Reward Signaling in the Gut-Brain Axis

项目摘要 肥胖不仅是美国人死亡的主要原因，也是几乎所有其他主要原因的危险因素。 死亡包括心脏病、肺病、中风和癌症。高脂高糖过量食用 食物是肥胖的驱动因素，但其机制尚不清楚。迷走神经结状神经节（NG）神经元 神经将脂肪和糖的摄入后信号从肠道传递到大脑，以调节食物摄入量， 加强食物选择。先前的研究表明，迷走神经活动对摄食后 信号减少肥胖，这可能会导致食物摄入量增加。为了了解 宏量营养素信号可能导致肥胖，需要了解其基本生理学，这还没有被 充分阐明。我的初步数据显示迷走神经中不同的神经元群体是 摄入后脂肪或糖信号，但这些信号是否足以加强条件反射行为 还不清楚我以前已经表明，消融表达胆囊收缩素受体（CCKR）的神经元， 影响脂肪而不是糖介导的饱腹感，表明CCKR可能是脂肪反应性的特异性标志物。 迷走神经传入神经元因此，我假设脂肪和糖激活表型， 在肠-脑轴中功能不同的迷走神经集合，这足以加强 条件行为，这种激活在肥胖症中减少。为了解决这些假设，我们将使用 FosTRAP小鼠，一种活性依赖性遗传靶向模型，选择性靶向迷走感觉神经元， 对脂肪或糖有反应。在目的1中，我们将测试脂肪或糖敏感迷走神经的光遗传学激活是否与神经元的功能有关。 神经元足以触发黑质纹状体多巴胺的释放，对于动物学习自我刺激，两个 奖励的标志。目的2：探讨CCK受体在大鼠迷走神经感觉神经元中表达的必要性。 脂肪，但不是糖的奖励，通过进行风味营养调节实验， 使用结合的神经毒素CCK-皂草素消融表达CCKR的迷走神经传入。在目标3中，我们 通过使用FosTRAP小鼠比较神经系统， 在同一动物内肥胖症发作之前和之后对胃内刺激的反应。这项工作将为 第一次描述了瘦和肥胖患者肠-脑奖赏回路中营养特异性信号传导的特征， 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.