Neurobiology of Intrinsic Primary Afferent Neurons

项目摘要/摘要 胃肠道(GI)是唯一能够进行内源性神经反射的器官系统。这些是 由一种独特的神经元类型启动，称为内源性初级传入神经元(IPANs)。IPAN是关键 协调神经反射，通过快速适应来有效地处理食物以吸收营养 改变管腔内容物以改变血管、分泌和运动功能。在豚鼠中，IPAN使用多个 神经可塑性适应炎症、激素和神经刺激的机制。从这些研究来看， 明确IPAN神经可塑性调节消化系统疾病。即使老鼠已经变成了脊椎动物 作为消化系统疾病首选的动物模型，小鼠的IPAN缺乏一致的标记物来准确地 对小鼠IPAN的研究是不可想象的。这些问题现在通过我们最近的转录组和 对神经元的形态分析，挑战了iPAN是一类单一神经元的教条，以及 相反，建议将IPAN分为四类。结合最新的形态(即 组织清除)和生理方法(即，遗传编码的标记和活动指示器) 现在能够以相对高通量的方式研究鼠标IPAN。这项提议的目标是测试 认为不同类别的IPAN具有独特的形态和生理特征的总体假设 有助于肠道功能。这一假设将在一系列旨在解决以下问题的实验中得到验证 三个特定目标：特定目标1：确定小鼠感受野的结构和连接性 IPANs.特定目标2：测定小鼠IPANs对机械和化学刺激的反应 3：确定IPANs在胃肠道生理学中的作用。总体而言，这些研究解决了一个关键差距 在我们对肠道功能的基本神经控制的知识中。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.