Anatomical and Functional Characterization of Gastrointestinal to Spinal Cord Circuits

胃肠道至脊髓回路的解剖学和功能特征

• 批准号: 10676125
• 负责人: Zachary McKenzie
• 金额: $ 3.55万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676125
• 关键词: Adult; Afferent Neurons; Anatomy; Axon; Calcitonin Gene-Related Peptide; Capsaicin; Central Nervous System; Chemicals; Child; Colon; Communication; Computer software; Confocal Microscopy; Data; Dependovirus; Distal; Electrodes; Electrophysiology (science); Esthesia; Exhibits; Gastrointestinal Contents; Gastrointestinal Diseases; Gastrointestinal Motility; Gastrointestinal Process; Gastrointestinal tract structure; Genetic; Genetic Markers; Goals; Histology; Image; Injections; Interneurons; Ion Channel; Irritants; Label; Link; Manuals; Mechanics; Methods; Modality; Morphology; Mus; Nervous System; Neurons; Operative Surgical Procedures; Organ; Pain; Pain Disorder; Painless; Pattern; Peripheral; Piezo 2 ion channel; Population; Preparation; Presynaptic Terminals; Property; Quality of life; Research; Role; Sensory; Signal Transduction; Sorting; Spinal Cord; Spinal Ganglia; Spinal cord posterior horn; Stimulus; Stretching; Structure; Synapses; Tissues; United States; Viral; Viscera; Wild Type Mouse; colon distension; dorsal column; dorsal horn; experimental study; gastrointestinal; gastrointestinal function; in vivo; insight; microbial; mouse genetics; multi-electrode arrays; nerve supply; neural circuit; neurotransmission; new therapeutic target; novel; open source; optogenetics; postsynaptic; presynaptic; programs; response; transmission process

Project Summary/Abstract: Viscerosensation is the communication between internal organs and the nervous system. Viscerosensory signals are transmitted from the gastrointestinal (GI) tract to the central nervous system by both vagal and dorsal root ganglia (DRG) neurons. While vagal innervation of the GI tract is considerably well-studied, far less is known about GI-innervating DRG neurons. Colon-innervating DRG neurons are critical for normal GI function. These neurons detect the chemical/gut microbial contents of the GI tract, modulate long- range control of GI motility, and are responsible for transmitting innocuous (non-painful) and noxious (painful) sensations from the GI tract. Recent studies have identified five major subtypes of colon-innervating DRG neurons, defined by their anatomical innervation patterns in the colon and ex vivo responses to stimuli. Colon-innervating DRG neurons transmit GI-relevant information to the spinal cord. These neurons project to multiple laminae of the spinal cord dorsal horn and are proposed to transmit information from the GI tract to a range of spinal cord interneurons and projection neurons, including postsynaptic dorsal column (PSDC) projection neurons. However, few studies have explored the anatomical organization of colon-innervating DRG neuron central arbors in the spinal cord. Further, a comprehensive understanding of the spinal cord neuron types to which colon-innervating DRG neurons send their diverse signals has yet to be explored. Finally, few studies have investigated the in vivo responses of spinal cord neurons across dorsal horn laminae to non-painful and painful GI stimuli. The goal of this proposal is to characterize the central morphologies and postsynaptic partners of colon- innervating DRG neurons. I hypothesize that colon-innervating DRG neuron central arbors will form distinct morphological subtypes based on the types of sensory information they transmit. I predict that colon-innervating DRG neurons that express the mechanosensitive ion channel, Piezo2, will project to deeper laminae of the dorsal horn to transmit innocuous sensations to multiple spinal cord neuron types. Conversely, I predict that peptidergic, colon-innervating DRG neurons that express the alpha form of Calcitonin Gene-Related Peptide (Calca) will transmit painful stimuli to laminae I/II interneurons. I further hypothesize that PSDC neurons will receive innocuous and noxious sensory information from the colon, through direct and indirect connections with colon- innervating DRG neurons. Using conditional mouse genetics, surgical, viral labeling, imaging, optogenetic and in vivo electrophysiological approaches, I will: 1) characterize the central arbors and postsynaptic partners of colon-innervating DRG neuron types in the spinal cord, and 2) identify the in vivo response properties of spinal cord neurons to innocuous and noxious colon stimuli. These experiments will advance our fundamental understanding of DRG to spinal cord circuits responsible for detecting, transmitting, and processing sensations from the colon. This research will provide critical insight, and may identify novel therapeutic targets, for GI pain.

项目总结/摘要：内脏感觉是内脏与神经之间的交流 系统内脏感觉信号从胃肠道（GI）传输到中枢神经系统 迷走神经和背根神经节（DRG）神经元。虽然胃肠道的迷走神经支配是相当重要的 尽管研究得很好，但对GI支配DRG神经元的了解却少得多。结肠神经支配DRG神经元是至关重要的 正常的胃肠道功能这些神经元检测胃肠道的化学/肠道微生物内容物，调节长- 范围控制胃肠道运动，并负责传输无害（无痛）和有毒（疼痛） 胃肠道的感觉 最近的研究已经确定了结肠神经支配DRG神经元的五种主要亚型，其定义如下： 结肠中的解剖学神经支配模式和对刺激的离体反应。结肠支配DRG神经元 将GI相关信息传递到脊髓。这些神经元投射到脊髓的多个板层 背角，并提出从胃肠道传递信息到一系列脊髓中间神经元， 投射神经元，包括突触后背柱（PSDC）投射神经元。然而，很少有研究 探讨了结肠神经支配的DRG神经元在脊髓中的中枢动脉的解剖组织。此外，本发明还 对结肠神经支配DRG神经元发送的脊髓神经元类型的全面了解 它们的各种信号尚待探索。最后，很少有研究调查脊髓损伤的体内反应。 脊髓神经元跨越背角板层的无痛和疼痛的GI刺激。 这项建议的目标是描述结肠的中央形态和突触后伙伴， 支配DRG神经元。我假设结肠神经支配DRG神经元中枢动脉将形成不同的 基于它们传递的感觉信息的类型的形态亚型。我预测结肠神经 表达机械敏感性离子通道Piezo 2的DRG神经元将投射到背侧皮层的更深层。 角传递无害的感觉到多种脊髓神经元类型。相反，我预测肽能， 表达降钙素基因相关肽（Calca）α形式的结肠神经支配DRG神经元将 传递疼痛刺激到I/II层中间神经元。我进一步假设PSDC神经元将接受 来自结肠的无害和有害的感觉信息，通过与结肠的直接和间接连接， 支配DRG神经元。使用条件小鼠遗传学、手术、病毒标记、成像、光遗传学和免疫学， 在体内电生理方法中，我将：1）表征中枢神经系统的中枢和突触后伙伴， 脊髓中结肠神经支配DRG神经元类型，以及2）鉴定脊髓中结肠神经支配DRG神经元的体内响应特性。 脊髓神经元对无害和有害的结肠刺激的反应。这些实验将推进我们的基本 了解背根神经节到脊髓回路，负责检测、传递和处理感觉 从结肠。这项研究将提供关键的见解，并可能确定新的治疗目标，胃肠道疼痛。