DENDRITIC RELEASE OF NEUROPEPTIDES: ROLE IN BODILY HOMEOSTASIS

神经肽的树突释放：在身体稳态中的作用

• 批准号: 9618919
• 负责人: Javier E Stern
• 金额: $ 25.62万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9618919
• 关键词: DENDRITIC; RELEASE; NEUROPEPTIDES; ROLE; BODILY

Bodily homeostasis involves orchestrated activities between hypothalamic autonomic and neuroendocrine neuronal networks. Importantly, an imbalanced interaction between them constitutes the basis for maladaptive responses (“neurohumoral activation”) observed in disease conditions (stress, heart failure and the metabolic syndrome). Importantly, neurohumoral activation (which includes centrally driven sympathetic activity and elevated circulating levels of vasopressin (VP)) directly correlates with prognosis, and mortality in these diseases. Thus, understanding the mechanisms involved in autonomic and neuroendocrine integration, both in health and disease conditions, is of critical physiological and clinical significance. The hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the generation of coordinated polymodal homeostatic responses. Still, the mechanism by which the activity of these functionally distinct neuronal populations is orchestrated during a homeostatic response remains elusive. We recently identified dendritic release of VP from magnocellular neurosecretory neurons as a novel signaling mechanism underlying “wireless” (non- synaptic) communication between neuroendocrine and presympathetic PVN neurons. We showed this interpopulation crosstalk to play a major role coordinated neurosecretory/sympathetic homeostatic responses to an osmotic challenge (OSM+). While significant progress has been obtained in our understanding of mechanisms underlying activity-dependent release of neuropeptides from axonal terminals, limited information is available regarding mechanisms regulating dendritic release, particularly during OSM+. Thus, we implemented a highly innovative approach that enables us to quantitatively monitor dendritic VP release in real time, while studying in a mechanistic manner the main processes involved in this interpopulation homeostatic crosstalk. We obtained exciting preliminary data that supports our innovative hypothesis of a fine-tuned interplay between glutamate NMDA receptors (NMDARs), backpropagating dendritic action potentials and K+ channels in regulating dendritic VP release and neurosecretory-presympathetic signaling crosstalk in response to OSM+. Moreover, we will test the hypothesis that astrocytes, recognized as key players in CNS function, exert a pivotal influencing dendritic release of VP, its diffusing efficacy in the ECS, and ultimately, the generation of multimodal homeostatic responses. These hypotheses will be tested in 3 specific aims: 1- To elucidate mechanisms by which action potentials (APs) and NMDARs interact during OSM+ to evoke dendritic VP release. 2- To elucidate mechanisms that regulate dendritic retrograde signaling and their impact on dendritic release. 3- To elucidate mechanisms that control the diffusion of VP in the extracellular space, influencing in turn its efficacy as an interpopulation signaling. We expect results from this work to broaden our understanding of basic cellular mechanisms contributing to the hypothalamic regulation of homeostasis, and how changes in these mechanisms may contribute to neurohumoral activation during disease states.

身体稳态涉及下丘脑自主神经和神经内分泌之间的协调活动 重要的是，它们之间的不平衡相互作用构成了神经网络的基础。 在疾病状况（压力、心力衰竭和 重要的是，神经体液激活（包括中枢驱动的交感神经 加压素（VP）的活性和循环水平升高与预后和死亡率直接相关 因此，了解自主神经和神经内分泌整合的机制， 无论在健康还是疾病条件下，都具有至关重要的生理和临床意义。 室旁核（PVN）在协调多模式稳态的产生中起着关键作用 尽管如此，这些功能不同的神经群体的活动机制仍然存在。 我们最近发现了 VP 的树突释放。 来自大细胞神经分泌神经元作为“无线”（非 我们展示了神经内分泌和前交感神经 PVN 神经元之间的突触）通讯。 群体间串扰在协调神经分泌/交感稳态反应中发挥重要作用 虽然我们对渗透挑战（OSM+）的理解已经取得了重大进展。 轴突末梢神经肽活性依赖性释放的机制，信息有限 关于调节树突释放的机制，特别是在 OSM+ 期间，我们实施了一个。 高度创新的方法使我们能够实时定量监测树突 VP 的释放，同时 以机械方式研究这种群体间稳态串扰所涉及的主要过程。 我们获得了令人兴奋的初步数据，支持我们关于微调相互作用的创新假设 谷氨酸 NMDA 受体 (NMDAR)、反向传播树突动作电位和 K+ 通道之间 调节树突 VP 释放和响应 OSM+ 的神经分泌-前交感神经信号串扰。 此外，我们将检验以下假设：星形胶质细胞被认为是中枢神经系统功能的关键参与者，发挥着 影响 VP 的关键树突释放、其在 ECS 中的扩散功效，以及最终的生成 这些假设将在 3 个具体目标中进行测试： 1- 阐明 OSM+ 期间动作电位 (AP) 和 NMDAR 相互作用以诱发树突 VP 的机制 2-阐明调节树突逆行信号传导的机制及其对释放的影响。 3- 阐明控制 VP 在细胞外空间扩散的机制， 我们期望这项工作的成果能够扩大 我们对有助于下丘脑稳态调节的基本细胞机制的理解， 以及这些机制的变化如何有助于疾病状态下的神经体液激活。