1 3463 137 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 2 3774 37 INTERACTION OF GONADAL HORMONES, DOPAMINERGIC SYSTEM, AND EPIGENETIC REGULATION IN THE GENERATION OF SEX DIFFERENCES IN SUBSTANCE USE DISORDERS: A SYSTEMATIC REVIEW. SUBSTANCE USE DISORDER (SUD) IS A CHRONIC CONDITION CHARACTERIZED BY PATHOLOGICAL DRUG-TAKING AND SEEKING BEHAVIORS. REMARKABLY DIFFERENT BETWEEN MALES AND FEMALES, SUGGESTING THAT DRUG ADDICTION IS A SEXUALLY DIFFERENTIATED DISORDER. THE NEUROBIOLOGICAL BASES OF SEX DIFFERENCES IN SUD INCLUDE SEX-SPECIFIC REWARD SYSTEM ACTIVATION, INFLUENCED BY INTERACTIONS BETWEEN GONADAL HORMONE LEVEL CHANGES, DOPAMINERGIC REWARD CIRCUITS, AND EPIGENETIC MODIFICATIONS OF KEY REWARD SYSTEM GENES. THIS SYSTEMATIC REVIEW, ADHERING TO PICOS AND PRISMA-P 2015 GUIDELINES, HIGHLIGHTS THE SEX-DEPENDENT ROLES OF ESTROGENS, PROGESTERONE, AND TESTOSTERONE IN SUD. IN PARTICULAR, ESTRADIOL ELEVATES AND PROGESTERONE REDUCES DOPAMINERGIC ACTIVITY IN SUD FEMALES, WHILST TESTOSTERONE AND PROGESTERONE AUGMENT SUD BEHAVIOR IN MALES. FINALLY, SUD IS ASSOCIATED WITH A SEX-SPECIFIC INCREASE IN THE RATE OF OPIOID AND MONOAMINERGIC GENE METHYLATION. THE STUDY REVEALS THE NEED FOR DETAILED RESEARCH ON GONADAL HORMONE LEVELS, DOPAMINERGIC OR REWARD SYSTEM ACTIVITY, AND EPIGENETIC LANDSCAPES IN BOTH SEXES FOR EFFICIENT SUD THERAPY DEVELOPMENT. 2023 3 5644 23 SEX AND THE MIGRAINE BRAIN. THE BRAIN RESPONDS DIFFERENTLY TO ENVIRONMENTAL AND INTERNAL SIGNALS THAT RELATE TO THE STAGE OF DEVELOPMENT OF NEURAL SYSTEMS. WHILE GENETIC AND EPIGENETIC FACTORS CONTRIBUTE TO A PREMORBID STATE, HORMONAL FLUCTUATIONS IN WOMEN MAY ALTER THE SET POINT OF MIGRAINE. THE CYCLIC SURGES OF GONADAL HORMONES MAY DIRECTLY ALTER NEURONAL, GLIAL AND ASTROCYTE FUNCTION THROUGHOUT THE BRAIN. ESTROGEN IS MAINLY EXCITATORY AND PROGESTERONE INHIBITORY ON BRAIN NEURONAL SYSTEMS. THESE CHANGES CONTRIBUTE TO THE ALLOSTATIC LOAD OF THE MIGRAINE CONDITION THAT MOST NOTABLY STARTS AT PUBERTY IN GIRLS. 2014 4 5970 22 TESTOSTERONE ACTS WITHIN THE MEDIAL AMYGDALA OF RATS TO REDUCE INNATE FEAR TO PREDATOR ODOR AKIN TO THE EFFECTS OF TOXOPLASMA GONDII INFECTION. RATS INFECTED WITH THE PROTOZOAN TOXOPLASMA GONDII EXHIBIT A REDUCED AVERSION TO CAT ODOR. THIS BEHAVIORAL CHANGE IS THOUGHT TO INCREASE TROPHIC TRANSMISSION OF THE PARASITE. INFECTED MALE RATS ALSO SHOW A GREATER TESTICULAR SYNTHESIS OF TESTOSTERONE AND EPIGENETIC CHANGE IN ARGININE VASOPRESSIN WITHIN THE MEDIAL AMYGDALA. HERE, WE SHOW THAT EXOGENOUS SUPPLY OF TESTOSTERONE WITHIN MEA OF UNINFECTED CASTRATES RECAPITULATES REDUCTION IN INNATE FEAR AKIN TO BEHAVIORAL CHANGE ATTRIBUTED TO THE PARASITE. WE ALSO SHOW THAT