRAL LIMBIC MR:GR IMBALANCE IS CAUSAL TO ALTERED PROCESSING OF INFORMATION IN CIRCUITS UNDERLYING FEAR, REWARD, SOCIAL BEHAVIOUR AND RESILIENCE, DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND IMPAIRMENT OF BEHAVIOURAL ADAPTATION. THE MR:GR BALANCE IS ALTERED BY GENE VARIANTS OF THESE RECEPTOR COMPLEXES AND EXPERIENCE-RELATED FACTORS, WHICH CAN INDUCE LASTING EPIGENETIC CHANGES IN THE EXPRESSION OF THESE RECEPTORS. A PARTICULAR POTENT EPIGENETIC STIMULUS IS THE MATERNAL ENVIRONMENT WHICH IS FUNDAMENTAL FOR THE MATERNAL MEDIATION HYPOTHESIS. THE OUTCOME OF PERINATAL GENE X ENVIRONMENT INTERACTION, AND THUS OF MR:GR-MEDIATED FUNCTIONS DEPENDS HOWEVER, ON THE DEGREE OF 'MATCHING' WITH ENVIRONMENTAL DEMANDS IN LATER LIFE. THE PREDICTIVE ADAPTATION HYPOTHESIS THEREFORE PRESENTS A CONCEPTUAL FRAMEWORK TO EXAMINE THE ROLE OF GLUCOCORTICOIDS IN UNDERSTANDING INDIVIDUAL PHENOTYPIC DIFFERENCES IN STRESS-RELATED BEHAVIOURS OVER THE LIFESPAN.	2010	
                                                   
10 1363  36 DEVELOPMENTAL INFLUENCES ON MEDICALLY UNEXPLAINED SYMPTOMS. BACKGROUND: MEDICALLY UNEXPLAINED (OR 'FUNCTIONAL') SYMPTOMS (MUS) ARE PHYSICAL SYMPTOMS THAT PROMPT THE SUFFERER TO SEEK HEALTHCARE BUT REMAIN UNEXPLAINED AFTER AN APPROPRIATE MEDICAL EVALUATION. EXAMPLES OF MUS ALSO OCCUR IN VETERINARY MEDICINE. FOR EXAMPLE, DOMESTIC CATS SUFFER A SYNDROME COMPARABLE TO INTERSTITIAL CYSTITIS, A CHRONIC PELVIC PAIN SYNDROME OF HUMANS. METHOD: REVIEW OF CURRENT EVIDENCE SUGGESTS THE HYPOTHESIS THAT DEVELOPMENTAL FACTORS MAY PLAY A ROLE IN SOME CASES OF MUS. MATERNAL PERCEPTION OF A THREATENING ENVIRONMENT MAY BE TRANSMITTED TO THE FETUS WHEN HORMONES CROSS THE PLACENTA AND AFFECT FETAL PHYSIOLOGY, EFFECTIVELY 'PROGRAMMING' THE FETAL STRESS RESPONSE SYSTEM AND ASSOCIATED BEHAVIORS TOWARD ENHANCED VIGILANCE. AFTER BIRTH, INTENSE STRESS RESPONSES IN THE INDIVIDUAL MAY RESULT IN SIMILAR VULNERABILITY, WHICH MAY BE UNMASKED BY SUBSEQUENT STRESSORS. RESULTS: EPIGENETIC MODULATION OF GENE EXPRESSION (EMGEX) APPEARS TO PLAY A CENTRAL ROLE IN CREATION OF THIS 'SURVIVAL PHENOTYPE'. THE RECENT DEVELOPMENT OF TECHNIQUES TO IDENTIFY THE PRESENCE OF EMGEX PROVIDES NEW TOOLS TO INVESTIGATE THESE QUESTIONS, AND DRUGS AND OTHER INTERVENTIONS THAT MAY REVERSE EMGEX ARE ALSO UNDER ACTIVE INVESTIGATION. CONCLUSION: VIEWING MUS FROM THE PERSPECTIVE OF UNDERLYING DEVELOPMENTAL INFLUENCES INVOLVING EMGEX THAT AFFECT FUNCTION OF A VARIETY OF ORGANS BASED ON FAMILIAL (GENETIC AND ENVIRONMENTAL) PREDISPOSITIONS RATHER THAN FROM THE TRADITIONAL VIEWPOINT OF ISOLATED ORGAN-ORIGINATING DISEASES HAS AT LEAST TWO IMPORTANT IMPLICATIONS: IT PROVIDES A PARSIMONIOUS EXPLANATION FOR FINDINGS HERETOFORE DIFFICULT TO RECONCILE, AND IT OPENS WHOLE NEW AREAS OF INVESTIGATION INTO CAUSES AND TREATMENTS FOR THIS CLASS OF DISORDERS.	