Neurobiology of Intrinsic Primary Afferent Neurons

内在初级传入神经元的神经生物学

• 批准号: 10477437
• 负责人: David R. Linden
• 金额: $ 55.8万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477437
• 关键词: Address; Afferent Neurons; Animal Model; Axon; Blood Vessels; Cavia; Cells; Chemical Stimulation; Chemicals; Cholecystokinin; Code; Colon; Consensus; Data; Diagnostic; Diagnostic Procedure; Digestive System Disorders; Disease; Drug Targeting; Electrophysiology (science); Enteral; Enteric Nervous System; Environment; Epithelial; Future; Ganglia; Gastrointestinal Physiology; Gastrointestinal tract structure; Health; Hormonal; Human; Inflammatory; Inflammatory Bowel Diseases; Intelligence; Interneurons; Intestines; Ion Channel; Ion Transport; Knowledge; Mechanical Stimulation; Mechanics; Mediating; Molecular; Morphology; Motor; Motor Neurons; Mucous Membrane; Mus; Muscle; Nerve; Neurobiology; Neuronal Plasticity; Neurons; Neuropeptides; Nutrient; Physiological; Physiology; Process; Publishing; Reflex action; Reporter; Reporting; Role; Sensory; Series; Stimulus; Stretching; Structure; Testing; Therapeutic; Tissues; Vertebrates; afferent nerve; body system; design; experimental study; gastrointestinal function; innovation; jejunum; mechanical stimulus; motility disorder; nerve supply; neuroregulation; neurotransmission; receptive field; relating to nervous system; response; transcriptome; uptake

Project Summary / Abstract The gastrointestinal (GI) tract is the only organ system that is capable of intrinsic neural reflexes. These are initiated by a unique neuron type called intrinsic primary afferent neurons (IPANs). IPANs are key to orchestrating neural reflexes that allow efficient processing of meals for nutrient uptake by rapidly adapting to changing luminal content to alter vascular, secretory and motor function. In the guinea pig, IPANs use multiple mechanisms of neuroplasticity to adapt to inflammatory, hormonal and neural stimuli. From these studies it is clear that IPAN neuroplasticity mediates digestive disease. Even though the mouse has become the vertebrate animal model of choice for digestive disease, murine IPANs have lacked consensus markers making precise studies of mouse IPANs inconceivable. These issues are now resolved by our recent transcriptome and morphological analysis of the ENS, which challenges the dogma that IPANs are a single class of neuron, and suggest that rather there are four classes of IPANs. In combination with recent advances in morphological (i.e. tissue clearing) and physiological approaches (i.e. genetically-encoded markers and activity indicators) we are now able to study mouse IPANs in a relatively high throughput manner. The objective of this proposal is to test the overall hypothesis that different classes of IPANs possess morphologies and physiology that uniquely contribute to intestinal function. This hypothesis will be tested in a series of experiments designed to address three specific aims: Specific Aim 1: determine the structure of receptive fields and connectivity of murine IPANs; Specific Aim 2: determine responses of murine IPANs to mechanical and chemical stimuli; Specific Aim 3: determine the role of IPANs in gastrointestinal physiology. Collectively, these studies address a critical gap in our knowledge on the basic neural control of gut functions. Deciphering sensory capabilities and functional responses of molecularly defined IPANs are likely to pave the way for future improvements in diagnostic and therapeutic strategies of digestive disease.

项目概要/摘要 胃肠道（GI）是唯一能够进行内在神经反射的器官系统。这些都是 由一种称为内在初级传入神经元（IPAN）的独特神经元类型发起。 IPAN 是关键 协调神经反射，通过快速适应来有效处理膳食以吸收营养 改变管腔内容物以改变血管、分泌和运动功能。在豚鼠中，IPAN 使用多种 适应炎症、激素和神经刺激的神经可塑性机制。从这些研究来看 明确 IPAN 神经可塑性介导消化系统疾病。尽管老鼠已经成为脊椎动物 作为消化系统疾病的首选动物模型，小鼠 IPAN 缺乏共识标记，无法精确确定 对小鼠 IPAN 的研究是不可思议的。这些问题现已通过我们最近的转录组和 ENS 的形态学分析，挑战了 IPAN 是单一类别神经元的教条，以及 建议 IPAN 有四类。结合形态学的最新进展（即 组织清除）和生理方法（即基因编码标记和活动指标） 现在能够以相对高通量的方式研究小鼠 IPAN。该提案的目的是测试 总体假设是不同类别的 IPAN 具有独特的形态和生理学 有助于肠道功能。这一假设将在一系列旨在解决问题的实验中得到检验 三个具体目标： 具体目标 1：确定小鼠感受野的结构和连通性 IPAN；具体目标 2：确定小鼠 IPAN 对机械和化学刺激的反应；具体目标 图3：确定IPAN在胃肠道生理学中的作用。总的来说，这些研究解决了一个关键差距 我们对肠道功能的基本神经控制的了解。解读感官能力和功能 分子定义的 IPAN 的反应可能为未来诊断和治疗的改进铺平道路。 消化系统疾病的治疗策略。