CASTRATION POST ESTABLISHMENT OF CHRONIC INFECTION PRECLUDES CHANGES IN FEAR AND MEDIAL AMYGDALA ARGININE VASOPRESSIN IN THE INFECTED MALE RATS. THESE OBSERVATIONS SUPPORT THE ROLE OF GONADAL HORMONES AND PURSUANT NEUROENDOCRINE CHANGES IN MEDIATING THE LOSS OF FEAR IN THE INFECTED RATS. THIS WORK ALSO DEMONSTRATES THAT TESTOSTERONE ACTING SPECIFICALLY WITHIN THE MEDIAL AMYGDALA SUFFICIENTLY EXPLAINS REDUCED DEFENSIVE BEHAVIORS OFTEN OBSERVED DURING THE APPETITIVE COMPONENT OF REPRODUCTIVE BEHAVIORS. 2020 5 1774 35 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY. 2018 6 3001 38 GENETIC, EPIGENETIC AND ENVIRONMENTAL IMPACT ON SEX DIFFERENCES IN SOCIAL BEHAVIOR. THE FIELD OF BEHAVIORAL NEUROENDOCRINOLOGY HAS GENERATED THOUSANDS OF STUDIES THAT INDICATE DIFFERENCES IN BRAIN STRUCTURE AND REACTIVITY TO GONADAL STEROIDS THAT PRODUCE SEX-SPECIFIC PATTERNS OF SOCIAL BEHAVIOR. HOWEVER, RAPIDLY EMERGING EVIDENCE SHOWS THAT GENETIC POLYMORPHISMS AND RESULTING DIFFERENCES IN THE EXPRESSION OF NEUROACTIVE PEPTIDES AND RECEPTORS AS WELL AS EARLY-LIFE EXPERIENCE AND EPIGENETIC CHANGES ARE IMPORTANT MODIFIERS OF SOCIAL BEHAVIOR. FURTHERMORE, DUE TO ITS INHERENT COMPLEXITY, THE NEUROCHEMICAL MECHANISMS UNDERLYING SEX DIFFERENCES IN SOCIAL BEHAVIOR ARE USUALLY STUDIED IN A TIGHTLY REGULATED LABORATORY SETTING RATHER THAN IN COMPLEX ENVIRONMENTS. IMPORTANTLY, SPECIFIC HORMONES MAY ELICIT A RANGE OF DIFFERENT BEHAVIORS DEPENDING ON THE CUES PRESENT IN THESE ENVIRONMENTS. FOR EXAMPLE, INDIVIDUALS EXPOSED TO A PSYCHOSOCIAL STRESSOR MAY RESPOND DIFFERENTLY TO THE EFFECTS OF A GONADAL STEROID THAN THOSE NOT EXPOSED TO CHRONIC STRESS. THE OBJECTIVE OF THIS REVIEW IS NOT TO RE-EXAMINE THE ACTIVATIONAL EFFECTS OF HORMONES ON SEX DIFFERENCES IN SOCIAL BEHAVIOR BUT RATHER TO CONSIDER HOW GENETIC AND ENVIRONMENTAL FACTORS MODIFY THE EFFECTS OF HORMONES ON BEHAVIOR. WE WILL FOCUS ON ESTROGEN AND ITS RECEPTORS BUT CONSIDERATION IS ALSO GIVEN TO THE ROLE OF ANDROGENS. FURTHERMORE, WE HAVE LIMITED OUR DISCUSSIONS TO THE IMPORTANCE OF OXYTOCIN AND VASOPRESSIN AS TARGETS OF GONADAL STEROIDS AND HOW THESE EFFECTS ARE MODIFIED BY GENETIC AND EXPERIENTIAL SITUATIONS. TAKEN TOGETHER, THE DATA CLEARLY UNDERSCORE THE NEED TO EXPAND RESEARCH INITIATIVES TO CONSIDER GENE-ENVIRONMENT INTERACTIONS FOR BETTER UNDERSTANDING OF THE NEUROBIOLOGY OF SEX DIFFERENCES IN SOCIAL BEHAVIOR. 