Gut-Brain Neurocircuit Modulating Eating Behavior

描述（由申请人提供）：食欲由肠道内的食物调节。在这里，肠内分泌细胞感知消化的营养物质并将感觉信号传递给底层神经。到目前为止，肠内分泌细胞和神经元之间的信息传递一直被描述为间接的，通过激素的旁分泌释放，因为肠内分泌细胞被认为缺乏与神经的突触接触。这种观点很大程度上归因于缺乏研究体内肠内分泌细胞的工具。我们最近开发了一种转基因小鼠，通过荧光方法鉴定肠内分泌细胞，并揭示了这些细胞中一个突出的基细胞质过程。我们称这个过程为神经足类动物。正是通过这个神经足，肠内分泌细胞在体外和体内与神经元连接，这一点得到了我所提供的初步数据的支持。这是一种新颖的感觉神经回路，具有连接肠道管腔和大脑的潜力，我在NIDDK指导研究科学家发展奖（K01）期间的研究目标是表征这种神经回路的功能。我的假设是肠内分泌细胞通过突触将感觉信息传递给底层神经。在杜克大学医学系和神经生物系经验丰富的咨询委员会的支持下，我组装了一个创新的工具箱来描述这种神经回路的功能。这些工具包括：自动3D电子显微镜来定义连接的超微结构（目标1），一种新的肠内分泌细胞和感觉神经元体外共培养系统来定义电路的电学特性（目标2），该研究计划有望对理解肠-脑信号传导做出重大贡献，它建立在一个全面的职业发展计划中，将我的胃肠病学专业知识与神经生物学的特殊培训联系起来。这5年的职业发展计划将为我提供必要的专业和科学技能，使我成为胃肠感觉神经生物学领域的独立科学家。

DESCRIPTION (provided by applicant): Appetite is modulated by food in the gut. Here, enteroendocrine cells sense digested nutrients and communicate the sensory signals to underlying nerves. The transmission of information between enteroendocrine cells and neurons so far has been described as indirect, via the paracrine release of hormones, because enteroendocrine cells are thought to lack synaptic contacts with nerves. This view can be largely attributed to the lack of tools to study enteroendocrine cells in vivo. We recently developed a transgenic mouse to identify enteroendocrine cells by means of fluorescence and uncover in these cells a prominent basal cytoplasmic process. We call this process a neuropod. It is through this neuropod that enteroendocrine cells connect with neurons both in vitro and in vivo as supported by preliminary data that I have produced. This is a novel sensory neurocircuit with the potential to link the lumen of the gut to the brain, and my research goal during the NIDDK Mentored Research Scientist Development Award (K01) is to characterize the function of this neurocircuit. My hypothesis is that enteroendocrine cells relay sensory information to underlying nerves through a synapse. I have assembled an innovative toolbox to characterize the function of this neurocircuit with the support of an experienced advisory committee from the Departments of Medicine and Neurobiology at Duke University. The tools include: automated 3D electron microscopy to define the ultrastructure of the connection (aim 1), a novel in vitro co-culture system of enteroendocrine cells and sensory neurons to define the electrical properties of the circuit (aim 2), and a mono-synaptic rabies virus to trace in vivo the cells of the circuit (aim 3) This research plan is expected to make a significant contribution to the understanding of gut-brain signaling and it is built within a comprehensive career development plan that will bridge my gastroenterology expertise with exceptional training in neurobiology. This 5-year career development plan will provide me with the necessary professional and scientific skills to become an independent scientist in the field of gastrointestinal sensory neurobiology.