2009	
                                                                                                                                                                                                                                                                                                                   
11 2949  35 GENETIC AND EPIGENETIC CONSEQUENCE OF EARLY-LIFE SOCIAL STRESS ON DEPRESSION: ROLE OF SEROTONIN-ASSOCIATED GENES. EARLY-LIFE ADVERSITY CAUSED BY POOR SOCIAL BONDING AND DEPRIVED MATERNAL CARE IS KNOWN TO AFFECT MENTAL WELLBEING AND PHYSICAL HEALTH. IT IS A FORM OF CHRONIC SOCIAL STRESS THAT PERSISTS BECAUSE OF A NEGATIVE ENVIRONMENT, AND THE CONSEQUENCES ARE LONG-LASTING ON MENTAL HEALTH. THE PRESENCE OF SOCIAL STRESS DURING EARLY LIFE CAN HAVE AN EPIGENETIC EFFECT ON THE BODY, POSSIBLY RESULTING IN MANY COMPLEX MENTAL DISORDERS, INCLUDING DEPRESSION IN LATER LIFE. HERE, WE REVIEW THE EVIDENCE FOR EARLY-LIFE SOCIAL STRESS-INDUCED EPIGENETIC CHANGES THAT MODULATE JUVENILE AND ADULT SOCIAL BEHAVIOR (DEPRESSION AND ANXIETY). THIS REVIEW HAS A PARTICULAR EMPHASIS ON THE INTERACTION BETWEEN EARLY-LIFE SOCIAL STRESS AND GENETIC VARIATION OF SEROTONIN ASSOCIATE GENES INCLUDING THE SEROTONIN TRANSPORTER GENE (5-HTT; ALSO KNOWN AS SLC6A4), WHICH ARE KEY MOLECULES INVOLVED IN DEPRESSION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  989  26 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 4578  34 N(6) -METHYLADENOSINE MODIFICATION IN CHRONIC STRESS RESPONSE DUE TO SOCIAL HIERARCHY POSITIONING OF MICE. APPROPRIATELY RESPONDING TO STRESSFUL EVENTS IS ESSENTIAL FOR MAINTAINING HEALTH AND WELL-BEING OF ANY ORGANISM. CONCERNING SOCIAL STRESS, THE RESPONSE IS NOT ALWAYS AS STRAIGHTFORWARD AS REACTING TO PHYSICAL STRESSORS, E.G., EXTREME HEAT, AND THUS HAS TO BE BALANCED SUBTLY. PARTICULARLY, REGULATORY MECHANISMS CONTRIBUTING TO GAINING RESILIENCE IN THE FACE OF MILD SOCIAL STRESS ARE NOT FULLY DECIPHERED YET. WE EMPLOYED AN INTRINSIC SOCIAL HIERARCHY STRESS PARADIGM IN MICE OF BOTH SEXES TO IDENTIFY CRITICAL FACTORS FOR POTENTIAL COPING STRATEGIES. WHILE GLOBAL TRANSCRIPTOMIC CHANGES COULD NOT BE OBSERVED IN MALE MICE, SEVERAL GENES PREVIOUSLY REPORTED TO BE INVOLVED IN SYNAPTIC PLASTICITY, LEARNING, AND ANXIETY-LIKE BEHAVIOR WERE DIFFERENTIALLY REGULATED IN FEMALE MICE. MOREOVER, CHANGES IN N(6)-METHYLADENOSINE (M(6)A)-MODIFICATION OF MRNA OCCURRED ASSOCIATED WITH CORTICOSTERONE LEVEL IN BOTH SEXES WITH, E.G., INCREASED GLOBAL AMOUNT IN SUBMISSIVE FEMALE MICE. IN ACCORDANCE WITH THIS, METTL14 AND WTAP, SUBUNITS OF THE METHYLTRANSFERASE COMPLEX, SHOWED