COORDINATION OF MOTILITY AND SECRETION

肠道感染和炎症通常与胃肠道运动和分泌紊乱有关。常见的症状之一是腹泻。在这些疾病状态下，肠神经系统和间质细胞网络发生的结构和功能改变可能导致肠功能的长期紊乱。为了了解神经网络是如何被编程来调节肌肉收缩和分泌的，我们将在正常豚鼠的结肠中研究以下具体目标。首先是确定当刺激是粘膜抚摸时，协调肌肉收缩和分泌的神经通路。目前的研究主要集中在反射的传入肢和传出肢。它们包括确定内源性和外源性5-羟色胺在协调肌肉收缩和分泌中的作用，确定唤起或解除粘膜下和肌肠神经节之间突触传递的药理药物，以及确定内在传入神经元的神经化学和电生理特性。第二个目的是确定在组胺刺激下协调重复收缩和重复分泌的神经通路。计划中的研究包括确定介导组胺作用的细胞结构，以及分析神经和间质细胞网络中兴奋的传播。使用的方法包括刷子机制，在体外全组织制备中，激活内在神经反射，同时记录应变计张力和短路电流。这些方法将补充活体组织的原位激光共聚焦成像，并将结合电生理学、形态学、免疫组织化学和神经元逆行标记，以获得整个肠神经丛和间质细胞网络的钙信号的空间分析。这些新方法有望为肠神经系统和间质细胞网络与肌肉和上皮细胞的相互作用提供新的信息。这些研究将为两种不同功能的整合提供新的见解，肌肉收缩和上皮分泌是推动和润滑肠道内容物所必需的。此外，它们可以确定用于治疗腹泻的治疗药物作用的潜在靶点。

Enteric infections and inflammation are often associated with disturbances in gastrointestinal motility and secretion. One of the common symptoms is diarrhea. Structural and functional alterations, which occur in the enteric nervous system and interstitial cell networks in these disease states, may lead to long term disturbances in intestinal function. In order to gain an understanding of how the neural networks are programmed to regulate muscle contraction and secretion, the following specific aims will be addressed in the colon of normal guinea pigs. The first is to determine the neural pathways that coordinate muscle contraction with secretion when the stimulus is mucosal stroking. Proposed studies focus on the afferent and efferent limbs of the reflex. They include determination of the role of endogenous and exogenous 5-HT in coordinating muscle contraction and secretion, on pharmacological drugs to evoke or uncouple synaptic transmission between submucosal and myenteric ganglia and on the neurochemical and electrophysiological identity of intrinsic afferent neurons. The second aim is to determine the neural pathways coordinating repetitive contraction and repetitive secretion when the stimulus is histamine. Planned studies include identification of the cellular structures mediating histamine's effects and analysis of the spread of excitation through neural and interstitial cell networks. Methodologies to be used include a brush mechanism, in an in vitro whole tissue preparation, to activate intrinsic neural reflexes while recording strain gauge tension and short circuit current simultaneously. These methods will complement in situ laser confocal imaging of living tissues and will be combined with electrophysiology, morphology, immunohistochemistry and retrograde labeling of neurons to obtain a spatial analysis of calcium signals throughout the enteric nerve plexus and network of interstitial cells. These novel approaches are expected to provide new information on interactions of the enteric nervous system and interstitial cell network with muscle and epithelial cells. These studies should provide new insights into integration of two diverse functions, muscle contraction and epithelial secretion, necessary for propelling and lubricating the intestinal contents. Furthermore, they may identify potential targets for the action of therapeutic drugs used in the treatment of diarrhea.