Neurobiology of Intrinsic Primary Afferent Neurons

项目总结/摘要 胃肠道（GI）是唯一能够进行内在神经反射的器官系统。这些是 由一种独特的神经元类型发起，称为内在初级传入神经元（IPAN）。IPAN是 协调神经反射，通过快速适应 改变管腔内容物以改变血管、分泌和运动功能。在豚鼠中，IPAN使用多个 神经可塑性机制，以适应炎症，激素和神经刺激。从这些研究来看， 明确IPAN神经可塑性介导消化系统疾病。即使老鼠已经变成了脊椎动物 作为消化系统疾病的动物模型选择，鼠IPAN缺乏一致的标志物， 对小鼠IPAN的研究是不可思议的。我们最近的转录组解决了这些问题， ENS的形态学分析，它挑战了IPAN是单一类别神经元的教条， 这表明IPAN有四种类型。结合形态学的最新进展（即 组织清除）和生理学方法（即遗传编码的标记物和活性指示物）， 现在能够以相对高通量的方式研究小鼠IPAN。本提案的目的是测试 不同类别的IPAN具有独特的形态学和生理学， 有助于肠道功能。这一假设将在一系列旨在解决 三个具体目标：具体目标1：确定小鼠感受野的结构和连接 IPAN;特异性目标2：确定小鼠IPAN对机械和化学刺激的反应;特异性目标 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， 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。

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.