ELEVATED LEVELS IN SUBMISSIVE FEMALE MICE. N(6)-ADENOSYL-METHYLATION IS THE MOST PROMINENT TYPE OF MRNA METHYLATION AND PLAYS A CRUCIAL ROLE IN PROCESSES SUCH AS METABOLISM, BUT ALSO RESPONSE TO PHYSICAL STRESS. OUR FINDINGS UNDERPIN ITS ESSENTIAL ROLE BY ALSO PROVIDING A LINK TO SOCIAL STRESS EVOKED BY HIERARCHY BUILDING WITHIN SAME-SEX GROUPS. AS RECENTLY, SEARCH FOR SMALL MOLECULE MODIFIERS FOR THE RESPECTIVE CLASS OF RNA MODIFYING ENZYMES HAS STARTED, THIS MIGHT EVEN LEAD TO NEW THERAPEUTIC APPROACHES AGAINST STRESS DISORDERS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                           
14 5465  36 RESILIENCE TO STRESS: LESSONS FROM RODENTS ABOUT NATURE VERSUS NURTURE. INDIVIDUAL DIFFERENCES IN HUMAN TEMPERAMENT INFLUENCE HOW WE RESPOND TO STRESS AND CAN CONFER VULNERABILITY (OR RESILIENCE) TO EMOTIONAL DISORDERS. FOR EXAMPLE, HIGH LEVELS OF BEHAVIORAL INHIBITION IN CHILDREN PREDICT INCREASED RISK OF MOOD AND ANXIETY DISORDERS IN LATER LIFE. THE BIOLOGICAL UNDERPINNINGS OF TEMPERAMENT ARE UNKNOWN, ALTHOUGH IMPROVED UNDERSTANDING CAN OFFER INSIGHT INTO THE PATHOGENESIS OF EMOTIONAL DISORDERS. OUR LABORATORY HAS USED A RAT MODEL OF TEMPERAMENTAL DIFFERENCES TO STUDY NEURODEVELOPMENTAL FACTORS THAT LEAD TO A HIGHLY INHIBITED, STRESS VULNERABLE PHENOTYPE. SELECTIVE BREEDING FOR HIGH VERSUS LOW BEHAVIORAL RESPONSE TO NOVELTY CREATED TWO RAT STRAINS THAT EXHIBIT DRAMATIC BEHAVIOR DIFFERENCES OVER MULTIPLE DOMAINS RELEVANT TO EMOTIONAL DISORDERS. LOW NOVELTY RESPONDER (BLR) RATS EXHIBIT HIGH LEVELS OF BEHAVIORAL INHIBITION, PASSIVE STRESS COPING, ANHEDONIA, DECREASED SOCIABILITY AND VULNERABILITY TO CHRONIC STRESS COMPARED TO HIGH NOVELTY RESPONDERS (BHRS). ON THE OTHER HAND, BHRS EXHIBIT HIGH LEVELS OF BEHAVIORAL DIS-INHIBITION, ACTIVE COPING, AND AGGRESSION. THIS REVIEW ARTICLE SUMMARIZES OUR WORK WITH THE BHR/BLR MODEL SHOWING THE DEVELOPMENTAL EMERGENCE OF THE BHR/BLR PHENOTYPES, THE ROLE THE ENVIRONMENT PLAYS IN SHAPING IT, AND THE INVOLVEMENT OF EPIGENETIC PROCESSES SUCH AS DNA METHYLATION THAT MEDIATE DIFFERENCES IN EMOTIONALITY AND STRESS REACTIVITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15 1159  35 CONTEXTUAL MODIFIERS OF HEALTHSPAN, LIFESPAN, AND EPIGENOME IN MICE UNDER CHRONIC SOCIAL STRESS. SUSTAINED LIFE STRESS AND LOW SOCIOECONOMIC STATUS ARE AMONG THE MAJOR CAUSES OF AGING-RELATED DISEASES AND DECREASED LIFE EXPECTANCY. EXPERIMENTAL RODENT MODELS CAN HELP TO IDENTIFY THE UNDERLYING MECHANISMS, YET VERY FEW STUDIES ADDRESS THE LONG-TERM CONSEQUENCES OF SOCIAL STRESS ON AGING. WE CONDUCTED A RANDOMIZED STUDY INVOLVING MORE THAN 300 MALE MICE OF COMMONLY USED LABORATORY STRAINS (C57BL/6J, CD1, AND SV129EV) CHOSEN FOR THE SPONTANEOUS