INVESTIGATING THE GUT-BRAIN SIGNALING DYNAMICS REGULATING FOOD INTAKE

项目摘要 最近肥胖症的增加是一个主要的公共卫生问题。由于能量平衡调节协调 通过胃肠（GI）道和大脑之间的交流，了解这些肠-脑 相互作用将使新的肥胖治疗的发展。下丘脑和后脑 整合来自肠道的信息以控制食物摄入的关键大脑区域。在这里，我将利用最近的 技术的进步，以探索这两个大脑区域在清醒，行为动物的调节。 在下丘脑内，表达刺鼠相关蛋白（AgRP）的神经元对食物摄入至关重要 控制AgRP神经元的活动在饥饿期间很高，并迅速被食物抑制。我最近的工作 表明AgRP神经元主要受卡路里摄入量的调节，而不是感觉检测到 食物，因为将大量营养素直接注入胃中会迅速抑制AgRP神经元的活性 in vivo.此外，这种作用通过施用胃肠道饱食信号来重现，胃肠道饱食信号通常在胃肠道饱食后释放。 食物消费然而，肠道将信号传递给AgRP神经元的机制仍然存在， 未知该补助金的指导阶段（目标I和II）将建立在我以前的工作基础上，阐明 肠道中的营养检测导致AgRP神经元活性降低的机制。具体地说， 这些目标将确定GI信号是通过迷走神经还是通过对大脑的直接作用进行传输， 将揭示AgRP轴突投射，它将营养信号传递到整个大脑。重要的是 指导实验将为我提供胃肠道外周操作的培训，以及体内 使用显微内窥镜和双光子显微镜对单个神经元进行钙成像， 技术专长，并使拟议的R 00实验。中脑孤束核（NTS） 是来自迷走神经传入的GI衍生信号整合的第一个中心位点，并且是 将信号从肠道传递到更高级的大脑结构，如下丘脑。为独立 在我的资助的第三阶段（目标III和IV），我设计了基于我的研究生和 博士后培训，以确定不同的后脑NTS神经元群体如何从GI接收信号 道，在前所未有的水平的时间和细胞的细节。这些互补的研究目标结合在一起 与拟议的职业发展活动将为我提供必要的培训， 过渡到独立，在我的导师团队的指导下，谁拥有广泛的集体 神经科学技术和指导经验。总的来说，这个奖项将促进我的职业生涯， 独立研究者表征肠-脑信号传导对体内活性动力学的作用， 进食相关神经元

PROJECT SUMMARY The recent increase in obesity is a major public health concern. Since energy balance regulation is coordinated by communication between the gastrointestinal (GI) tract and the brain, understanding these gut-brain interactions will enable the development of novel obesity treatments. The hypothalamus and the hindbrain are critical brain regions that integrate information from the gut to control food intake. Here, I will leverage recent technological advances to explore the regulation of both these brain regions in awake, behaving animals. Within the hypothalamus, agouti-related protein (AgRP)-expressing neurons are essential for food intake control. Activity in AgRP neurons is high during hunger and is rapidly inhibited by food. My recent work demonstrates that AgRP neurons are primarily regulated by calorie intake, rather than sensory detection of food, since direct gastric infusion of macronutrients into the stomach rapidly suppresses AgRP neuron activity in vivo. Further, this effect is recapitulated by administration of GI satiation signals normally released following food consumption. However, the mechanisms through which the gut transmits signals to AgRP neurons remain unknown. The mentored phase (Aims I and II) of this grant will build upon my previous work by elucidating the mechanisms through which nutrient detection in the gut leads to AgRP neuron activity reductions. Specifically, these aims will determine whether GI signals are transmitted vagally or through direct action on the brain, and will uncover the AgRP axon projections that transmit nutritive signals throughout the brain. Importantly, the mentored experiments will afford me training in peripheral manipulation of the GI tract, as well as in vivo calcium imaging of individual neurons using microendoscopy and 2-photon microscopy, expanding my technical expertise and enabling the proposed R00 experiments. The hindbrain nucleus tractus solitarius (NTS) is the first central site of integration of GI-derived signals from vagal afferents, and is a key signaling node that transmits signals from the gut to higher-order brain structures such as the hypothalamus. For the independent phase (Aims III and IV) of my grant, I have designed experiments that build upon both my graduate and postdoctoral training to determine how different hindbrain NTS neuron populations receive signals from the GI tract, at unprecedented levels of temporal and cellular detail. These complementary research aims combined with the proposed career development activities will provide me with the training necessary to successfully transition to independence, under the guidance of my mentorship team who have extensive collective experience with neuroscience techniques and mentorship. Overall, this award will facilitate my career as an independent investigator characterizing the role of gut-brain signaling on the in vivo activity dynamics of feeding-relevant neurons.