CONTROL OF MOTILITY IN THE SPHINCTER OF ODDI

这项研究的总体目标是确定括约肌Oddi(SO)如何 功能可以由调节SO活动的输入来调节 神经元。了解SO功能的调节具有临床意义 重要的是，大约15%的美国人口患有疾病 胆道系统的功能障碍是导致 与胆道疾病相关的发病率。我们的战略是让 使用新设计的技术组合来确定 SO神经元的兴奋性是调制的，并识别其调节的 驱动和调节这些细胞的输入。越来越多的证据表明 最初被认为是不同的亚群的 神经元(张力型和相型)实际上是两种电学表型， 同样的，神经元也可以表达。第一个具体目标是建立 导致神经元改变其功能的细胞机制 电生理表型介于可兴奋(强直)和少得多之间 可兴奋(相)模式，以及哪些生理信号可以启动 这些班次。我们将测试新的假设，即神经激素的输入 可以作用于这些细胞来上调和/或下调钾电导 抑制神经元的兴奋性，而这些变化发生在 与进食周期同步。这种形式的表现性，它将 在神经元中进行评估，可能以类似的方式发生在神经元中 遍及整个胃肠道。第二个具体目标是测试 粘膜CCK释放可激活SO神经元的假说 通过十二指肠和SO之间的神经网络。一个神经元&gt；so 将使用逆行示踪剂确认投影并确定其特征 免疫组织化学。双腔管风琴将被用来 确定是否激活十二指肠肌间神经丛和药剂 释放CCK，引起SO中神经元活性增加。这个 第三个具体目标是确定兴奋性的起源和介体 SO神经元的突触输入。要了解局部神经元是如何控制 它们的效应器组织靶标，至关重要的是识别驱动和 这些神经元接收到的调制信号。目标3的研究将 包括电生理记录和免疫组织化学，在 结合选择性损伤和药理分析， 确定可以对其进行监管的投入的来源和中介 功能。 提案研究是高度可行的，并有望推动我们的 了解神经激素对括约肌功能的控制。如果我们的 理论是确凿的，这些研究将阐明 SO功能外在控制的贡献者，展示了新的 括约肌调节的机制，并质疑神经元 有固定的电生理表型。

The overall goal of this study is to determine how sphincter od Oddi (SO) function can be regulated by inputs which modulate the activity of SO neurons. Understanding the regulation of SO function is clinically important as approximately 15% of the US population suffers from disease of the biliary system, and SO malfunction is a major contributor to morbidity associated with biliary tract disease. Our strategy is to make use of newly devised combinations of techniques to determine how the excitability of SO neurons is modulated, and to identify the regulatory inputs that drive and modulate these cells. Mounting evidence suggests that what were originally though of as distinct subpopulations of SO neurons (Tonic and Phasic) are actually two electrical phenotypes that the same SO neuron can express. The first specific aim is to establish the cellular mechanisms that cause SO neurons to changes their electrophysiological phenotype between excitable (tonic) and much less excitable (phasic) modes, and what physiological signals could initiate these shifts. We will test the novel hypothesis that neurohormonal inputs can act on these cells to up-and/or down-modulate a potassium conductance that inhibit neuronal excitability, and that these changes occur in synchrony with the feeding cycle. This form of phenopasticity, which will be evaluated in SO neurons, could occur in a similar manner in neurons throughout the gastrointestinal tract. The second specific aim is to test the hypothesis that SO neurons can be activated by mucosal CCK release through a neural internet between the duodenum and the SO. A neuron>SO projection will be confirmed and characterized with retrograde tracers and immunohistochemistry. A double chamber organ both will be used to determine whether activation of the duodenal myenteric plexus and agents that release CCK, cause and increase in neuronal activity in the SO. The third specific aim is to identify the origins and mediators of excitatory synaptic inputs to the SO neurons. To understand how local neurons control their effector tissue targets, it is crucial to identify the driving and modulatory signals received by those neurons. The studies of aim 3 will involve electrophysiological recording and immunohistochemistry, in combination with selective lesions and pharmacological analysis, to determine the origins and mediators of inputs that can regulate SO function. The proposal studies are highly feasible and promise to advance our understanding of the neurohormonal control of sphincter function. If our theories are substantiated, these studies will elucidate the major contributors of extrinsic control of SO function, demonstrate novel mechanisms of sphincter regulation, and question the dogma that a neuron has fixed electrophysiological phenotype.