AGGRESSION GRADIENT AND STRESS-VULNERABILITY. MICE WERE EXPOSED TO A LIFELONG CHRONIC PSYCHOSOCIAL STRESS PROTOCOL TO MODEL SOCIAL GRADIENTS IN AGING AND DISEASE VULNERABILITY. LOW SOCIAL RANK, INFERRED BASED ON A DISCRETIZED AGGRESSION INDEX, WAS FOUND TO NEGATIVELY IMPACT LIFESPAN IN OUR STUDY POPULATION. HOWEVER, SOCIAL RANK INTERACTED WITH GENETIC BACKGROUND IN THAT LOW-RANKING C57BL/6J, HIGH-RANKING SV129EV, AND MIDDLE-RANKING CD1 MICE HAD LOWER SURVIVAL, RESPECTIVELY, IMPLYING A COST OF MAINTAINING A GIVEN SOCIAL RANK THAT VARIES ACROSS STRAINS. MACHINE LEARNING LINEAR DISCRIMINANT ANALYSIS IDENTIFIED BASELINE FAT-FREE MASS AS THE MOST IMPORTANT PREDICTOR OF MOUSE GENETIC BACKGROUND AND SOCIAL RANK IN THE PRESENT DATASET. FINALLY, STRAIN AND SOCIAL RANK DIFFERENCES WERE SIGNIFICANTLY ASSOCIATED WITH EPIGENETIC CHANGES, MOST SIGNIFICANTLY IN SV129EV MICE AND IN HIGH-RANKING COMPARED TO LOWER RANKING SUBJECTS. OVERALL, WE IDENTIFIED GENETIC BACKGROUND AND SOCIAL RANK AS CRITICAL CONTEXTUAL MODIFIERS OF AGING AND LIFESPAN IN AN ETHOLOGICALLY RELEVANT RODENT MODEL OF SOCIAL STRESS, THEREBY PROVIDING A PRECLINICAL EXPERIMENTAL PARADIGM TO STUDY THE IMPACT OF SOCIAL DETERMINANTS OF HEALTH DISPARITIES AND ACCELERATED AGING.	2023	
                                                                                                                                                                                                                                                                                                                                           
16 3714  39 INHERITANCE OF SOCIAL DOMINANCE IS ASSOCIATED WITH GLOBAL SPERM DNA METHYLATION IN INBRED MALE MICE. DOMINANCE RELATIONSHIPS BETWEEN MALES AND THEIR ASSOCIATED TRAITS ARE USUALLY HERITABLE AND HAVE IMPLICATIONS FOR SEXUAL SELECTION IN ANIMALS. IN PARTICULAR, SOCIAL DOMINANCE AND ITS RELATED MALE PHEROMONES ARE HERITABLE IN INBRED MICE; THUS, WE WONDERED WHETHER EPIGENETIC CHANGES DUE TO ALTERED LEVELS OF DNA METHYLATION DETERMINE INHERITANCE. HERE, WE USED C57BL/6 MALE MICE TO ESTABLISH A SOCIAL DOMINANCE-SUBORDINATION RELATIONSHIP THROUGH CHRONIC DYADIC ENCOUNTERS, AND THIS RELATIONSHIP AND PHEROMONE COVARIATION OCCURRED IN THEIR OFFSPRING, INDICATIVE OF HERITABILITY. THROUGH TRANSCRIPTOME SEQUENCING AND WHOLE-GENOME DNA METHYLATION PROFILING OF THE SPERM OF BOTH GENERATIONS, WE FOUND THAT DIFFERENTIAL METHYLATION OF MANY GENES WAS INDUCED BY SOCIAL DOMINANCE-SUBORDINATION IN SIRES AND COULD BE PASSED ON TO THE OFFSPRING. THESE METHYLATED GENES WERE MAINLY RELATED TO GROWTH AND DEVELOPMENT PROCESSES, NEURODEVELOPMENT, AND CELLULAR TRANSPORTATION. THE EXPRESSION OF THE GENES WITH SIMILAR FUNCTIONS IN WHOLE-GENOME