NEURAL REGULATION OF THE FETAL PARAVENTRICULAR NUCLEUS

胎儿室旁核的神经调节

• 批准号: 6410459
• 负责人: THOMAS Joseph MCDONALD
• 金额: $ 17.7万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410459
• 关键词: adrenocorticotropic hormone; arginine vasopressin; birth; corticotropin releasing factor; cortisol; embryo /fetus; embryo /fetus disorder; embryo /fetus surgery; gene expression; gestational age; glucocorticoids; hippocampus; hormone regulation /control mechanism; hypotension; hypothalamic pituitary adrenal axis; hypothalamus; immunocytochemistry; in situ hybridization; neuroregulation; paraventricular nucleus; pregnancy; premature labor; protooncogene; sheep; stereotaxic techniques

INTRODUCTION: The hypothalamo-pituitary adrenal (HPA) axis is the final common pathway for glucocorticoid (GC) secretion in response to challenges to homeostasis. Adult HPA axis function is modified by inhibitory hippocampal (HC) inputs, but the role of the fetal HC is unknown. The purpose of the present proposal is to gain fundamental new knowledge about integrative control of adrenocorticotropin (ACTH) secretion by the fetal sheep HC: 1) in response to acute hypotension and 2) during the pre- parturient fetal ACTH rise. HYPOTHESES: 1) Neuronal inputs from the fetal HC via the fornix to the hypothalamus modify fetal HPA axis functions that result in a) the fetal plasma ACTH response to acute (10 min) hypotension and b) the initiation of parturition. 2) GC feedback at the fetal HC modifies HC neural input to the fetal HPA axis altering its activity level during both a) the fetal ACTH response to acute hypotension and b) the initiation of parturition. 3) Antenatal GCs exert feedback globally in the brain altering fetal HC and HPA axis activity level differently than GC feedback at the HC alone. SPECIFIC AIMS: To investigate the roles of 1) neuronal inputs via the fornix from the HC to the hypothalamus in a) the HPA axis hormonal response to acute hypotension and b) the timing of parturition; 3) GC feedback at the level of the whole central nervous system on the HC activity modifying the hormonal response of the fetal HPA axis to acute hypotension. METHODS: 1) Chronic instrumentation of age dated fetal sheep. 2) Fornix transections and HC GC crystal implants done stereotaxically at 120 +/-1, GC infusions at 130 +/-1 days of gestational age (dGA). 3) Hypotensive challenges done at two critical developmental stages, 132 +/-1 and 142 +/- 1 dGA. 4) Radioimmunoassay of fetal peripheral plasma ACTH, vasopressin (AVP) and cortisol and maternal cortisol and progesterone 5) Immunocytochemical staining and in situ hybridization for corticotropin- releasing hormone AVP, GC receptors I (CR/MR) and II (GR), c-fos mRNA and protein and glial fibrillary acid protein in fetal HC and hypothalamus. RATIONALE: The PI is currently the only investigator in North America performing the fetal stereotaxic neurosurgical techniques necessary to investigate HC control of the HPA. The fetal sheep is the most widely used model to study the integration of neural and endocrine control of the fetal adrenal. The studies outlined above will determine fetal HC contributions to HPA axis function during both homeostatic challenge and the normal hypothalamic development that controls the timing of parturition. The results of these studies will improve understanding of fetal stress responses and regulation of both term and pre-term parturition.

简介： 下丘脑-垂体肾上腺 (HPA) 轴是最终的轴。 应对挑战时糖皮质激素 (GC) 分泌的共同途径 达到体内平衡。成人 HPA 轴功能被抑制改变 海马（HC）输入，但胎儿 HC 的作用尚不清楚。这 本提案的目的是获得关于 胎儿促肾上腺皮质激素（ACTH）分泌的综合控制 绵羊 HC：1) 应对急性低血压，2) 在预治疗期间 临产胎儿ACTH升高。 假设：1) 胎儿 HC 的神经元输入通过穹窿到达 下丘脑改变胎儿 HPA 轴功能，导致 a) 胎儿 血浆 ACTH 对急性（10 分钟）低血压的反应和 b) 启动 临产。 2) 胎儿 HC 处的 GC 反馈将 HC 神经输入修改为 胎儿 HPA 轴在 a) 胎儿期期间改变其活动水平 ACTH 对急性低血压的反应和 b) 分娩的开始。 3) 产前 GC 在大脑中全局施加反馈，改变胎儿 HC 和 HPA 轴活动水平与单独 HC 处的 GC 反馈不同。 具体目标：研究 1) 神经元输入的作用 a) HPA 轴激素从 HC 到下丘脑的穹窿 对急性低血压的反应和 b) 分娩时间； 3）气相色谱仪 整个中枢神经系统对 HC 的反馈 改变胎儿 HPA 轴对急性的激素反应的活性 低血压。 方法： 1) 对已确定年龄的胎羊进行慢性仪器测定。 2）穹窿 在 120 +/-1 下进行立体定位横切和 HC GC 晶体植入， GC 输注在胎龄 130 +/-1 天 (dGA) 时进行。 3）低血压 在两个关键发展阶段完成的挑战，132 +/-1 和 142 +/- 1 dGA。 4）胎儿外周血浆ACTH、加压素放射免疫测定 (AVP) 和皮质醇以及母体皮质醇和黄体酮 5) 促肾上腺皮质激素的免疫细胞化学染色和原位杂交 释放激素 AVP、GC 受体 I (CR/MR) 和 II (GR)、c-fos mRNA 和 胎儿 HC 和下丘脑中的蛋白质和神经胶质原纤维酸性蛋白。 理由：PI 是目前北美唯一的调查员 执行必要的胎儿立体定位神经外科技术 研究 HC 对 HPA 的控制。胎羊是应用最广泛的 研究神经和内分泌控制整合的模型 胎儿肾上腺。上述研究将确定胎儿 HC 在稳态挑战和 下丘脑的正常发育控制着 分娩。这些研究的结果将增进对 胎儿应激反应以及足月和早产的调节 分娩。