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： 在发育过程中，中枢神经系统与身体建立精确的连接， 协调器官功能。大脑和身体之间交流的一个重要组成部分是迷走神经 神经（脑神经 X），支配多个器官系统，包括心脏、肺和消化道 调节血压、心率、呼吸和消化。尽管具有如此重要的作用，分子 引导迷走神经到达这些器官目标的机制仍然完全未知。我们开发了 斑马鱼胚胎作为研究迷走神经发育的强大模型，利用其 光学清晰度和遗传可及性。迷走神经由两条上行感觉纤维组成，传输信息 大脑的器官状态，以及向器官传递相互运动命令的下行运动投射。 迷走神经还针对头部的咽弓衍生肌肉，莫恩斯实验室此前曾研究过 描述了大脑中运动神经元的位置与其目标之间的拓扑关系 头，并发现了开发这张地图的时空机制。初步数据 我在这里展示了迷走神经运动对器官的投射也是按地形组织的，其中 支配不同器官（心脏、胃、肠）的迷走神经运动神经元在空间上是分离的 后脑迷走神经核。我还观察到迷走神经运动投射比它们更早地到达内脏。 感觉对应物，使我假设内脏的正确运动神经支配是 随后的感觉神经支配。在这里，我建议通过以下目标来解决这些假设。在 目标 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 引导迷走运动神经元亚群到达心脏和肠道的机制。我将确定候选分子 （转录因子和细胞表面蛋白）确定躯体神经支配的地形组织 并使用反向遗传学测试这些候选者的作用。在目标2中，我将确定指导机制 迷走神经感觉神经元到适当的器官目标并测试感觉神经支配对 迷走神经运动神经支配的正确建立。这项工作将揭示沟通的主要途径 大脑和器官之间的联系是在发育过程中建立的。