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的丰富遗传多样性来解码大脑与肠道的通信 运动迷走神经最初被视为一个单一的实体-副交感神经休息的主要手臂， Digest的回应。随着时间的推移，随着各种迷走神经活动被发现，它被视为一种复合物， 许多功能上离散的运动单元，其本身是差分调节的。事实上， 起源于迷走神经背侧运动核（DMV）的神经元控制着中枢神经系统中至少三个不同的过程。 胃（分泌酸，收缩和放松），两个在胰腺（外分泌和内分泌） 还有胆囊的收缩同样，这些运动单位也受到许多输入的调节--头神经 信号，预期吃准备肠道和身体的食物，并通过迷走神经感觉神经元和肠道 通过迷走神经-迷走神经反射和内分泌-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， 实际上存在许多功能上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运动单元。这些问题阻碍了该领域的发展。 该Multi-PI R 01应用通过以下方式解决了该问题：a）使用单细胞RNA谱分析来对 DMV运动神经元的不同亚型，并鉴定指定每种亚型的遗传标记，B）通过 组装或产生“基因标记”-重组酶小鼠，其能够依赖于重组酶探索 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的各自靶点 器官和下游肠神经元，每个DMV神经元在调节GI生理学中发挥的作用，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独特调节的方式。 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 专业知识具有高度相关性，也具有很强的互补性。洛厄尔实验室已经：a）初步发现 迷走神经运动神经元的遗传上不同的子集（通过单细胞RNA测序），B）正在转换这种 将信息输入神经元亚型特异性重组酶小鼠，以及c）具有使用重组酶小鼠的专业知识 和重组酶依赖技术来研究神经回路。另一方面， 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 胃肠道生理学，以及c）已经初步发现了下游肠道生理学的不同子集， 神经元结合起来，洛厄尔和利伯勒斯实验室已经准备好去卷积迷走神经运动功能。