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: 10443804
• 负责人: STEPHEN Daniel LIBERLES
• 金额: $ 70.67万
• 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/10443804
• 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.

利用迷走运动神经元丰富的遗传多样性破译脑与肠道之间的通讯 运动迷走神经最初被认为是一个单一的实体--副交感神经休息的主臂和 摘要的回应。随着时间的推移，随着不同的迷走神经动作被发现，它开始被视为 许多功能离散的电机单元，它们本身是差异化调节的。事实上，神经元 起源于迷走神经背侧运动核(DMV)控制着大脑中至少三个不同的突起。 胃(胃酸的分泌、收缩和松弛)，胰腺有两种(外分泌和内分泌) 以及胆囊壁的收缩。同样，这些运动单位也受到许多输入的调节--由头 预计进食的信号，以准备肠道和身体的食物，并通过迷走神经和肠道 荷尔蒙通过迷走神经和内分泌迷走神经的反射，协调营养的消化和吸收。 然而，理解这一调节的神经基础的一个主要障碍是不知道它是如何 实际上存在许多功能离散的迷走神经运动单位，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电机单元。这些问题阻碍了这一领域的发展。 此多PI R01应用程序通过以下方式解决此问题：a)使用单细胞RNA分析来编目 DMV运动神经元的不同亚型，并识别指定每个亚型的遗传标记，b)通过 组装或产生“基因标记”-重组酶小鼠，使重组酶依赖于探索 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靶点 器官(S)和下游肠神经元(S)，每个DMV神经元在调节胃肠道生理中所起的作用，以及 DMV神经元亚型受中枢神经传入、迷走神经传入和激素的独特调节方式。 Lowell和Liberles实验室非常适合这项工作，因为他们的知识和技术领域 专业知识是高度相关的，也是非常互补的。洛厄尔实验室已经：a)初步发现 基因上不同的迷走运动神经元亚群(通过单细胞RNA测序)，b)正在将这种 向神经元亚型特异性重组酶小鼠提供信息，以及c)在使用重组酶小鼠方面具有专业知识 和重组酶依赖的技术来研究神经回路。另一方面，自由实验室 有：a)发现了功能和遗传上截然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)在处理迷走神经纤维的活动和评估对 胃肠生理学，以及c)初步发现了下游肠道的不同亚群 神经元。加在一起，洛厄尔和利伯勒斯的实验室已经做好了解除迷走神经运动功能的准备。