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: 9769162
• 负责人: Javier E Stern
• 金额: $ 25.54万
• 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/9769162
• 关键词: Action Potentials; Astrocytes; Axon; Binding; Chronic; Communication; Data; Dendrites; Development; Diabetes Mellitus; Diffuse; Diffusion; Disease; Electrolytes; Excess Dietary Salt; Extracellular Space; Feedback; Generations; Glutamates; Health; Heart failure; Homeostasis; Hypertension; Hypothalamic structure; Liquid substance; Mediating; Metabolic syndrome; Modeling; Monitor; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuraxis; Neurons; Neuropeptides; Neurosecretory Systems; Patients; Pattern; Physiological; Pituitary Gland; Play; Population; Potassium Channel; Presynaptic Terminals; Process; Receptor Activation; Regulation; Role; Series; Signal Transduction; Sodium Chloride; Stress; System; Testing; Therapeutic; Time; Vasopressins; Wireless Technology; Work; clinically significant; innovation; interdisciplinary approach; magnocellular; mortality; multimodality; neuronal cell body; novel; osmoreceptor; outcome forecast; paraventricular nucleus; receptor; response; salt intake; treatment strategy

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.

身体内稳态涉及下丘脑自主神经和神经内分泌之间的协调活动 神经网络重要的是，它们之间的不平衡互动构成了 适应不良反应（“神经体液激活”）在疾病状况（应激、心力衰竭和 代谢综合征）。重要的是，神经体液激活（包括中枢驱动的交感神经系统） 血管加压素（VP）的活性和循环水平升高）与预后和死亡率直接相关。 这些疾病。因此，了解自主神经和神经内分泌整合的机制， 在健康和疾病条件下，具有重要的生理和临床意义。下丘脑 室旁核（PVN）在协调多模态稳态的产生中起着关键作用 应答尽管如此，这些功能不同的神经元群体的活动的机制是不同的。 在体内平衡反应中的协调仍然难以捉摸。我们最近发现了VP的树突状释放 从大细胞神经分泌神经元作为一种新的信号机制的基础“无线”（非- 突触）之间的神经内分泌和前交感PVN神经元的通讯。我们展示了这个 种群间串扰在协调神经分泌/交感神经稳态反应中起主要作用 渗透压挑战（OSM+）。虽然我们在理解 轴突末梢神经肽活性依赖性释放的潜在机制，信息有限 是关于机制调节树突状细胞的释放，特别是在OSM+。因此，我们实现了一个 高度创新的方法，使我们能够定量监测树突状VP释放在真实的时间，而 以一种机械的方式研究这种种群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，支持我们的创新假设微调的相互作用 谷氨酸NMDA受体（NMDARs），反向传播树突状细胞动作电位和K+通道之间的关系 在调节树突状VP释放和神经分泌交感神经前信号串扰响应OSM+。 此外，我们将检验星形胶质细胞作为中枢神经系统功能的关键参与者， 关键影响VP的树突状释放，其在ECS中的扩散功效，以及最终， 多模态稳态反应这些假设将在3个具体目标进行测试：1-阐明 OSM+期间动作电位（AP）和NMDAR相互作用以诱发树突状VP的机制 release. 2-阐明调节树突状细胞逆行信号传导的机制及其对 树突状释放3-为了阐明控制VP在细胞外空间扩散的机制， 反过来影响其作为种群间信号的功效。我们希望这项工作的成果能够扩大 我们对下丘脑调节体内平衡的基本细胞机制的理解， 以及这些机制的变化如何在疾病状态下促进神经体液激活。