Developmental mechanisms specifying vagal innervation of organ targets

指定器官目标迷走神经支配的发育机制

• 批准号: 10752553
• 负责人: Austin Seroka
• 金额: $ 6.95万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752553
• 关键词: Ablation; Address; Afferent Neurons; Automobile Driving; Axon; Back; Brain; Brain Stem; Branchial arch structure; Candidate Disease Gene; Cell Nucleus; Cell Surface Proteins; Central Nervous System; Cephalic; Communication; Complex; Computer Analysis; Data; Deglutition; Dependence; Desire for food; Development; Digestion; Disease; Embryo; Environment; Fiber; Gastrointestinal tract structure; Genes; Genetic; Genetic Transcription; Head; Heart; Heart Rate; Homeostasis; Image; Interoception; Intestines; Location; Lung; Maps; Modeling; Molecular; Monitor; Motor; Motor Neurons; Muscle; Nervous System; Neurons; Nodose Ganglion; Nutrient; Optics; Organ; Pathway interactions; Peristalsis; Positioning Attribute; Resolution; Respiration; Role; Rosaniline Dyes; Sensory; Signal Transduction; Specific qualifier value; Stomach; Study models; Synapses; Testing; Tissues; Vagus nerve structure; Vertebrates; Viscera; Visceral; Work; Zebrafish; blood pressure regulation; body system; candidate identification; differential expression; experimental study; extracellular; gastrointestinal function; heart function; hindbrain; mind/body; nerve supply; organ growth; reverse genetics; segregation; single cell sequencing; single-cell RNA sequencing; spatiotemporal; tool; transcription factor; transmission process; uptake

Project Summary / Abstract: During development, the central nervous system establishes precise connections with the body to coordinate organ function. A crucial component of this communication between the brain and body is the vagus nerve (cranial nerve X), which innervates multiple organ systems including the heart, lungs, and digestive tract to regulate blood pressure, heart rate, respiration, and digestion. Despite this important role, the molecular mechanisms guiding the vagus nerve to these organ targets remain completely unknown. We have developed the zebrafish embryo as a powerful model for interrogating vagus nerve development, taking advantage of its optical clarity and genetic accessibility. The vagus is comprised of both ascending sensory fibers that transmit organ state to the brain, and descending motor projections that deliver reciprocal motor commands to the organs. The vagus nerve also targets pharyngeal arch-derived muscles in the head, and the Moens lab has previously described a topographic relationship between the positions of motor neurons in the brain and their targets in the head, and has discovered a spatio-temporal mechanisms for the development of this map. The preliminary data I present here demonstrates that vagal motor projections to the organs are also organized topographically, where vagal motor neurons innervating different organs (heart, stomach, intestines) are spatially segregated within the hindbrain vagus nucleus. I also observe vagal motor projections reaching the viscera much earlier than their sensory counterparts, leading me to hypothesize that correct motor innervation of the viscera is required for subsequent sensory innervation. Here, I propose to address these hypotheses through the following aims. In Aim 1, I will use genetic tools along with live imaging and single-cell RNA sequencing to determine the molecular mechanisms guiding subsets of vagus motor neurons to the heart and gut. I will identify candidate molecules (transcription factors and cell-surface proteins) determining the topographic organization of somatic innervation and test the role of these candidates using reverse genetics. In Aim 2, I will determine the mechanisms guiding vagal sensory neurons to the appropriate organ targets and test the dependence of sensory innervation on the correct establishment of vagal motor innervation. This work will reveal how a major pathway of communication between the brain and organs is established during development.

项目摘要 /摘要： 在开发过程中，中枢神经系统与身体建立了与身体的精确联系 坐标器官功能。大脑和身体之间这种交流的关键组成部分是迷走神经 神经（颅神经X），它支配了多个器官系统，包括心脏，肺和消化道 调节血压，心率，呼吸和消化。尽管这一重要作用，分子 引导迷走神经到这些器官靶标的机制仍然是完全未知的。我们已经发展了 斑马鱼的胚胎是询问迷走神经发育的强大模型，利用它 光学清晰度和遗传可及性。迷走神经由传输的两个上升感觉纤维组成 器官状态到大脑，并下降的电动机投影，向器官传递相互电动机命令。 迷走神经还靶向头部咽弓的肌肉，Moens实验室以前具有 描述了运动神经元在大脑中的位置与其目标之间的地形关系 Head，并发现了一种时空机制，以开发该地图。初步数据 我在这里表明，对器官的迷走运动投影也在地形上组织了 神经支配不同的器官（心脏，胃，肠道）的迷走神经神经元在空间上被隔离 后脑迷走核。我还观察到迷走运动的投影比他们的内脏更早 感觉对应物，导致我假设内脏需要正确的电机神经支配 随后的感觉神经。在这里，我建议通过以下目标解决这些假设。在 AIM 1，我将使用遗传工具以及实时成像和单细胞RNA测序来确定分子 机制将迷走运动神经元的子集引导到心脏和肠道。我将确定候选分子 （转录因子和细胞表面蛋白）确定躯体神经的地形组织 并使用反向遗传学测试这些候选者的作用。在AIM 2中，我将确定指导的机制 迷走性感觉神经元对适当的器官靶标，并测试感觉神经对 正确建立迷走运动神经支配。这项工作将揭示如何沟通的主要途径 在开发过程中建立了大脑和器官之间。