2009 7 5662 38 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 8 3092 39 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 4067 25 MATERNAL AND PEDIATRIC HEALTH AND DISEASE: INTEGRATING BIOPSYCHOSOCIAL MODELS AND EPIGENETICS. THE CONCEPTS OF ALLOSTASIS (STABILITY THROUGH ADAPTATION) AND ACCUMULATED LIFE STRESS (MCEWEN'S ALLOSTATIC LOAD) AIM TO UNDERSTAND CHILDHOOD AND ADULT OUTCOMES. CHRONIC MALNUTRITION, CHANGES IN SOCIAL CONDITION, AND ADVERSE EARLY-LIFE EXPERIENCES MAY PROGRAM PHENOTYPES AND CONTRIBUTE TO LONG-LASTING DISEASE RISK. HOWEVER, INTEGRATION OF LIFE COURSE APPROACHES, SOCIAL AND ECONOMIC CONTEXTS, AND COMPARISON AMONG DIFFERENT BIOPSYCHOSOCIAL MODELS HAS NOT GENERALLY BEEN EXPLORED. THIS REVIEW CRITICALLY EXAMINES THE LITERATURE AND EVALUATES RECENT INSIGHTS INTO HOW ENVIRONMENTAL STRESS CAN ALTER LIFELONG HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND IMMUNE SYSTEM RESPONSIVENESS AND INDUCE METABOLIC AND NEURODEVELOPMENTAL MALADAPTATION. MODELS OF BIOPSYCHOSOCIAL STRESS OVERLAP BUT MAY CONSIDER DIFFERENT CONDITIONS. CONCEPTS INCLUDE ALLOSTASIS, WHICH INCORPORATES HORMONAL RESPONSES TO PREDICTABLE ENVIRONMENTAL CHANGES, AND GERONIMUS'S "WEATHERING," WHICH AIMS TO EXPLAIN HOW SOCIALLY STRUCTURED, REPEATED STRESS CAN ACCUMULATE AND INCREASE DISEASE VULNERABILITY. WEATHERING EMPHASIZES ROLES OF INTERNALIZED/INTERPERSONAL RACISM IN OUTCOMES DISPARITIES. FOR MEXICAN IMMIGRANTS AND MEXICAN AMERICANS, THE "ACCULTURATION" FRAMEWORK HAS PROVEN ESPECIALLY USEFUL TO EXPLORE DISPARITIES, INCLUDING PRETERM BIRTH AND NEUROPSYCHIATRIC RISKS IN CHILDHOOD. COMPLEXITIES OF STRESS ASSESSMENTS AND RECENT RESEARCH INTO EPIGENETIC MECHANISMS MEDIATING EFFECTS OF PHYSICAL, NUTRITIONAL, PSYCHOLOGICAL, AND SOCIAL STRESS ARE REVIEWED. 2016 10 2949 36 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 11 4621 44 NEUROBIOLOGICAL AND SYSTEMIC EFFECTS OF CHRONIC STRESS. 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, WHICH PROMOTE ADAPTATION ("ALLOSTASIS") BUT ALSO CONTRIBUTE TO PATHOPHYSIOLOGY ("ALLOSTATIC LOAD/OVERLOAD") WHEN OVERUSED AND DYSREGULATED. THE ADULT AS WELL AS DEVELOPING BRAIN POSSESSES A REMARKABLE ABILITY TO SHOW STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING AND SYNAPSE TURNOVER. STRESS CAN CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE 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, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE THREAT PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION REQUIRES INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES. THERE ARE IMPORTANT SEX DIFFERENCES IN HOW THE BRAIN RESPONDS TO STRESSORS. MOREOVER, ADVERSE EARLY LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCES LASTING EFFECTS ON BRAIN AND BODY VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS KEY, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT UTILIZE BRAIN-BODY INTERACTIONS. POLICIES OF GOVERNMENT AND THE PRIVATE SECTOR ARE IMPORTANT TO PROMOTE HEALTH AND INCREASE "HEALTHSPAN." 