Neuronal Excitability and Motility in Colitis

肠壁中的神经元控制肠道对摄入的食物的反应；它们还调节 消化、养分吸收和废物消除的过程。炎症性肠病(IBD) 肠道功能的各种特征，包括运动、分泌和敏感性都会改变。作为大脑中的神经细胞 肠道调节所有这些功能，很可能是这些神经元的变化导致了 受苦受难的人所经历的痛苦。在过去的三年里，我们评估了炎症- 以循序渐进的方式引起结肠回路的变化，我们已经确定了基本的 特别是三个部位的变化：(1)粘膜层5-羟色胺的可获得性增加；(2)固有的 感觉神经元的超兴奋性；(3)神经元之间突触信号的易化。建议数 实验旨在阐明这些变化背后的机制，以及这些变化是如何 影响结肠动力，以及炎症恢复后持续的变化。在具体目标1中，我们 将使用电生理学和分子方法来测试内在感觉神经元的假设 超兴奋性涉及中间电导、钙激活的K~*通道和钙通道的下调 上调超极化激活的阳离子通道。在具体目标2中，我们将使用电生理学 和电子显微镜通过检测突触易化的变化来研究突触易化的机制 肌间突触前神经递质释放、突触后敏感性和神经末梢密度 神经丛。在具体目标3中，我们将研究结肠蠕动、时空运动模式和 神经肌肉反应，以确定哪些炎症引起的反射回路变化起作用 结肠动力的改变以及这种改变是如何发生的。在特定的目标4中，我们将测试炎症诱导的 神经可塑性和相关的运动性变化持续到炎症恢复后。这样的变化 不会被标准的诊断程序检测到，并可能是肠道功能在 炎症性肠病和炎症性肠易激综合征(IBS)的缓解。一个 将使用一系列技术，包括细胞内电压和电流记录，实时定量 聚合酶链式反应、电子显微镜和数字增强型动力分析。通过这种方式，我们将 提供发炎结肠中神经传递的独特、集成/翻译视图。调查结果： 这些研究都是高度可行的，将增进我们对病理生理学的理解。 发炎的结肠，他们将提高我们对IBS的理解。

Neurons in the wall of the intestine control how the gut reacts to an ingested meal; they also regulate the processes of digestion, nutrient absorption, and waste elimination. In inflammatory bowel disease (IBD), various features of gut function, including motility, secretion and sensitivity are altered. As nerve cells of the bowel regulate all of these functions, it is likely that changes in these neurons cause the symptoms that lead to the suffering experienced by afflicted individuals. In the past 3 years, we have evaluated inflammation- induced changes along the circuitry of the colon in a step-wise fashion, and we have identified fundamental changes at three sites in particular: (1) increased serotonin availability in the mucosal layer; (2) intrinsic sensory neuron hyperexcitability; and (3) facilitation of synaptic signals between neurons. The proposed experiments are designed to elucidate the mechanisms that underlie these changes, how these changes affect colonic motility, and what changes persist following recovery from inflammation. In specific aim 1, we will use electrophysiology and molecular approaches to test the hypothesis that intrinsic sensory neuron hyperexcitability involves down-regulation of intermediate conductance, Ca2+-activated K* channels and an up-regulation of hyperpolarization-activated cation channels. In specific aim 2, we will use electrophysiology and electron microscopy to investigate the mechanisms of synaptic facilitation by testing for changes in presynaptic neurotransmitter release, postsynaptic sensitivity and nerve terminal density in the myenteric plexus. In specific aim 3, we will study colonic peristalsis, spatiotemporal motility patterns and neuromuscular responses to determine which inflammation-induced changes in the reflex circuitry contribute to altered colonic motility and how this occurs. In specific aim 4, we will test whether inflammation-induced neuroplasticity and related changes in motility persist beyond recovery from inflammation. Such changes would be undetectable by standard diagnostic procedures, and could underlie altered gut function during remission from inflammatory bowel disease and in post-inflammatory irritable bowel syndrome (IBS). An array of techniques will be used, including intracellular voltage and current recordings, real time quantitative polymerase chain reaction, electron microscopy, and digitally enhanced motility assays. In this way, we will provide a unique, integrated/translational view of neurotransmission in the inflamed colon. The findings of these investigations, all of which are highly feasible, will enhance our understanding of the pathophysiology of the inflamed colon, and they will improve our comprehension of IBS.