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.

身体稳态涉及下丘脑自主与神经内分泌之间的精心策划活动 神经元网络。重要的是，它们之间的不平衡互动构成了 在疾病条件下观察到的不良适应反应（“神经肿瘤激活”）（压力，心力衰竭和 代谢综合征）。重要的是，神经肿瘤激活（包括集中驱动的同情 活性和加压素（VP）的循环水平升高与预后直接相关，而死亡率 这些疾病。这是理解自主和神经内分泌融合所涉及的机制， 在健康和疾病状况下，身体和临床意义都至关重要。下丘脑 室室内核（PVN）在协调的多态稳态生成中起关键作用 回答。尽管如此，这些功能上不同神经元种群的活性的机制是 在稳态反应期间精心策划的仍然难以捉摸。我们最近确定了VP的树突释放 从磁细胞神经分泌元作为“无线”的新型信号传导机制（非 - 神经内分泌与同情性PVN神经元之间的突触）通信。我们证明了这一点 插入串扰，扮演主要角色协调的神经分泌/交感神经稳态反应 进行渗透挑战（OSM+）。尽管我们对我们的理解取得了重大进展 从轴突末端的神经肽释放的基础机制，有限的信息 有关调节树突释放的机制，特别是在OSM+期间。那我们实施了 高度创新的方法使我们能够实时定量监视树突副总裁释放，而 以机械方式研究该插入式体内串扰涉及的主要过程。 我们获得了令人兴奋的初步数据，该数据支持我们对微调互动的创新假设 在谷氨酸NMDA受体（NMDAR）之间，向后传播树突作用电位和K+通道之间 在控制树突状VP释放和神经分泌 - 交感神经信号传导串扰时，响应OSM+。 此外，我们将检验以下假设：星形胶质细胞被认为是CNS功能的关键参与者 关键影响副总裁的树突释放，其在EC中的扩散效率，最终产生 多模式稳态反应。这些假设将以3个特定目的进行检验：1-阐明 在OSM+期间，动作电位（AP）和NMDAR相互作用以引起树枝状VP的机制 发布。 2-阐明调节树突逆行信号及其对影响的机制 树突释放。 3-阐明控制VP在细胞外空间中扩散的机制， 影响其有效性作为人口信号传导。我们期望这项工作的结果扩大 我们对有助于下丘脑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期间的神经肿瘤激活。