NEURAL REGULATION OF THE FETAL PARAVENTRICULAR NUCLEUS

下丘脑-垂体肾上腺(HPA)轴是最后一个 糖皮质激素(GC)分泌应对挑战的共同途径 到动态平衡。成人HPA轴功能被抑制所改变 海马区(HC)输入，但胎儿HC的作用尚不清楚。这个 本提案的目的是获得关于以下方面的基本新知识 胎儿促肾上腺皮质激素分泌的综合调控 绵羊HC：1)对急性低血压的反应；2)在 临产胎儿ACTH升高。 假设：1)胎儿大脑皮质经穹隆传入大脑的神经元。 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 关于分娩的事。2)胎儿HC处的GC反馈将HC神经输入修改为 胎儿HPA轴在以下两个阶段改变其活动水平： ACTH对急性低血压的反应和b)分娩的开始。 3)产前GCs在大脑中整体施加反馈，改变胎儿HC HPA轴的活动水平不同于仅在HC的GC反馈。 具体目标：研究1)神经元输入通过 从HC到下丘脑的穹隆a)HPA轴荷尔蒙 对急性低血压的反应和b)分娩时间；3)GC 在整个中枢神经系统水平对HC的反馈 调节胎儿HPA轴对急性发作的激素反应的活动 低血压。 方法：1)胎龄羊的慢性测量。2)Fornix 以120/-1的速度进行横切术和HC-GC晶体植入， 胎龄130天/-1天(DGA)时输注GC。3)低血压 在两个关键发展阶段--132/-1和142/--面临的挑战 1个DGA。4)胎儿外周血浆促肾上腺皮质激素、血管加压素放射免疫测定 (AVP)、皮质醇和母体皮质醇和孕酮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胶质纤维酸性蛋白。 理由：私家侦探目前是北美唯一的调查员 进行必要的胎儿立体定位神经外科技术 调查HPA的HC控制。胎羊是应用最广泛的 模型研究神经和内分泌控制的整合 胎儿肾上腺。上面概述的研究将确定胎儿HC 对HPA轴功能的贡献在平衡挑战和 正常的下丘脑发育，控制着 分娩。这些研究的结果将提高对 胎儿应激反应与足月和早产的调节 分娩。

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.