NEURAL REGULATION OF THE FETAL PARAVENTRICULAR NUCLEUS

引言：下丘脑-垂体-肾上腺（HPA）轴是最后的 糖皮质激素（GC）分泌响应挑战的共同途径 自我平衡成人HPA轴功能被抑制性改变 海马（HC）的输入，但胎儿HC的作用是未知的。的 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（ACTH）分泌的综合控制 绵羊HC：1）对急性低血压的反应和2）在预 临产胎儿ACTH升高。 假设：1）从胎儿HC通过穹窿到大脑中动脉的神经元输入。 下丘脑修饰胎儿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）开始 分娩。2)胎儿HC处的GC反馈修改HC神经输入， 胎儿HPA轴在以下两个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)胎儿GC在大脑中发挥全局反馈作用，改变胎儿HC 和HPA轴的活动水平不同的GC反馈在HC单独。 具体目的：研究1）神经元输入通过 穹窿从HC到下丘脑a）HPA轴激素 对急性低血压的反应和B）分娩时间; 3）GC 整个中枢神经系统对HC的反馈 活性改变胎儿HPA轴的激素反应， 低血压 方法：1）胎龄测定的胎羊慢性内固定。2)穹窿 在120 +/-1下立体定向进行横切和HC GC晶体植入， 130 +/-1天胎龄（dGA）时GC输注。3)降压 在132 +/-1和142 +/-两个关键发育阶段完成的挑战 1 dGA。4)胎儿外周血促肾上腺皮质激素、加压素的放射免疫测定 (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 蛋白和胶质细胞酸性蛋白。 依据：PI目前是北美唯一的研究者 进行胎儿立体定位神经外科技术， 调查HPA的HC控制。胎羊是最广泛使用的 模型来研究神经和内分泌控制的整合， 胎儿肾上腺上述研究将确定胎儿HC 对HPA轴功能的贡献， 正常的下丘脑发育控制着 分娩这些研究的结果将提高人们对 胎儿应激反应及足月和早产儿的调节 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.