Multisensory Integration Producing Nausea and Vomiting

项目概要/摘要： 几十年来，人们一直认为，尽管触发刺激，相同的脑干区域负责 产生恶心和呕吐。然而，我们最近的初步研究表明恶心和呕吐 是复杂的条件，包括各种不同的生理反应，个体之间， 根据触发刺激。这项资助使用协同方法来描述分歧， 前庭和其他信号的脑干神经元的会聚和多感觉整合， 呕吐。具体目标1包括第一次全面比较脑干通路，参与 在硫酸铜胃内输注或前庭神经麻痹后产生恶心和呕吐 刺激诱发运动病。通过使用我们最近开发的创新统计方法，我们 将从Fos标记模式中识别由这些刺激激活的神经网络。我们假设 不同的脑干网络参与了动物的胃肌电的客观变化， 在刺激前庭与胃肠道受体之后指示恶心的活动。具体目标2 和3分别使用神经生理技术来表征呕吐输入的整合， 臂旁核（PBN）神经元将这些信号传递到幕上脑区， 迷走神经背侧运动核（DMV）及其附近的副交感节前神经元（PPGN） 疑核，将信号传递到外周效应器。目标3还将比较 在整合这些信号中起关键作用的两个相邻区域的神经元的PPGN： 孤束核（NTS）和外侧被盖区（LTF），后者包括脑干“呕吐中心”。目标3 结合了对前庭刺激PPGN的反应的第一个表征;尽管这些神经元 协调呕吐期间胃肠道活动的变化，实际上对修饰一无所知 在催吐刺激引起的放电频率上。通过对比前庭和前庭神经输入的整合， 脑干神经元的这些关键组（PPGN和PBN、NTS和LTF中的那些）中的胃肠传入， 我们可以测试我们的整体假设，即引发呕吐的信号在脑干中独立处理， 并且只聚集在直接控制呕吐反应的神经元上。了解前庭和 胃肠道信号在脑干呕吐通路中的转化是产生新的见解的关键 治疗恶心和呕吐。在拟议的研究结束时，我们将确定脑干 介导恶心和呕吐的网络，恶心相关和呕吐信号对活动的影响 这些网络中的神经元，以及它们对前庭和 胃肠信号

Project Summary/Abstract: For decades, it has been assumed that despite the triggering stimulus, the same brainstem areas are responsible for producing nausea and emesis. However, our recent preliminary studies suggested that nausea and vomiting are complex conditions that include a variety of physiological responses that vary between individuals, and in accordance with the triggering stimulus. This grant uses synergistic approaches to characterize the divergence, convergence, and multisensory integration by brainstem neurons of vestibular and other signals that can produce emesis. Specific Aim 1 includes the first comprehensive comparison of the brainstem pathways that participate in generating nausea and emesis following the intragastric infusion of copper sulfate or presentation of vestibular stimuli to induce motion sickness. By utilizing an innovative statistical approach that we recently developed, we will identify the neural networks that are activated by these stimuli from Fos labeling patterns. We hypothesize that different brainstem networks are engaged in animals that exhibit objective changes in stomach myoelectric activity indicative of nausea following stimulation of vestibular versus gastrointestinal receptors. Specific Aims 2 and 3 respectively use neurophysiologic techniques to characterize the integration of emetic inputs by parabrachial nucleus (PBN) neurons that transmit these signals to supratentorial brain areas, and by parasympathetic preganglionic neurons (PPGNs) in the dorsal motor nucleus of the vagus (DMV) and near-by nucleus ambiguus that transmit the signals to peripheral effectors. Aim 3 will also compare the responses of PPGNs to those of neurons in two adjacent areas that play a key role in integrating these signals: nucleus tractus solitarii (NTS) and the lateral tegmental field (LTF), which comprises the brainstem “vomiting center.” Aim 3 incorporates the first characterization of responses to vestibular stimulation of PPGNs; although these neurons coordinate the changes in gastrointestinal activity during vomiting, virtually nothing is known about modifications in their firing rate elicited by emetic stimuli. By contrasting the integration of inputs from vestibular and gastrointestinal afferents in these key groups of brainstem neurons (PPGNs and those in PBN, NTS, and LTF), we can test our overall hypothesis that signals that elicit vomiting are processed independently in the brainstem, and only converge on neurons that directly control emetic responses. Understanding how vestibular and gastrointestinal signals are transformed in brainstem emetic pathways is key to generating insights into new treatments for nausea and vomiting. At the conclusion of the proposed studies, we will have identified brainstem networks that mediate nausea and vomiting, the influences of nausea-related and emetic signals on the activity of neurons in those networks, and their differential and/or synergistic responsiveness to vestibular and gastrointestinal signals.