METHYLATION/BISULFITE SEQUENCING WAS ALSO DIFFERENTIATED BY SOCIAL DOMINANCE-SUBORDINATION, AS REVEALED BY RNA-SEQ. IN PARTICULAR, THE GENE DENND1A, WHICH REGULATES NEURAL SIGNALING, WAS DIFFERENTIALLY METHYLATED AND EXPRESSED IN THE SPERM AND MEDIAL PREFRONTAL CORTEX IN PAIRED MALES BEFORE AND AFTER DOMINANCE-SUBORDINATION ESTABLISHMENT, SUGGESTING THE POTENTIAL EPIGENETIC CONTROL AND INHERITANCE OF SOCIAL DOMINANCE-RELATED AGGRESSION. WE SUGGEST THAT SOCIAL DOMINANCE MIGHT BE PASSED ON TO MALE OFFSPRING THROUGH SPERM DNA METHYLATION AND THAT THE DIFFERENCES COULD POTENTIALLY AFFECT MALE COMPETITION IN OFFSPRING BY AFFECTING THE DEVELOPMENT OF THE NERVOUS SYSTEM.	2023	
                                                                                                                                                                                                                                                                                                                              
17 4701  27 NICOTINE AND THE ADOLESCENT BRAIN. ADOLESCENCE ENCOMPASSES A SENSITIVE DEVELOPMENTAL PERIOD OF ENHANCED CLINICAL VULNERABILITY TO NICOTINE, TOBACCO, AND E-CIGARETTES. WHILE THERE ARE SOCIOCULTURAL INFLUENCES, DATA AT PRECLINICAL AND CLINICAL LEVELS INDICATE THAT THIS ADOLESCENT SENSITIVITY HAS STRONG NEUROBIOLOGICAL UNDERPINNINGS. ALTHOUGH DEFINITIONS OF ADOLESCENCE VARY, THE HALLMARK OF THIS PERIOD IS A PROFOUND REORGANIZATION OF BRAIN REGIONS NECESSARY FOR MATURE COGNITIVE AND EXECUTIVE FUNCTION, WORKING MEMORY, REWARD PROCESSING, EMOTIONAL REGULATION, AND MOTIVATED BEHAVIOR. REGULATING CRITICAL FACETS OF BRAIN MATURATION ARE NICOTINIC ACETYLCHOLINE RECEPTORS (NACHRS). HOWEVER, PERTURBATIONS OF CHOLINERGIC SYSTEMS DURING THIS TIME WITH NICOTINE, VIA TOBACCO OR E-CIGARETTES, HAVE UNIQUE CONSEQUENCES ON ADOLESCENT DEVELOPMENT. IN THIS REVIEW, WE HIGHLIGHT RECENT CLINICAL AND PRECLINICAL DATA EXAMINING THE ADOLESCENT BRAIN'S DISTINCT NEUROBIOLOGY AND UNIQUE SENSITIVITY TO NICOTINE. FIRST, WE DISCUSS WHAT DEFINES ADOLESCENCE BEFORE REVIEWING NORMATIVE STRUCTURAL AND NEUROCHEMICAL ALTERATIONS THAT PERSIST UNTIL EARLY ADULTHOOD, WITH AN EMPHASIS ON DOPAMINERGIC SYSTEMS. WE REVIEW HOW ACUTE EXPOSURE TO NICOTINE IMPACTS BRAIN DEVELOPMENT AND HOW DRUG RESPONSES DIFFER FROM THOSE SEEN IN ADULTS. FINALLY, WE DISCUSS THE PERSISTENT ALTERATIONS IN NEURONAL SIGNALING AND COGNITIVE FUNCTION THAT RESULT FROM CHRONIC NICOTINE EXPOSURE, WHILE HIGHLIGHTING A LOW DOSE, SEMI-CHRONIC EXPOSURE PARADIGM THAT MAY BETTER MODEL ADOLESCENT TOBACCO USE. WE ARGUE THAT NICOTINE EXPOSURE, INCREASINGLY OCCURRING AS A RESULT OF E-CIGARETTE USE, MAY INDUCE EPIGENETIC CHANGES THAT SENSITIZE THE BRAIN TO OTHER DRUGS AND PRIME IT FOR FUTURE SUBSTANCE ABUSE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                  