2017 12 23 36 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 13 2913 39 GENE REGULATORY MECHANISMS UNDERLYING SEX DIFFERENCES IN BRAIN DEVELOPMENT AND PSYCHIATRIC DISEASE. THE SEXUAL DIFFERENTIATION OF THE MAMMALIAN NERVOUS SYSTEM REQUIRES THE PRECISE COORDINATION OF THE TEMPORAL AND SPATIAL REGULATION OF GENE EXPRESSION IN DIVERSE CELL TYPES. SEX HORMONES ACT AT MULTIPLE DEVELOPMENTAL TIME POINTS TO SPECIFY SEX-TYPICAL DIFFERENTIATION DURING EMBRYONIC AND EARLY DEVELOPMENT AND TO COORDINATE SUBSEQUENT RESPONSES TO GONADAL HORMONES LATER IN LIFE BY ESTABLISHING SEX-TYPICAL PATTERNS OF EPIGENETIC MODIFICATIONS ACROSS THE GENOME. THUS, MUTATIONS ASSOCIATED WITH NEUROPSYCHIATRIC CONDITIONS MAY RESULT IN SEXUALLY DIMORPHIC SYMPTOMS BY ACTING ON DIFFERENT NEURAL SUBSTRATES OR CHROMATIN LANDSCAPES IN MALES AND FEMALES. FINALLY, AS STRESS HORMONE SIGNALING MAY DIRECTLY ALTER THE MOLECULAR MACHINERY THAT INTERACTS WITH SEX HORMONE RECEPTORS TO REGULATE GENE EXPRESSION, THE CONTRIBUTION OF CHRONIC STRESS TO THE PATHOGENESIS OR PRESENTATION OF MENTAL ILLNESS MAY BE ADDITIONALLY DIFFERENT BETWEEN THE SEXES. HERE, WE REVIEW THE MECHANISMS THAT CONTRIBUTE TO SEXUAL DIFFERENTIATION IN THE MAMMALIAN NERVOUS SYSTEM AND CONSIDER SOME OF THE IMPLICATIONS OF THESE PROCESSES FOR SEX DIFFERENCES IN NEUROPSYCHIATRIC CONDITIONS. 2018 14 1750 27 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD. 2020 15 5310 26 PSYCHOBIOLOGY AND MOLECULAR GENETICS OF RESILIENCE. EVERY INDIVIDUAL EXPERIENCES STRESSFUL LIFE EVENTS. IN SOME CASES ACUTE OR CHRONIC STRESS LEADS TO DEPRESSION AND OTHER PSYCHIATRIC DISORDERS, BUT MOST PEOPLE ARE RESILIENT TO SUCH EFFECTS. RECENT RESEARCH HAS BEGUN TO IDENTIFY THE ENVIRONMENTAL, GENETIC, EPIGENETIC AND NEURAL MECHANISMS THAT UNDERLIE RESILIENCE, AND HAS SHOWN THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES IN SEVERAL NEURAL CIRCUITS INVOLVING NUMEROUS NEUROTRANSMITTER AND MOLECULAR PATHWAYS. THESE CHANGES SHAPE THE FUNCTIONING OF THE NEURAL CIRCUITS THAT REGULATE REWARD, FEAR, EMOTION REACTIVITY AND SOCIAL BEHAVIOUR, WHICH TOGETHER ARE THOUGHT TO MEDIATE SUCCESSFUL COPING WITH STRESS. 2009 16 5107 42 POLYCYSTIC OVARY SYNDROME: A BRAIN DISORDER CHARACTERIZED BY EATING PROBLEMS ORIGINATING DURING PUBERTY AND ADOLESCENCE. POLYCYSTIC OVARY SYNDROME (PCOS) IS AN ENDOCRINE CONDITION ASSOCIATED WITH REPRODUCTIVE AND PSYCHIATRIC DISORDERS, AND WITH OBESITY. EATING DISORDERS, SUCH AS BULIMIA AND RECURRENT DIETING, ARE ALSO LINKED TO PCOS. THEY CAN LEAD TO THE EPIGENETIC DYSREGULATION OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS, THEREBY IMPACTING