Reward Signaling in the Gut-Brain Axis

项目总结 在美国，肥胖不仅是主要的死亡原因，也是几乎所有其他主要死亡原因的风险因素 死亡包括心脏病、肺部疾病、中风和癌症。高脂肪、高糖的过度摄入 食物是肥胖的驱动力，但其机制尚不清楚。迷走神经节(NG)神经元 神经将摄入后的脂肪和糖的信号从肠道传递到大脑，以调节食物的摄入量和 加强食物选择。先前的研究表明，迷走神经活动对进食后的反应 肥胖患者的信号会减少，这可能会导致食物摄入量增加。要了解如何改变 常量营养素信号可能导致肥胖需要了解其基本生理学，而这还没有 完全阐明了。我的初步数据显示，迷走神经中的不同神经元群需要 摄入后脂肪或糖的信号，但这些信号是否足以加强条件性行为 目前还不清楚。我先前已经证明，消融表达CCKR的神经元 影响脂肪而不是糖介导的饱腹感，表明CCKR可能是脂肪反应的特异性标志 迷走神经传入神经元。因此，我假设脂肪和糖激活表型和 肠道-脑轴上不同功能的迷走神经集合，这足以加强 条件性行为，这种激活在肥胖时会减少。为了解决这些假设，我们将使用 FosTRAP小鼠，一种活动依赖的基因靶向模型，选择性靶向迷走感觉神经元 对脂肪或糖有反应。在目标1中，我们将测试脂肪或糖感受性迷走神经的光遗传激活 神经元足以触发黑质纹状体多巴胺的释放，并让动物学会自我刺激，两个 这是奖励的标志。在目标2中，我们将测试CCK受体表达迷走神经细胞的必要性。 脂肪，但不是糖的奖励，通过在有和没有选择性的情况下进行风味营养调节实验 使用结合神经毒素CCK-Saporin消融表达CCKR的迷走神经传入。在《目标3》中，我们将 用FosTRAP小鼠比较神经细胞，测试高脂肪、高糖饮食摄入如何扰乱营养感知 同一动物肥胖发生前后对胃内刺激的反应。这项工作将为 首次表征瘦身和肥胖者肠道-大脑奖赏回路中的营养特异性信号 未来研究的条件和可能的治疗靶点。

PROJECT SUMMARY Obesity is not only a leading cause of death in the US, but also a risk factor for nearly all other top causes of death including heart disease, pulmonary disease, stroke, and cancer. Overconsumption of high-fat high-sugar foods is a driver of obesity, but the mechanism for this is unclear. Nodose ganglia (NG) neurons of the vagus nerve transmit post-ingestive signals for fats and sugars from the gut to the brain to regulate food intake and reinforce food choice. Previous studies have demonstrated that vagal activity in response to post-ingestive signals is reduced in obesity, which may lead to increased food intake. To understand how altered macronutrient signaling may lead to obesity requires understanding its basic physiology, which has not been fully elucidated. My preliminary data reveals distinct neuronal populations in the vagus nerve are required for post-ingestive fat or sugar signaling, but whether these signals are sufficient to reinforce conditioned behavior is unclear. I have previously shown that ablation of neurons expressing cholecystokinin receptor (CCKR) affects fat- but not sugar-mediated satiation, indicating CCKR may be a specific marker for fat responsive vagal afferent neurons. Accordingly, I hypothesize that fats and sugars activate phenotypically and functionally distinct vagal ensembles in the gut-brain axis, which are sufficient to reinforce conditioned behavior, and this activation is reduced in obesity. To address these hypotheses, we will use FosTRAP mice, an activity-dependent genetic targeting model, to selectively target vagal sensory neurons that respond to either fat or sugar. In aim 1, we will test whether optogenetic activation of fat or sugar sensing vagal neurons is sufficient to trigger nigrostriatal dopamine release, and for animals to learn to self-stimulate, two hallmarks of reward. In aim 2, we will test the necessity of CCK receptor expressing vagal sensory neurons in fat, but not sugar reward, by performing a flavor-nutrient conditioning experiment with and without selective ablation of vagal afferents expressing CCKR, using the conjugated neurotoxin CCK-Saporin. In aim 3, we will test how high-fat high-sugar diet intake disrupts nutrient sensing by using FosTRAP mice to compare neural responses to intragastric stimuli before and after the onset of obesity within the same animal. This work will for the first time characterize nutrient-specific signaling in the gut-brain reward circuitry in lean and obese conditions for future study and possible therapeutic targets.