Gut-Brain Neurocircuit Modulating Eating Behavior

描述(申请人提供)：胃口由肠道中的食物调节。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潜在的神经。到目前为止，肠内分泌细胞和神经元之间的信息传递被描述为间接的，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。这一观点在很大程度上可以归因于缺乏研究活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，并在这些细胞中发现了一个显着的基本细胞质过程。我们称这一过程为神经荚。正如我提供的初步数据所支持的那样，正是通过这个神经舱，肠内分泌细胞在体外和体内都与神经元连接。这是一种新的感觉神经回路，有可能将肠道的管腔与大脑联系起来，我在NIDDK导师研究科学家发展奖(K01)期间的研究目标是描述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潜在的神经。在杜克大学医学系和神经生物学系一个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个神经回路的功能。这些工具包括：用于确定连接超微结构的自动化3D电子显微镜(Aim 1)、用于确定回路电学特性的新型肠内分泌细胞和感觉神经元体外共培养系统(Aim 2)、用于在体内跟踪回路细胞的单突触狂犬病病毒(Aim 3)这项研究计划预计将对了解肠道-大脑信号做出重大贡献，它是在全面的职业发展计划内建立的，将把我的胃肠病专业知识与出色的神经生物学培训联系起来。这份5年的职业发展计划将为我提供必要的专业和科学技能，使我成为一名胃肠道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.