In utero programming of CRF neurons by glucocorticoids

糖皮质激素对 CRF 神经元的子宫内编程

基本信息

批准号：
7390810
负责人：
DEAN MYERS
金额：
$ 24.32万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7390810
关键词：
Accounting Address Adrenal Glands Adrenalectomy Adult Age Amygdaloid structure Animals Anterior Pituitary Gland Anxiety Automobile Driving Barker Hypothesis Behavior Behavioral Betamethasone Blood - brain barrier anatomy Cardiovascular Diseases Cell Nucleus Clinical Corticosterone Corticotropin Corticotropin Receptors Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Daily Development Disease Dyslipidemias Epidemiology Epigenetic Process Estrous Cycle Event Exhibits Exposure to Female Fetus Fright Functional disorder Future Gene Expression Glucocorticoid Receptor Glucocorticoids Glucose Intolerance High Risk Woman Hippocampus (Brain)Hyperactive behavior Hyperglycemia Hypertension Individual Insulin Resistance Intervention Laboratories Medial Mediator of activation protein Messenger RNA Metabolic Diseases Metabolic Syndrome X Mineralocorticoid Receptor Molecular Neurons Neuropeptides Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Numbers Pathology Patient currently pregnant Peptides Perinatal Exposure Phenotype Physiological Pituitary Gland Pituitary-Adrenal System Predisposition Pregnancy Pregnant Women Premature Birth Premature Infant Premature Labor Principal Investigator Production RU-486 Rattus Risk Role Site Staging Standards of Weights and Measures Stress Structure Structure of terminal stria nuclei of preoptic region Syndrome Time Variant antalarmin clinically relevant day embryo/fetus experience exposed human population fetal programming in utero indexing male maternal stress paraventricular nucleus parvocellular programs response theories tool

项目摘要

DESCRIPTION (provided by applicant): Mounting evidence supports the theory that inopportune and/or excessive exposure of a developing fetus to glucocorticoids (GCs) during critical windows of gestation results in the acquisition of behavioral, neuroendocrine and physiological disorders as adults. This phenomenon has been referred to as "fetal programming". Synthetic GCs are routinely administered to pregnancy women at high risk for preterm labor and delivery. Disorders in the offspring arising from synthetic GCs include disturbances of the hypothalamo-pituitary-adrenal (HPA) axis, altered fear/anxiety, metabolic disorders and hypertension. Since excessive GC production in adults promotes hypertension, hyperglycemia/insulin resistance and dyslipidemia, developmental programming of increased HPA function and related behaviors is potentially integral in the establishment of these disorders. In offspring exposed to synthetic GCs in utero, expression of corticotropin releasing factor (CRF) is increased in both the central nucleus of the amygdala (CeA) and the hypothalamic paraventricular nucleus (PVN) at adulthood. CRF is the primary neuropeptide regulating anterior pituitary ACTH secretion, and a major modulator of fear/anxiety. We propose that programming CRF neuron development and expression in the PVN and CeA is central in the GC-programmed excessive HPA activity and high anxiety phenotype. AIM 1 will determine if maternal delivery of synthetic GCs increases both CRF expression and the number of CRF neurons in the PVN and CeA and determine the timing of the onset of increased expression as well as the developmental window of susceptibility. AIM 2 will determine if AVP expression in the mpPVN is programmed via maternal administration of synthetic glucocorticoids. AIM 3 direclty examines the role of CRF in programming fear/anxiety and the increased function of the HPA axis in response to in utero exposure to maternally administered synthetic glucocorticoids. Aim 3 will also assess the role of the BNST vs. amgydala as the site of CRF action in the programming of fear/anxiety. AIM 4 will determine if GC stimulation of the amygdala is essential for maintaining increased CRF expression in the CeA and PVN, increased anxiety/fear and increased HPA function in the offspring of pregnant rats which received synthetic GCs.

描述（由申请人提供）：越来越多的证据支持这一理论，即发育中的胎儿在妊娠关键时期不适当和/或过度接触糖皮质激素（GC）会导致成年后出现行为、神经内分泌和生理疾病。这种现象被称为“胎儿编程”。合成GC通常用于早产和分娩高风险的孕妇。合成GC引起的后代疾病包括下丘脑-垂体-肾上腺（HPA）轴紊乱、恐惧/焦虑改变、代谢紊乱和高血压。由于成人中过量的 GC 产生会促进高血压、高血糖/胰岛素抵抗和血脂异常，因此 HPA 功能增加和相关行为的发育编程可能是这些疾病形成中不可或缺的一部分。在子宫内接触合成GC的后代中，成年期杏仁核中央核（CeA）和下丘脑室旁核（PVN）中促肾上腺皮质激素释放因子（CRF）的表达增加。 CRF 是调节垂体前叶 ACTH 分泌的主要神经肽，也是恐惧/焦虑的主要调节剂。我们认为，PVN 和 CeA 中 CRF 神经元发育和表达的编程是 GC 编程的过度 HPA 活性和高度焦虑表型的核心。 AIM 1 将确定母体递送合成 GC 是否会增加 CRF 表达以及 PVN 和 CeA 中 CRF 神经元的数量，并确定表达增加的开始时间以及易感性的发育窗口。 AIM 2 将确定 mpPVN 中的 AVP 表达是否是通过母体施用合成糖皮质激素来编程的。 AIM 3 直接检查 CRF 在恐惧/焦虑编程中的作用，以及在子宫内暴露于母体合成糖皮质激素时 HPA 轴功能增强的情况。目标 3 还将评估 BNST 与杏仁核作为 CRF 作用部位在恐惧/焦虑编程中的作用。 AIM 4 将确定 GC 对杏仁核的刺激是否对于维持接受合成 GC 的怀孕大鼠后代中 CeA 和 PVN 中 CRF 表达的增加、焦虑/恐惧的增加以及 HPA 功能的增加至关重要。