Vagal Influence on Brainstem Plasticity and Neural Coding of Taste

 描述（由申请人提供）：Roux-en-Y胃旁路术（RYGB）是实现主要长期减肥的最有效方法。接受过RYGB的患者经常报告对高热量食物的厌恶。然而，RYGB对味觉改变的影响的机制还不完全清楚。我们的长期目标是了解饮食诱导的肥胖（DIO）和RYGB后决定味觉改变的神经机制。具体来说，我们想详细的神经解剖学，神经化学和神经生理学后遗症的重组subjummatic迷走神经传入，导致肥胖和以下RYGB，因为它们涉及到味觉信号在孤束核（NTS）。我们的中心假设是，迷走神经的胃分支的损害，RYGB的后果，诱导突触可塑性和电路重组的中间（喂养）和喙（味觉）NTS。考虑到NTS整合了味觉和胃肠道传入信息，我们预测初级内脏传入信号的这些变化从根本上改变了味觉信息的编码方式。我们的中心假设将通过实现以下具体目标进行测试：具体目标1：测试的假设，胃迷走神经切断术（VGX）和RYGB手术诱导重组和突触可塑性的吻侧NTS通过短暂的中央迷走神经传入终末从尾部和中间NTS撤回。将在水平脑切片中使用顺行示踪剂、突触特异性标记物和膜片钳电生理学的组合在形态和功能水平上研究迷走神经支配的变化。我们预计，由于NTS内已知的尾侧至吻侧投射，DIO经历的减弱迷走神经输入和RYGB的进一步改变将反映在NTS中谷氨酸释放和功效的细微变化中。具体目标二：利用清醒大鼠孤束核的电生理记录，我们将检验肥胖、胃VGX和RYGB选择性地改变味觉相关的核内通讯，并且这种作用将反映在味觉诱发的核内通讯中的假设。 NTS神经元之间的反应。分析将集中在量化的功能之间的连接合奏同时记录的NTS细胞，以及确定的信息贡献率和时间编码的味觉诱发反应。这项工作是创新的，因为它连接的作用，迷走神经损伤诱导的可塑性与味觉改变后DIO和RYGB的NTS。结果，拟议的项目，将提供一个更深入的了解肥胖和RYGB对脑干味觉信号的神经回路的影响。这些知识将使更系统和有针对性的操作，旨在揭示RYGB减少高热量食物消耗的机制，并促进新型手术和非手术治疗干预的发展，以促进有效的减肥。

 DESCRIPTION (provided by applicant): Roux-en-Y gastric bypass (RYGB) is the most effective method to achieve major, long-term weight loss. Patients who have undergone RYGB often report an aversion to calorie-dense foods. However, mechanisms underlying the effects of RYGB on taste alterations are incompletely understood. Our long-term goal is to understand the neural mechanisms that determine taste alterations following diet-induced obesity (DIO) and RYGB. Specifically, we want to detail the neuroanatomical, neurochemical and neurophysiological sequelae of reorganization of subdiaphragmatic vagal afferents, resulting from obesity and following RYGB, as they relate to gustatory signaling in nucleus of the solitary tract (NTS). Our central hypothesis is that damage to the gastric branches of the vagus, a consequence of RYGB, induces synaptic plasticity and circuit reorganization in the intermediate (feeding) and rostral (gustatory) NTS. Considering the NTS integrates both gustatory and gastrointestinal afferent information, we predict these changes in primary visceral afferent signaling fundamentally change how information about taste is encoded. Our central hypothesis will be tested by achieving the following specific aims: Specific Aim 1: Test the hypothesis that gastric vagotomy (VGX) and RYGB surgery induce reorganization and synaptic plasticity in the rostral NTS via transient withdrawal of central vagal afferent terminals from the caudal and intermediate NTS. Changes in vagal innervation will be investigated at the morphological and functional levels using a combination of anterograde tracers, synapse specific markers and patch-clamp electrophysiology in horizontal brain sections. We expect that, because of the known caudal-to-rostral projections within the NTS, the weakened vagal input experienced by DIO and further altered by RYGB will be reflected in subtle alterations in glutamate release and efficacy in the NTS. Specific Aim 2: Using electrophysiological recordings from the NTS of awake rats, we will test the hypothesis that obesity, gastric VGX and RYGB selectively modify taste-related intranuclear communication and that this effect will be reflected in the taste-evoked responses among NTS neurons. Analyses will focus on quantifying functional connections among ensembles of simultaneously recorded NTS cells as well as determining the information contributed by rate and temporal coding in taste-evoked responses. The proposed work is innovative because it connects the role of vagus nerve damage-induced plasticity within the NTS with taste alterations following DIO and RYGB. Results, of the proposed project, will provide a deeper understanding of the effects of obesity and RYGB on the neural circuitry underlying gustatory signaling in the brainstem. This knowledge will enable more systematic and targeted manipulations, aimed at revealing mechanisms by which RYGB reduces consumption of high-caloric foods and advance the development of novel surgical and non-surgical therapeutic interventions, to promote effective weight loss.