REGULATION OF VASOPRESSIN SECRETION

这个项目的目标是了解神经元将不同的调节信号整合到功能反应中的机制。在这些研究中，下丘脑-神经下丘脑系统(HNS)的加压素(VP)神经元将作为模型神经元，因为它们对广泛的传入做出反应，并将这些信息整合到生理上适当的激素分泌速率中。除了对来自脑干、下丘脑和前脑的传入信号作出反应外，VP神经元还对非突触信号做出反应，如细胞外液的渗透压和类固醇激素。这些实验将解决两个假设：1)电离子受体激动剂代表VP神经元的初级调节器，这些神经递质的作用通过G蛋白连接的受体激动剂和类固醇激素来调节。2)G蛋白结合的激动剂也调节VP基因的表达和/或mRNA的稳定性，而不依赖于离子型受体激动剂。本研究的具体目的是：1.评价兴奋性氨基酸(EAA)在VP释放和VPmRNA调节中的作用。2.探讨EAA离子型受体激动剂与G蛋白连接受体激动剂之间的关系。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动调节作用。HNS的外植体将在所有拟议的实验中使用。这些外植体对渗透压缓慢增加的反应是VP释放持续增加，VPmRNA量增加。EAA激动剂、ATP和GABA能拮抗剂也能刺激这些外植体释放VP。在适当的情况下，将使用对这一提议感兴趣的特定基因零突变的小鼠品系的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.