Presynaptic Mechanisms of Neurotransmission in NTS

NTS 中神经传递的突触前机制

• 批准号: 7337370
• 负责人: Michael Christian Andresen
• 金额: $ 34.75万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337370
• 关键词: Address; Afferent Neurons; Automobile Driving; Axon; Baroreflex; Brain Stem; Calcium; Calcium Channel; Cardiovascular system; Cephalic; Characteristics; Chromosome Pairing; Class; Cranial Nerves; Disease; Electrophysiology (science); Exocytosis; Fluorescent Dyes; Foundations; Frequencies; Glutamates; Heart failure; Homeostasis; Hypertension; Image; In Vitro; Individual; Intensive Care; Investigation; Ion Channel; Knowledge; Label; Laboratories; Life; Link; Methods; Molecular; Morphology; N-Type Calcium Channels; Nerve; Neuromodulator; Neurons; Nucleus solitarius; Opioid Receptor; Optics; Output; Pathogenesis; Pathway interactions; Peptides; Peripheral; Pharmaceutical Preparations; Physicians; Potassium; Potassium Channel; Preparation; Pressoreceptors; Presynaptic Terminals; Property; Prosencephalon; Range; Records; Reflex action; Regulation; Research; Research Personnel; Respiratory System; Role; Scientist; Shock; Sodium; Stroke; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; System; TRPV1 gene; Testing; Vasopressins; Vesicle; Work; afferent nerve; electrical measurement; experience; improved; in vivo; insight; interest; neuronal cell body; neurotransmission; neurotransmitter release; patch clamp; presynaptic; programs; receptor; relating to nervous system; selective expression; size; synaptic depression; tool; transmission process

Beat to beat regulation of the cardiovascular system depends on an intact baroreflex. This reflex arc first synapses in the nucleus tractus solitarius (NTS) where glutamate is released. Baroreflex function is compromised in common life threatening disease states: hypertension, shock, and heart failure. Work in large, accessible CNS terminals suggests that the presynaptic control of glutamate release involves ion channels and 2nd messenger systems that regulate vesicle exocytosis. Glutamate regulation differs across neurons, but the mechanisms are poorly understood. Reflex pathways regulating the cardiovascular and respiratory systems depend on brainstem neurons and these reflexes are initiated by cranial nerve primary afferents acting within the nucleus tractus solitarius (NTS). Little is known about how primary afferents behave centrally. The small size of these terminals has made direct investigation difficult. We have developed methods to permit patch clamp recording from single nerve terminals in NTS. Our Research Plan will use these methods to address our driving hypothesis that important mechanisms of regulation in NTS depend on the identity of the afferent neuron. Our Preliminary Work demonstrates that NTS neurons offer a unique opportunity because: 1. we can directly visualize, identify, stimulate and electrophysiologically record from single nerve terminals, 2. NTS receives pharmacologically distinguishable afferent terminals that form subclasses known to arise from molecularly distinct peripheral neurons, 3. Subsets of these terminals can be labeled to provide links to functionally distinct afferents. Our Plan encompasses the efforts of two labs with complementary expertise suited to this problem. We will use direct patch recording and stimulation of single terminals, as well as imaging, to study the mechanism of frequency dependent synaptic depression and peptide modulation of glutamate release. The work capitalizes on using markers of primary afferent terminals to distinguish the various sub classes (TRPV1 and P2X3; C- and A-type afferent terminals, respectively). Specific Aims concern differential sodium, potassium and calcium channel expression across A- and C-type cranial afferent synaptic terminals plus the presence of new presynaptic mechanisms regulating synaptic cleft calcium. The different sub classes of afferent nerve terminal will be also be compared in terms of their control of glutamate release and modulation by peptides.

心血管系统的节拍调节取决于完整的压力反射。首先是这个反射弧 孤束核 (NTS) 中的突触是释放谷氨酸的地方。压力感受反射功能是 常见危及生命的疾病状态：高血压、休克和心力衰竭。工作于 大型、可触及的中枢神经系统末梢表明，谷氨酸释放的突触前控制涉及离子 调节囊泡胞吐作用的通道和第二信使系统。谷氨酸调节因人而异 神经元，但其机制尚不清楚。调节心血管和神经系统的反射通路 呼吸系统依赖于脑干神经元，这些反射是由初级脑神经发起的 传入神经作用于孤束核（NTS）内。人们对初级传入神经如何作用知之甚少 表现集中。这些终端尺寸较小，导致直接调查变得困难。我们有 开发了允许从 NTS 中的单个神经末梢进行膜片钳记录的方法。我们的研究计划 将使用这些方法来解决我们的驱动假设，即 NTS 中的重要调节机制 取决于传入神经元的身份。我们的初步工作表明 NTS 神经元提供了 独特的机会，因为： 1. 我们可以直接可视化、识别、刺激和电生理记录 来自单个神经末梢，2. NTS 接收药理学上可区分的传入终端，形成 已知由分子上不同的周围神经元产生的亚类，3。这些终端的子集可以是 标记为提供功能不同传入的链接。我们的计划包括两个实验室的努力 适合这个问题的补充专业知识。我们将使用直接补丁录制和刺激单 终端以及成像来研究频率依赖性突触抑制的机制 谷氨酸释放的肽调节。这项工作利用了初级传入终端的标记 区分各种子类（TRPV1 和 P2X3；分别为 C 型和 A 型传入端子）。 具体目标涉及 A 型和 C 型的钠、钾和钙通道表达差异 颅传入突触末梢加上调节突触的新突触前机制的存在 钙裂。传入神经末梢的不同亚类也将根据其功能进行比较 通过肽控制谷氨酸释放和调节。