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Sex differences in fetal programming by glucocorticoids: Adult hypothalamus and Autonomic Nervous System

糖皮质激素对胎儿编程的性别差异：成人下丘脑和自主神经系统

基本信息

批准号：
10349465
负责人：
Robert J Handa
金额：
$ 45.27万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349465
关键词：
Address Adult Adult Children Agonist Angiotensin II Animals Anxiety Area Autonomic nervous system Behavior Behavioral Brain Brain Stem Brain region CRH gene Cell Nucleus Cells Coupled Data Development Dexamethasone Disease Endocrine Environment Equilibrium Exposure to Female Fetus Functional disorder Gene Expression Genetic Models Glucocorticoids Goals Heart Rate Hormonal Hormone Responsive Hormone secretion Hormones Hypothalamic structure Immune In Situ Hybridization Inflammation Insulin-Like-Growth Factor I Receptor Lateral Major Depressive Disorder Malnutrition Measures Mediator of activation protein Messenger RNA Mus Nerve Nervous System Physiology Nervous System control Neural Pathways Neurons Neuropeptides Neurophysiology - biologic function Neurosecretory Systems Neurotransmitters Oxytocin Receptor Pathway interactions Physiological Physiology Population Pregnancy Rattus Recombinant adeno-associated virus (rAAV)Renin-Angiotensin System Reporter Genes Role Sex Bias Sex Differences Signal Transduction Stress TNF gene Technology Testing Therapeutic Tissues Transgenic Mice Viral Vector Virion antagonist brain circuitry cell type depressive symptoms designer receptors exclusively activated by designer drugs environmental change fetal fetal programming genetic approach heart rate variability in utero male mind control mouse genetics mouse model nano-string neonate neurodevelopment offspring pregnant prenatal prenatal exposure prenatal stress pressure programs receptor response restraint sex stress reactivity

项目摘要

PROJECT SUMMARY / ABSTRACT The overarching goal, and ultimate impact, of this project is to identify the cellular and physiological pathways whereby developmental overexposure to glucocorticoids cause long-term, sex-selective programming of adult anxiety- and depressive-like behaviors, neuroendocrine function and autonomic nervous system responses to stress. Developmental programming, the permanent adaptation of the fetus to maternal environmental signals can elevate fetal glucocorticoids to program neurodevelopment. Preliminary data in mice and rats show sex- biased changes following late-gestation exposure to the synthetic glucocorticoid, dexamethasone. These include increased anxiety- and depressive-like behaviors, and hyperreactive neuroendocrine and autonomic nervous system responses to stress and changes in gene expression in the hypothalamus. In all cases, adult females showing a greater change than males. We hypothesize that these adult dysfunctions have a common mechanism related to programmed changes in the hypothalamic paraventricular n. (PVN), a brain region that has been shown to influence all of these physiological endpoints. Our studies show similar responses in both rats and mice allowing these studies to exploit the well-described physiology of the rat as well as the power of mouse genetic approaches. 3 specific aims are described. Aim 1 will determine the causal factors for long- term alterations in anxiety-and depressive-like behaviors, neuroendocrine response to stress and an imbalance of the autonomic nervous system. Moreover, this aim will examine the central renin-angiotensin system as a central mediator of the observed changes in brain function following prenatal glucocorticoid overexposure. Aim 2 will determine the impact of prenatal glucocorticoid exposure on connectivity between hypothalamic preautonomic and brainstem autonomic nuclei and use mouse genetic approaches and viral vectors to specifically activate neuron populations in the PVN. Aim 3 will use transcutaneous vagal nerve stimulation to modulate autonomic nervous system balance and reverse the effects of prenatal glucocorticoid exposure on adult behaviors, neuroendocrine, and autonomic responses to stress. The results of these studies will identify, not only the brain circuitry underlying the sex-biased developmental programming of behavioral, endocrine and autonomic responses in adulthood, but also reveal potential therapeutic mechanisms whereby these changes can be reversed in adulthood.

项目摘要/摘要