Gut to brain pathways regulating conditioned appetitive behavior

7.项目摘要/摘要 在过去的35年里，美国的肥胖率增加了一倍多，这一结果主要基于 增加卡路里消耗。现代食物环境中充满了与以下物质相关的刺激 奖励食物，通过习得的联想，这些刺激可以压倒生理上的满足感和满足感 并引发过度的食物寻觅和消费。海马体传统上是大脑的一个区域 与记忆功能联系在一起，最近与正常和 过度的进食行为。海马神经元接受胃肠道衍生的饱足和饱足相关的信号，在 部分来自迷走神经，因为迷走神经介导的饱足信号强烈激活海马神经元。这个 然而，GI来源的迷走神经信号在调节食物摄取控制的高阶习得方面的作用是 人们对此知之甚少。此外，结构连通性调节胃肠道生理和 海马体仍未被开发。这项提案中的初步数据暗示迷走神经感觉的作用 大鼠海马区依赖记忆过程中的信号传递。这项提案的主要目标是 探讨胃肠道(GI)源性迷走神经切断的新假说 会对海马体依赖的学习控制食欲行为产生负面影响，伴随着 减少海马神经元中神经可塑性和神经发生的标记物(目标1)。其他内容 实验将利用基于病毒的神经解剖方法来识别多突触/间接突触 GI来源的迷走神经信号与海马体通讯的途径(目标2)。至 为了解决这些假设，目标1中的实验将利用一种新的复杂的外科病变，约80% Gi来源的迷走神经传入神经，同时100%保持迷走神经运动信号的完整(CCK-Saporin Noose 神经节注射)与一系列检查海马区的啮齿动物行为模式相结合 基于与能量状态、[2]外部食物相关的内感线索的依赖食欲学习[1] 基于奖励的语境处理，以及与食物相关的社交线索。Aim 2将利用一种创新的 共同注射(Coin)神经追踪和双重病毒追踪策略以确定潜在的中继脑区域 将迷走神经感觉信号与海马神经元联系起来。集体研究将确定行为， 迷走神经影响认知和摄食的解剖学和分子机制 行为。

7. Project Summary/Abstract Over the past 35 years obesity rates have more than doubled in the United States, an outcome based largely on increased caloric consumption. The modern food environment is abundant with stimuli associated with rewarding food, and through learned associations these stimuli can override physiological satiation and satiety cues and trigger excessive food seeking and consumption. The hippocampus is a brain region traditionally linked with memory function and more recently with the higher-order learned control of both normal and excessive feeding behavior. Hippocampal neurons receive GI-derived satiation- and satiety-related signaling, in part, from the vagus nerve, as vagally-mediated satiation signals robustly activate hippocampal neurons. The role of GI-derived vagal signaling in regulating higher-order learned aspects of food intake control, however, is poorly understood. Furthermore, the structural connectivity mediating interactions between GI physiology and the hippocampus remains unexplored. Preliminary data in this proposal implicate a role of vagus nerve sensory signaling in hippocampal-dependent memory processes in rats. The principle goals of this proposal are to investigate the novel hypotheses that ablation of gastrointestinal (GI)-derived vagal sensory nerve disruption will negatively impact hippocampal-dependent learned control of appetitive behavior, accompanied by reductions in markers of neural plasticity and neurogenesis in hippocampal neurons (Aim 1). Additional experiments will utilize viral-based neuroanatomical methodologies to identify the multisynaptic/indirect pathways through which GI-derived vagal nerve signaling communicates to the hippocampus (Aim 2). To address these hypotheses, experiments in Aim 1 will utilize a novel and sophisticated surgical lesion of ~80% of GI-derived vagal afferent nerves, while leaving 100% of vagal motor signaling intact (CCK-saporin nodose ganglia injections) in combination with an array of rodent behavioral paradigms that examine hippocampal- dependent appetitive learning based on [1] interoceptive cues related to energy status, [2] external food reward-based contextual processing, and [3] social food-related cues. Aim 2 will utilize an innovative coinjection (COIN) neural tracing and dual viral tracing strategies to determine potential relay brain regions that connect vagal sensory signaling with hippocampal neurons. Collectively studies will identify behavioral, anatomical, and molecular mechanisms through which the vagus nerve influences cognition and feeding behavior.