ON OVARIAN FOLLICULOGENESIS. WE POSTULATE THAT PCOS IS INDUCED BY PSYCHOLOGICAL DISTRESS AND EPISODES OF OVEREATING AND/OR DIETING DURING PUBERTY AND ADOLESCENCE, WHEN BODY DISSATISFACTION AND EMOTIONAL DISTRESS ARE OFTEN PRESENT. WE PROPOSE THAT UPREGULATED ACTIVATION OF THE CENTRAL HPG AXIS DURING THIS PERIOD CAN BE EPIGENETICALLY ALTERED BY PSYCHOLOGICAL STRESSORS AND BY BULIMIA/RECURRENT DIETING, WHICH ARE COMMON DURING ADOLESCENCE AND WHICH CAN LEAD TO PCOS. THIS HYPOTHESIS IS BASED ON EVENTS THAT OCCUR DURING A LARGELY NEGLECTED STAGE OF FEMALE REPRODUCTIVE DEVELOPMENT. TO DATE, MOST RESEARCH INTO THE ORIGINS OF PCOS HAS FOCUSED ON THE PRENATAL INDUCTION OF THIS DISORDER, PARTICULARLY IN UTERO ANDROGENIZATION AND THE ROLE OF ANTI-MULLERIAN HORMONE. ESTABLISHING CAUSALITY IN OUR PERIPUBERTAL MODEL REQUIRES PROSPECTIVE COHORT STUDIES FROM INFANCY. MECHANISTIC STUDIES SHOULD CONSIDER THE ROLE OF THE GUT MICROBIOTA IN ADDITION TO THE EPIGENETIC REGULATION OF (NEURO) HORMONES. FINALLY, CLINICIANS SHOULD CONSIDER THE IMPORTANCE OF UNDERLYING CHRONIC PSYCHOLOGICAL DISTRESS AND EATING DISORDERS IN PCOS. 2020 17 992 36 CHRONIC STRESS AND ADIPOSE TISSUE IN THE ANOREXIC STATE: ENDOCRINE AND EPIGENETIC MECHANISMS. ALTHOUGH ADIPOSE TISSUE METABOLISM IN OBESITY HAS BEEN WIDELY STUDIED, THERE IS LIMITED RESEARCH ON THE ANOREXIC STATE, WHERE THE ENDOCRINE SYSTEM IS DISRUPTED BY REDUCED ADIPOSE TISSUE MASS AND THERE ARE DEPOT-SPECIFIC CHANGES IN ADIPOCYTE TYPE AND FUNCTION. STRESS EXPOSURE AT DIFFERENT STAGES OF LIFE CAN ALTER THE BALANCE BETWEEN ENERGY INTAKE AND EXPENDITURE AND THEREBY CONTRIBUTE TO THE PATHOGENESIS OF ANOREXIA NERVOSA. THIS REVIEW INTEGRATES INFORMATION FROM HUMAN CLINICAL TRIALS TO DESCRIBE ENDOCRINE, GENETIC AND EPIGENETIC ASPECTS OF ADIPOSE TISSUE PHYSIOLOGY IN THE ANOREXIC CONDITION. CHANGES IN THE HYPOTHALAMUS-PITUITARY-THYROID, -ADRENAL, AND -GONADAL AXES AND THEIR RELATIONSHIPS TO APPETITE REGULATION AND ADIPOCYTE FUNCTION ARE DISCUSSED. BECAUSE OF THE ROLE OF STRESS IN TRIGGERING OR MAGNIFYING ANOREXIA, AND THE DYNAMIC BUT ALSO PERSISTENT NATURE OF ENVIRONMENTALLY-INDUCED EPIGENETIC MODIFICATIONS, EPIGENETICS IS LIKELY THE LINK BETWEEN STRESS AND LONG-TERM CHANGES IN THE ENDOCRINE SYSTEM THAT DISRUPT HOMOEOSTATIC FOOD INTAKE AND ADIPOSE TISSUE METABOLISM. HEREIN, WE FOCUS ON THE ADIPOCYTE AND CHANGES IN ITS FUNCTION, INCLUDING ALTERATIONS REINFORCED BY ENDOCRINE DISTURBANCE AND DYSFUNCTIONAL ADIPOKINE REGULATION. THIS INFORMATION IS CRITICAL BECAUSE OF THE POOR UNDERSTANDING OF ANOREXIC PATHOPHYSIOLOGY, DUE TO THE LACK OF SUITABLE RESEARCH MODELS, AND THE COMPLEXITY OF GENETIC AND ENVIRONMENTAL INTERACTIONS. 