INVESTIGATING THE GUT-BRAIN SIGNALING DYNAMICS REGULATING FOOD INTAKE

项目总结 最近肥胖症的增加是一个主要的公共卫生问题。由于能量平衡调节是协调的 通过胃肠道(GI)和大脑之间的通信，了解这些肠脑 相互作用将使新的肥胖治疗方法的开发成为可能。下丘脑和后脑 关键的大脑区域，整合来自肠道的信息来控制食物摄入量。在这里，我将利用最近 探索清醒的行为动物的这两个大脑区域的调节的技术进步。 在下丘脑中，刺鼠相关蛋白(AgRP)表达的神经元是食物摄取所必需的 控制力。在饥饿期间，AgRP神经元的活性很高，并迅速受到食物的抑制。我最近的作品 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 食物，因为直接向胃内注入大量营养素会迅速抑制AgRP神经元的活动 在活体内。此外，这种影响通过给药通常在以下情况下释放的GI饱和信号来概括 食物消费。然而，肠道向AgRP神经元传递信号的机制仍然存在 未知。这项资助的指导阶段(目标I和目标II)将建立在我以前工作的基础上，通过阐明 肠道营养检测导致AgRP神经元活性降低的机制。具体来说， 这些目标将决定GI信号是通过迷走神经还是通过大脑的直接作用传递的，以及 将揭示在整个大脑中传递营养信号的AgRP轴突投射。重要的是， 有指导的实验将为我提供胃肠道外周操作以及活体操作方面的培训 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，扩展我的 技术专长，并支持拟议的R00实验。后脑孤束核(NTS) 是来自迷走神经传入的GI信号整合的第一个中心部位，也是一个关键的信号节点， 将信号从肠道传输到更高级的大脑结构，如下丘脑。对于独立派来说 在我的助学金阶段(目标III和IV)，我设计了建立在我的毕业生和 博士后培训以确定不同的后脑NTS神经元群体如何接收来自GI的信号 区域，以前所未有的时间和细胞细节水平。这些互补的研究目标结合在一起 通过拟议的职业发展活动将为我提供成功所需的培训 过渡到独立，在我的指导团队的指导下，他们拥有广泛的集体 有神经科学技术和指导经验。总体而言，这个奖项将促进我作为一名 独立研究人员表征了肠道-脑信号在体内活动动力学中的作用 与摄食相关的神经元。

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.