Functional mapping of efferent gut neuroepithelial circuits

总结 自世纪之交的威廉·贝利斯爵士和欧内斯特·斯塔林时代以来，肠道和大脑被认为只能通过激素间接地交换感官信息。利用现代分子工具，我们最近发现了一个肠道神经上皮回路类似于舌头中的味觉细胞由感觉肠内分泌细胞的神经支配形成。这种外周神经回路提高了在细胞水平上理解内脏高敏感性的可能性内脏高敏感性是几种人类疾病的核心症状，包括肠易激综合征、慢性腹痛和饮食失调。 肠内分泌细胞接受来自肠腔中的营养物质和细菌的感觉刺激，并通过激发动作电位作出反应。 因此，这种神经上皮细胞暗示了肠道感觉信号调节大脑功能的路径和大脑调节胃肠道敏感性的容器。我们组建了一个跨学科团队，具有肠道感觉神经生物学，生物医学工程和临床胃肠病学的专业知识，通过利用新开发的动物模型和体内技术来定义这种神经上皮回路的脑-肠传出功能。 胃肠道化学感觉信号的重点一直是传入肠-脑途径，但脑-肠传出途径，调节胃肠道的敏感性已很少描述。在这个有限的竞争-CNOOT2提案中，我们专注于传出部分，为未来的综合绘图研究提供基础知识。我们将努力实现以下目标： 1. 小肠内分泌细胞的迷走神经分布。 2. 目的：明确在体神经上皮环路的迷走神经调制。 通过功能映射，我们设想为未来的神经调节和饮食疗法开发一个平台，以减轻内脏感觉功能障碍的疾病。

SUMMARY Since the times of Sir William Bayliss and Ernest Starling at the turn of the 20th century, the gut and the brain were thought to exchange sensory information only indirectly, through hormones. Using modern molecular tools, we recently uncovered a gut neuroepithelial circuit—analogous to that of taste cells in the tongue—formed by the innervation of sensory enteroendocrine cells. This peripheral neural circuit raise the possibility of understanding visceral hypersensitivity at the cellular level—a core symptom of several human disorders, including irritable bowel syndrome, chronic abdominal pain, and eating disorders. Enteroendocrine cells receive sensory stimuli from nutrients and bacteria in the gut lumen and respond by firing action potentials. Thus, this neuroepithelial suggests a path for gut sensory signals to modulate brain function and a receptacle for the brain to modulate gastrointestinal sensitivity. We formed an interdisciplinary team, with expertise in gut sensory neurobiology, biomedical engineering, and clinical gastroenterology, to define the brain-to-gut efferent function of this neuroepithelial circuit by taking advantage of newly developed animal models and in vivo technology. The focus on gastrointestinal chemosensory signaling has been afferent gut-to-brain pathways but the brain-to-gut efferent paths that modulate gastrointestinal sensitivity have been poorly described at best. In this Limited Competition - SPARC OT2 proposal, we focus on the efferent portion to produce foundational knowledge for future comprehensive mapping studies. We will pursue the following aims: 1. To map the vagal innervation of enteroendocrine cells in the small intestine. 2. To define the vagal modulation of the neuroepithelial circuit in vivo. By functionally mapping it, we envision developing a platform for future neuromodulation and dietary therapies to alleviate disorders of visceral sensory dysfunction.