18 1749  25 EARLY LIFE INTERVENTIONS CAN SHAPE AGING. IT IS WELL DOCUMENTED THAT THE ENVIRONMENT OF THE DEVELOPING FETUS, INCLUDING AVAILABILITY OF NUTRIENTS AND PRESENCE OF TOXINS, CAN HAVE MAJOR IMPACT ON ADULT PHENOTYPE, AGE-RELATED TRAITS AND RISK OF CHRONIC DISEASE. THERE IS ALSO ACCUMULATING EVIDENCE THAT POSTNATAL ENVIRONMENT CAN IMPACT ADULT CHARACTERISTICS RELATED TO EVOLUTIONARY FITNESS, HEALTH, AND AGING. TO DETERMINE WHETHER EARLY LIFE HORMONAL INTERVENTIONS CAN ALTER TRAJECTORY OF AGING, WE HAVE EXAMINED THE EFFECTS OF EARLY LIFE GROWTH HORMONE (GH) REPLACEMENT THERAPY IN PROP1(DF) (AMES DWARF) MICE WHICH ARE GH DEFICIENT AND REMARKABLY LONG LIVED. TWICE-DAILY GH INJECTIONS BETWEEN THE AGES OF TWO AND EIGHT WEEKS COMPLETELY NORMALIZED ("RESCUED") A NUMBER OF ADULT METABOLIC CHARACTERISTICS BELIEVED TO CONTRIBUTE TO EXTENDED LONGEVITY OF THESE MUTANTS. IMPORTANTLY, LONGEVITY OF AMES DWARF MICE WAS REDUCED BY EARLY LIFE GH TREATMENT. THIS WAS ASSOCIATED WITH HISTONE H3 MODIFICATIONS. WE CONCLUDE THAT THE TRAJECTORY OF MAMMALIAN AGING CAN BE MODIFIED BY EARLY LIFE INTERVENTIONS. MECHANISTIC LINKS AMONG INTERVENTIONS DURING POSTNATAL DEVELOPMENT, ADULT METABOLIC CHARACTERISTICS, AGING, AND LONGEVITY, APPARENTLY INVOLVE EPIGENETIC PHENOMENA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 5810  26 STRESS & SLEEP: A RELATIONSHIP LASTING A LIFETIME. STRESS IS AN ADAPTATIVE RESPONSE AIMED AT RESTORING BODY HOMEOSTASIS. THE CLASSICAL NEUROENDOCRINE STRESS RESPONSE INVOLVING THE ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS MODULATES MANY PHYSIOLOGICAL ASPECTS, SUCH AS THE WAKE-SLEEP CYCLE. IN THE PRESENT REVIEW, WE WILL FIRST REPORT A SERIES OF HUMAN AND RODENT STUDIES SHOWING THAT EACH ACTOR OF THE HPA AXIS HAS THE POTENTIAL TO INTERFERE WITH SLEEP HOMEOSTASIS AND, THEN, WE WILL HIGHLIGHT HOW ACUTE OR CHRONIC STRESS DIFFERENTLY MODULATES THE WAKE-SLEEP CYCLE. MOREOVER, WE WILL PRESENT NEW AND INTERESTING STUDIES DEALING WITH THE RELATIONSHIP BETWEEN SLEEP AND STRESS ON A DIFFERENT (LONGER) TIME SCALE. PARTICULARLY, WE WILL DISCUSS HOW THE EXPOSURE TO PERINATAL STRESS, PROBABLY THROUGH EPIGENETIC MODULATIONS, IS SUFFICIENT TO CAUSE PERSISTENT SLEEP DERANGEMENTS DURING ADULT LIFE. IN LIGHT OF THIS EVIDENCE, THE MAIN MESSAGE OF THE PRESENT REVIEW IS THAT THE COMPLEX RELATIONSHIP BETWEEN SLEEP AND STRESS CHANGES DRAMATICALLY ON THE BASIS OF THE TIME SCALE CONSIDERED AND, CONSEQUENTLY, "TIME" SHOULD BE CONSIDERED AS A CRITICAL FACTOR WHEN FACING THIS TOPIC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  677  23 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