Regulation of enteric motor neurocircuits by enteric glia in health and disease

项目摘要 肠的反射性运动行为包括痉挛是由肠神经系统控制的 (ENS)一个嵌入肠壁的复杂神经网络。ENS内的扰动有助于 肠易激综合征、炎症性肠病和重度动力障碍的发生 疾病，如慢性假性肠梗阻，但机制负责持续 肠神经回路的变化是未知的。最近的数据表明，肠神经胶质细胞，非神经元细胞， 包围肠神经元，调节神经元兴奋性并促进神经炎症。总目标 这项建议的目的是确定肠神经胶质细胞和神经元之间的专门相互作用如何调节运动性， 这些机制的改变如何导致疾病这一提议检验了中心假设， 肠神经胶质细胞是专门加强活动的上行兴奋性神经通路参与正常 收缩运动，以及炎症对这种调节系统的破坏有助于神经元的 兴奋过度这一双重假设将在两个具体的目标，利用基因编码测试 研究神经元-胶质细胞相互作用的钙指示剂，研究胶质细胞如何调节 特定类型的肠神经元，以及肠神经可塑性的炎症后模型，以研究神经胶质细胞 导致炎症后神经元过度兴奋。目的1将检验肠神经胶质细胞 是专门用于感觉兴奋性神经元和增强上行神经通路参与 运动的收缩期目标1.1将使用基因编码的钙指示剂来研究神经胶质细胞的募集 运动反射中的极化神经通路。目的1.2将联合收割机与肠上皮细胞的化学活化结合起来， 神经胶质与神经元和神经胶质成像使用遗传编码的钙指标，以测试假设，神经胶质 不同地影响肠神经元的子集。目的2将验证胶质细胞参与神经元细胞凋亡的假设。 通过增加对兴奋性神经元的正反馈和通过减少结肠炎后的过度兴奋 来自抑制性神经元的抑制性反馈。Aim 2.1将研究神经胶质细胞和 兴奋性神经元导致结肠炎后神经元过度兴奋。Aim 2.2将使用突变小鼠， 选择性药物，研究胶质细胞如何通过与抑制剂的相互作用促进神经元过度兴奋 神经元本研究的结果将为神经胶质细胞调节兴奋性的机制提供新的见解 肠神经回路的结构更好地理解调节运动的神经胶质机制将有助于 通过揭示改变胃肠反射的新靶点来开发运动障碍的治疗方法。

PROJECT SUMMARY Reflexive motor behaviors of the intestine including peristalsis are controlled by the enteric nervous system (ENS); a complex neural network embedded in the gut wall. Perturbations within the ENS contribute to the development of dysmotility in irritable bowel syndrome, inflammatory bowel disease, and severe motility disorders such as chronic intestinal pseudo-obstruction, but the mechanisms responsible for persistent changes in enteric neural circuitry are unknown. Recent data show that enteric glia, non-neuronal cells that surround enteric neurons, regulate neuronal excitability and contribute to neuroinflammation. The overall goal of this proposal is to define how specialized interactions between enteric glia and neurons regulate motility and how alterations in those mechanisms contribute to disease. This proposal tests the central hypothesis that enteric glia are specialized to potentiate the activity of ascending excitatory neural pathways involved in normal contractile motility, and that disruption of this regulatory system by inflammation contributes to neuronal hyperexcitability. This dual hypothesis will be tested in two specific aims that utilize genetically encoded calcium indicators to study neuron-glia interactions, glial chemogenetic actuators to study how glia modulate specific types of enteric neurons, and a post-inflammatory model of enteric neuroplasticity to study how glia contribute to neuronal hyperexcitability following inflammation. Aim 1 will test the hypothesis that enteric glia are specialized to sense excitatory neurons and potentiate ascending neural pathways involved in the contractile phase of motility. Aim 1.1 will use genetically encoded calcium indicators to study glial recruitment by polarized neural pathways in motility reflexes. Aim 1.2 will combine the chemogenetic activation of enteric glia with neuronal and glial imaging using genetically encoded calcium indicators to test the hypothesis that glia differentially affect subsets of enteric neurons. Aim 2 will test the hypothesis that glia contribute to neuronal hyperexcitability following colitis by increasing positive feedback to excitatory neurons and by reducing inhibitory feedback from inhibitory neurons. Aim 2.1 will study how altered interactions between glia and excitatory neurons contribute to neuronal hyperexcitability following colitis. Aim 2.2 will use mutant mice and selective drugs to study how glia contribute to neuronal hyperexcitability through interactions with inhibitory neurons. The results of this study will provide novel insight into glial mechanisms that regulate the excitability of enteric neural circuits. A better understanding of the glial mechanisms that regulate motility will facilitate the development of therapeutics for dysmotility by revealing novel targets to modify gastrointestinal reflexes.