Leveraging the Rich Genetic Diversity of Vagal Motor Neurons to Decode Brain-to-Gut Communication

利用迷走神经运动神经元丰富的遗传多样性来解码脑肠通讯

• 批准号: 10206129
• 负责人: STEPHEN Daniel LIBERLES
• 金额: $ 71.74万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206129
• 关键词: Acetylcholine; Acids; Address; Affect; Afferent Neurons; Area; Assimilations; Back; Brain; Catalogs; Cells; Cephalic; Communication; Communities; Contracts; Digestion; Duodenum; Eating; Endocrine; Enteral; Feedback; Fiber; Food; Fundus; Future; Gallbladder; Gastrointestinal Physiology; Gene Expression Profile; Genes; Genetic; Genetic Engineering; Genetic Markers; Genetic Variation; Hormones; Investigation; Knowledge; Logic; Maps; Measures; Microscopy; Motor; Motor Neurons; Mus; Neurons; Neurosciences; Nutrient; Organ; Pancreas; Pancreatic Polypeptide; Parasympathetic Nervous System; Peptide YY; Physiological; Physiology; Play; Process; RNA; Rabies; Reflex action; Regulation; Relaxation; Rest; Role; Signal Transduction; Specific qualifier value; Stomach; Stretching; Technical Expertise; Technology; Time; arm; base; cholinergic neuron; dorsal motor nucleus; experience; genetic approach; mind control; motor control; mouse genetics; neural circuit; optogenetics; pancreatic juice; recombinase; relating to nervous system; response; single-cell RNA sequencing; tool; transcriptomics

Leveraging the Rich Genetic Diversity of Vagal Motor Neurons to Decode Brain-to-Gut Communication The motor vagus was originally treated as a single entity – the principal arm of the parasympathetic ‘rest and digest’ response. Over time, as diverse vagal actions were uncovered, it came to be viewed as a composite of many functionally discrete motor units, which are themselves differentially regulated. Indeed, neurons originating in the dorsal motor nucleus of the vagus (DMV) control at least three different processes in the stomach (secretion of acid, contraction and relaxation), two in the pancreas (exocrine and endocrine secretion) and also contraction of the gallbladder. Likewise, these motor units are regulated by many inputs – by cephalic signals that anticipate eating to prepare the gut and body for food, and by vagal sensory neurons and gut hormones that, via vago-vagal and endocrine-vagal reflexes, coordinate digestion and assimilation of nutrients. A major impediment to understanding the neural basis for this regulation, however, is that it is not known how many functionally discrete vagal motor units actually exist, and, more importantly, there is a lack of any means for selectively mapping and manipulating the different motor units. These issues have held the field back. This Multi-PI R01 application addresses this problem by: a) using single cell RNA profiling to catalogue the different subtypes of DMV motor neurons and identify genetic markers that specify each subtype, b) by assembling or generating “gene marker”-recombinase mice that enable recombinase-dependent exploration of the DMV neuron subtypes, and then c) by utilizing these mice to determine each neuron’s respective target organ(s) and downstream enteric neuron(s), the role each DMV neuron plays in regulating GI physiology, and the ways the DMV neuron subtypes are uniquely regulated by CNS afferents, vagal afferents and hormones. The Lowell and Liberles labs are ideally suited to this effort because their knowledge and areas of technical expertise are highly relevant, and also very complementary. The Lowell lab has: a) preliminarily discovered genetically distinct subsets of vagal motor neurons (via single cell RNA sequencing), b) is converting this information into neuron subtype-specific recombinase mice, and c) has expertise in using recombinase mice and recombinase-dependent technologies to investigate neural circuits. The Liberles lab, on the other hand has: a) discovered functionally and genetically distinct vagal sensory neurons – the afferent arms of the vago- vagal reflexes, b) has extensive experience with manipulating activity of vagal fibers and assessing effects on gastrointestinal physiology, and c) has preliminarily discovered distinct subsets of the downstream enteric neurons. Combined, the Lowell and Liberles labs are well poised to deconvolute vagal motor function.

利用迷走神经运动神经元丰富的遗传多样性来解码脑肠通讯 运动迷走神经最初被视为一个单一的实体——副交感神经“休息和休息”的主要臂。 摘要’的回应。随着时间的推移，随着各种迷走神经行为的被发现，它开始被视为以下行为的综合体： 许多功能上离散的运动单元，它们本身受到不同的调节。确实，神经元 起源于迷走神经背侧运动核 (DMV) 控制至少三个不同的过程 胃（酸的分泌，收缩和舒张），胰腺的两个（外分泌和内分泌分泌） 还有胆囊的收缩。同样，这些运动单位受到许多输入的调节——通过头侧 预期进食的信号，使肠道和身体为食物做好准备，并通过迷走感觉神经元和肠道 通过迷走神经和内分泌迷走神经反射协调营养物质的消化和同化的激素。 然而，理解这种调节的神经基础的一个主要障碍是，不知道如何 许多功能上离散的迷走神经运动单位实际上存在，更重要的是，缺乏任何手段 用于选择性地映射和操纵不同的运动单位。这些问题阻碍了该领域的发展。 该 Multi-PI R01 应用程序通过以下方式解决了这个问题：a) 使用单细胞 RNA 分析来对 DMV 运动神经元的不同亚型，并识别指定每种亚型的遗传标记，b) 组装或生成“基因标记”重组酶小鼠，使重组酶依赖性探索成为可能 DMV 神经元亚型，然后 c) 通过利用这些小鼠来确定每个神经元各自的目标 器官和下游肠神经元，每个 DMV 神经元在调节胃肠道生理学中所起的作用，以及 DMV 神经元亚型受 CNS 传入神经、迷走神经传入神经和激素的独特调节方式。 洛厄尔和利伯莱斯实验室非常适合这项工作，因为他们的知识和技术领域 专业知识高度相关，而且互补性很强。洛厄尔实验室已经：a）初步发现 遗传上不同的迷走运动神经元子集（通过单细胞 RNA 测序），b) 正在将其转化为 信息进入神经元亚型特异性重组酶小鼠，并且 c) 拥有使用重组酶小鼠的专业知识 以及依赖重组酶的技术来研究神经回路。另一方面，Liberles 实验室 已经：a）发现了功能和遗传上不同的迷走神经感觉神经元——迷走神经的传入臂 迷走神经反射，b）在操纵迷走神经纤维活动和评估对迷走神经纤维的影响方面拥有丰富的经验 胃肠道生理学，并且c）初步发现了下游肠的不同亚群 神经元。洛厄尔和利伯莱斯实验室相结合，已做好了解迷走神经运动功能的准备。