2020 18 6408 36 THE SEX-DEPENDENT RESPONSE TO PSYCHOSOCIAL STRESS AND ISCHAEMIC HEART DISEASE. STRESS IS AN IMPORTANT RISK FACTOR FOR MODERN CHRONIC DISEASES, WITH DISTINCT INFLUENCES IN MALES AND FEMALES. THE SEX SPECIFICITY OF THE MAMMALIAN STRESS RESPONSE CONTRIBUTES TO THE SEX-DEPENDENT DEVELOPMENT AND IMPACTS OF CORONARY ARTERY DISEASE (CAD). COMPARED TO MEN, WOMEN APPEAR TO HAVE GREATER SUSCEPTIBILITY TO CHRONIC FORMS OF PSYCHOSOCIAL STRESS, EXTENDING BEYOND AN INCREASED INCIDENCE OF MOOD DISORDERS TO INCLUDE A 2- TO 4-FOLD HIGHER RISK OF STRESS-DEPENDENT MYOCARDIAL INFARCTION IN WOMEN, AND UP TO 10-FOLD HIGHER RISK OF TAKOTSUBO SYNDROME-A STRESS-DEPENDENT CORONARY-MYOCARDIAL DISORDER MOST PREVALENT IN POST-MENOPAUSAL WOMEN. SEX DIFFERENCES ARISE AT ALL LEVELS OF THE STRESS RESPONSE: FROM INITIAL PERCEPTION OF STRESS TO BEHAVIOURAL, COGNITIVE, AND AFFECTIVE RESPONSES AND LONGER-TERM DISEASE OUTCOMES. THESE FUNDAMENTAL DIFFERENCES INVOLVE INTERACTIONS BETWEEN CHROMOSOMAL AND GONADAL DETERMINANTS, (MAL)ADAPTIVE EPIGENETIC MODULATION ACROSS THE LIFESPAN (PARTICULARLY IN EARLY LIFE), AND THE EXTRINSIC INFLUENCES OF SOCIO-CULTURAL, ECONOMIC, AND ENVIRONMENTAL FACTORS. PRE-CLINICAL INVESTIGATIONS OF BIOLOGICAL MECHANISMS SUPPORT DISTINCT EARLY LIFE PROGRAMMING AND A HEIGHTENED CORTICOLIMBIC-NORADRENALINE-NEUROINFLAMMATORY REACTIVITY IN FEMALES VS. MALES, AMONG IMPLICATED DETERMINANTS OF THE CHRONIC STRESS RESPONSE. UNRAVELLING THE INTRINSIC MOLECULAR, CELLULAR AND SYSTEMS BIOLOGICAL BASIS OF THESE DIFFERENCES, AND THEIR INTERACTIONS WITH EXTERNAL LIFESTYLE/SOCIO-CULTURAL DETERMINANTS, CAN GUIDE PREVENTATIVE AND THERAPEUTIC STRATEGIES TO BETTER TARGET CORONARY HEART DISEASE IN A TAILORED SEX-SPECIFIC MANNER. 2023 19 2808 32 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 20 1877 22 EMERGING ROLES OF EPIGENETIC MECHANISMS IN THE ENDURING EFFECTS OF EARLY-LIFE STRESS AND EXPERIENCE ON LEARNING AND MEMORY. EPIGENETIC MECHANISMS ARE INVOLVED IN PROGRAMMING GENE EXPRESSION THROUGHOUT DEVELOPMENT. IN ADDITION, THEY ARE KEY CONTRIBUTORS TO THE PROCESSES BY WHICH EARLY-LIFE EXPERIENCE FINE-TUNES THE EXPRESSION LEVELS OF KEY NEURONAL GENES, GOVERNING LEARNING AND MEMORY THROUGHOUT LIFE. HERE WE DESCRIBE THE LONG-LASTING, BI-DIRECTIONAL EFFECTS OF EARLY-LIFE EXPERIENCE ON LEARNING AND MEMORY. WE DISCUSS HOW ENRICHED POSTNATAL EXPERIENCE ENDURINGLY AUGMENTS SPATIAL LEARNING, AND HOW CHRONIC EARLY-LIFE STRESS RESULTS IN PERSISTENT AND PROGRESSIVE DEFICITS IN THE STRUCTURE AND FUNCTION OF HIPPOCAMPAL NEURONS. THE EXISTING AND EMERGING ROLES OF EPIGENETIC MECHANISMS IN THESE FUNDAMENTAL NEUROPLASTICITY PHENOMENA ARE ILLUSTRATED. 2011