Molecular pathways underlying organ-specific targeting by the vagus nerve

项目总结/摘要 这个项目的长期目标是揭示迷走神经感觉神经元如何在神经元内活动的基本神经生物学机制。 神经元在发育过程中发现、支配特定的终末器官和组织并与之相互作用。感官 迷走神经的神经元检测并传递来自内部器官的各种信号，包括摄入的 营养素、血压变化和胃的机械扩张。从解剖学上讲，它是一种独特的 从靠近后脑的一对神经节发出的长的脑神经，但贯穿整个 并支配无数的靶组织。从这些神经节中，每个迷走神经感觉神经元都发出一个 单个假单极轴突，其靶向特定的内部器官外周和专用的脑干回路 中心。忠实地建立这种连接对于神经控制生理功能至关重要， 如呼吸、心率和消化。尽管它的至关重要的作用和新兴的重要性，脑内脏 迷走神经的复杂解剖结构是如何形成的， 在发展过程中，迷走神经的错误布线是否可能导致自主神经疾病， 神经系统该项目建议利用新的遗传和先进的成像技术，开始 通过结合解剖学（目标1）、细胞学（目标2）和分子学（目标3）来实现长期目标 方法。目的1将建立一个全面的，高分辨率的地图迷走神经的发展， 整个动物的背景下，通过利用遗传标记，组织清除，和高分辨率显微镜。目的 2将阐明肠神经元迁移和迷走神经传入生长之间的相互作用，通过利用切割- 边缘小鼠遗传学工具，以选择性地操纵不同的细胞类型。目标3将识别分子 迷走神经寻路的决定因素，通过结合公开可用的数据和小鼠遗传学工具， 标记和干扰迷走神经感觉神经元中候选基因表达。日益明显的是 迷走神经连接在新陈代谢和能量稳态中起作用，这意味着 相关疾病。因此，该项目的结果将开辟新的调查路线， 沟通是在健康和疾病中建立和维持的。

PROJECT SUMMARY / ABSTRACT The long-term goal of this project is to reveal basic neurobiological mechanisms about how vagal sensory neurons find, innervate, and interact with specific end-organs and tissues during development. Sensory neurons of the vagus nerve detect and transmit diverse signals from internal organs, including ingested nutrients, changes in blood pressure, and mechanical distension of the stomach. Anatomically, it is a uniquely long cranial nerve that emanates from a single pair of ganglia near the hindbrain yet courses through the entire body and innervates a myriad of target tissues. From these ganglia, each vagal sensory neuron sprouts a single pseudounipolar axon that targets a specific internal organ peripherally and a dedicated brainstem circuit centrally. Faithfully establishing this connectivity is essential for neural control of physiological functions such as breathing, heart rate and digestion. Despite its vital role and the emerging importance of brain-viscera communication, it remains largely unknown how the intricate anatomical structure of the vagus nerve forms during development, and whether miswiring of the vagus nerve may contribute to diseases of the autonomic nervous system. This project proposes to leverage novel genetic and advanced imaging techniques to begin addressing the long-term goal by combining anatomical (Aim 1), cellular (Aim 2), and molecular (Aim 3) approaches. Aim 1 will establish a comprehensive, high-resolution map of vagus nerve development in the context of the whole animal, by utilizing genetic labeling, tissue clearing, and high- resolution microscopy. Aim 2 will elucidate the interplay between enteric neuron migration and vagal afferent outgrowth, by utilizing cutting- edge mouse genetics tools to selectively manipulate different cell types. Aim 3 will identify molecular determinants of vagus nerve pathfinding, by combining publicly available data and mouse genetics tools to label and perturb candidate gene expression in vagal sensory neurons. It is becoming increasingly apparent that vagus nerve connectivity plays a role in metabolism and energy homeostasis, with implications in related disorders. Therefore, results of this project will open new lines of inquiry on how viscera-to-brain communication is established and maintained in health and disease.!