REGULATION OF VASOPRESSIN SECRETION

该项目的目标是了解神经元将各种调节信号整合到功能反应中的机制。下丘脑-神经垂体系统（HNS）的抗利尿激素（VP）神经元将作为这些研究的模型神经元，因为它们对广泛的传入事件作出反应，并将这些信息整合到生理上适当的激素分泌率中。除了响应来自脑干、下丘脑和前脑的神经递质和神经肽的传入信号外，VP神经元还响应非突触信号，如细胞外液的渗透压和类固醇激素。提出的实验将解决两个假设：1)嗜离子受体的激动剂代表副脑神经细胞的主要调节剂，这些神经递质的作用是通过g蛋白连接受体和类固醇激素的激动剂调节的。2) g蛋白连接激动剂也独立于嗜离子受体激动剂调节VP基因表达和/或mRNA稳定性。该提案的具体目标是：1。目的探讨兴奋性氨基酸（EAA）在VP释放和VPmRNA调控中的作用。2. 评价EAA嗜离子受体激动剂与g蛋白连接受体激动剂的关系。3. 探讨类固醇激素对EAA刺激的调节作用。4. 探讨VP和OT对神经垂体激素分泌的自调节作用。HNS的外植体将用于所有拟议的实验。这些外植体对渗透压的缓慢增加做出反应，持续增加VP释放和VPmRNA含量。这些外植体的VP释放也受到EAA激动剂、ATP和gaba能拮抗剂的刺激。在适当的情况下，将使用来自具有本提案感兴趣的特定基因零突变的小鼠株的HNS外植体。

The goal of this project is to understand the mechanisms which allow neurons to integrate diverse regulatory signals into functional responses. Vasopressin (VP) neurons of the hypothalamo-neurohypophseal system (HNS) will serve as the model neuron in these studies, because they respond to wide ranging afferents, and integrate this information into a physiologically appropriate rate of hormone secretion. In addition to responding to afferents from the brainstem, hypothalamus, and forebrain that utilize an array of neurotransmitters and neuropeptides, the VP neurons also respond to non-synaptic signals such as osmolality of the extracellular fluid and steroid hormones. The proposed experiments will address two hypotheses: 1) Agonists of ionotropic receptors represent the primary regulators of VP neurons, and the action of these neurotransmitters is modulated via agonists of G-protein linked receptors and steroid hormones. 2) G-protein linked agonists also regulate VP gene expression and/or mRNA stability independent of ionotropic receptor agonists. The specific aims of the proposal are: 1. To evaluate the role of excitatory amino acids (EAA) in the regulation of VP release and VPmRNA. 2. To evaluate the relationship between EAA ionotropic receptor agonists and G-protein linked receptor agonists. 3. To evaluate modulation of EAA stimulation by steroid hormones. 4. To evaluate the autoregulation of neurohypophyseal hormone secretion by VP and OT. Explants of the HNS will be used in all of the proposed experiments. These explants respond to a slow increase in osmolality with a sustained increase in VP release and an increase in VPmRNA content. VP release from these explants is also stimulated by EAA agonists, ATP and GABAergic antagonists. Where appropriate, HNS explants from mice strains with null mutations in specific genes of interest to this proposal will be used.