Neurobiology of Intrinsic Primary Afferent Neurons

内在初级传入神经元的神经生物学

• 批准号: 10654779
• 负责人: David R. Linden
• 金额: $ 55.62万
• 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/10654779
• 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); Endowment; Enteral; Enteric Nervous System; Environment; Epithelium; Experimental Designs; 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; Myenteric Plexus; Nervous System; Neurobiology; Neuronal Plasticity; Neurons; Neuropeptides; Nutrient; Physiological; Physiology; Process; Publishing; Reflex action; Reporter; Reporting; Role; Sensory; Series; Stimulus; Stretching; Structure; Submucosa; Testing; Therapeutic; Tissues; Vertebrates; afferent nerve; body system; experimental study; gastrointestinal function; improved; innovation; jejunum; mechanical stimulus; motility disorder; nerve supply; neural; neural initiation; neuroregulation; neurotransmission; receptive field; 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.

项目摘要 /摘要 胃肠道（GI）道是唯一能够具有内在神经反射的器官系统。这些都是 由独特的神经元类型发起，称为固有的原发性传入神经元（IPAN）。 ipans是关键 策划神经反射，通过迅速适应饮食有效地加工餐食以摄取营养。 更改腔内含量以改变血管，分泌和运动功能。在豚鼠中，ipans使用多个 神经塑性的机制适应炎症，激素和神经刺激。从这些研究是 清楚地表明，IPAN神经可塑性介导了消化系统疾病。即使鼠标已成为脊椎动物 消化疾病首选的动物模型，鼠缺乏确定的共识标记 小鼠IPAN的研究不可思议。这些问题现在通过我们最近的转录组和 对ENS的形态分析，这挑战了IPAN是一类神经元的教条，并且 建议有四类的IPAN。结合形态学的最新进展（即 组织清除）和生理方法（即遗传编码的标记和活动指标）我们是 现在能够以相对较高的吞吐量研究鼠标IPAN。该建议的目的是测试 不同类别的IPAN具有形态和生理学的总体假设是独特的 有助于肠道功能。该假设将在旨在解决的一系列实验中进行检验 三个特定目的：特定目标1：确定接收场的结构和鼠的连通性 ipans;具体目标2：确定鼠IPAN对机械和化学刺激的反应；具体目标 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的差距 根据我们对肠道功能的基本神经控制的了解。解密的感觉功能和功能 分子定义的IPAN的响应可能为诊断和未来改善的道路铺平了道路 消化疾病的治疗策略。