Vestibular Regulation of Respiratory Muscle Activity

描述（由申请人提供）：呕吐是横膈膜和腹部肌肉共同收缩产生高胃内压的刻板模式的结果。本应用程序的目的是破译产生呕吐的髓质电路对前庭输入的处理，并确定该信号处理如何受到引起呕吐的其他输入的影响。特异性目标1将绘制出在前庭受体刺激引起呕吐和伴随恶心时激活的神经元的位置，并将这些位置与胃肠道（GI）输入引发的呕吐时激活的神经元进行比较。特异性目标2将采用前庭核（VN）亚区失活来确定产生前庭诱发呕吐的必要区域。一旦脑干区域包含参与产生呕吐的神经元被确定，随后的实验将确定这些区域的细胞对自然前庭刺激加上GI受体的激活的反应。特异性目标3将考虑孤束核（NTS）和VN的神经元反应，它们分别接受来自外周的GI和迷路输入，可诱导呕吐和恶心。特异性Aim 4A将确定呕吐模式产生的一个组成部分的神经元的反应：位于NTS和面后核之间的背髓外侧被盖区（LTF）。具体的Aim 4B将考虑PBN的信号处理，它参与将内脏感觉信号传递到前脑，以深入了解前庭和内脏输入在产生恶心和产生呕吐的髓质元素的关键区域的整合如何不同。在Aim 4的结论中，我们将对已知参与触发和协调呕吐以及伴随的情感反应的主要脑干区域的迷路刺激神经元的反应进行彻底采样。我们还将系统地确定前庭信号从VN传递到NTS，最后传递到LTF和PBN时，前庭信号在呕吐回路中是如何转换的。此外，我们将确定其他呕吐信号的存在如何影响迷宫输入的处理，以及这种处理是否在呕吐前或呕吐后立即发生深刻改变。因此，这些研究将提供对产生晕动病的信号整合的见解。

DESCRIPTION (provided by applicant): Vomiting is a consequence of a stereotyped pattern of co-contractions of the diaphragm and abdominal muscles that generate high intragastric pressures. The goal of this application is to decipher the processing of vestibular inputs by the medullary circuitry that produces vomiting, and to determine how this signal processing is affected by other inputs that can elicit emesis. Specific Aim 1 will map the locations of neurons activated during vomiting and accompanying nausea elicited by stimulation of vestibular receptors and compare the sites to those activated during emesis triggered by gastrointestinal (GI) inputs. Specific Aim 2 will employ inactivation of subregions of the vestibular nuclei (VN) to identify the area that is essential for producing vestibular-elicited vomiting. Once the brainstem regions containing neurons that participate in generating vomiting are established, subsequent experiments will ascertain the responses of cells in these areas to natural vestibular stimulation added to activation of GI receptors. Specific Aim 3 will consider neuronal responses in nucleus tractus solitarius (NTS) and the VN, which respectively receive GI and labyrinthine inputs from the periphery that can induce emesis and nausea. Specific Aim 4A will determine the responses of neurons in a region that is a component of the vomiting pattern generator: the dorsal medullary lateral tegmental field (LTF) positioned between NTS and the retrofacial nucleus. Specific Aim 4B will consider the processing of signals by PBN, which is involved in transmitting viscerosensory signals to the forebrain, to provide insights into how integration of vestibular and visceral inputs together differs in this region critical for generating nausea and medullary elements that produce vomiting. At the conclusion of Aim 4 we will have thoroughly sampled the responses of neurons to labyrinthine stimulation in the major brainstem areas known to participate in triggering and coordinating vomiting and accompanying affective responses. We will also systematically determine how vestibular signals are transformed in the emetic circuit as they are relayed from the VN to NTS and finally to LTF and the PBN. Furthermore, we will ascertain how the presence of other emetic signals affects the processing of labyrinthine inputs, and whether this processing is profoundly altered immediately before or after an episode of vomiting. As such, the studies will provide insights into the signal integration responsible for the generation of motion sickness. PUBLIC HEALTH RELEVANCE: Vomiting is highly significant and common clinical problem. Nausea and vomiting can occur during poisoning, cancer chemotherapy, recovery from anesthesia, activities in virtual environments (including civilian and military training simulators), and travel in cars, airplanes, and spacecraft. Motion sickness is the most common malady linked with the vestibular system, but the processing of vestibular signals by the brainstem neurons that trigger and coordinate emesis is poorly understood. The proposed experiments comprise the first systematic study of how vestibular signals are transformed by the neural pathways that trigger and coordinate vomiting and will also ascertain how inputs from the viscera affect this processing; as such, the work will provide fundamental new insights into the mechanisms that generate vomiting.