Efferent vagal modulation of neuropod cells in the small intestine

摘要 功能性胃肠病是消化内科最常见的疾病。等 如肠易激综合征或功能性消化不良等疾病，通过改变GI敏感性来识别， 能动性虽然病理生理学是复杂的，但一个保守的特征是脑中的双向改变- 直觉信号因此，这些被归类为脑肠道相互作用的障碍。而迷走神经是 主要的脑肠联系，大脑如何中继神经信号，调节胃肠道上皮感觉功能是 未知我的长期职业目标是记录起源于大脑的神经回路如何改变大脑的活动。 肠道感知营养的能力在NIH指导研究科学家发展的支持下， Award -K 01，该提案的目的是描绘一个脑到肠的神经回路，可用于 改变肠道上皮的感觉传导。这将通过三个目标实现： 目标1.测定肠感觉细胞释放的神经递质和激素， 对兴奋性神经递质刺激的反应。将进行体外类器官和分选的单细胞测定。 用于测量培养物中的释放量。这一目标将证明兴奋性神经递质可以 刺激肠内分泌细胞囊泡释放。 目标二。迷走神经刺激与感觉上皮细胞钙成像和电生理学配对， 评估迷走神经元与肠感觉细胞突触的功能连接。这一目标将 证明了神经元增加近端感觉细胞兴奋性的功能连接 小肠 目标3.利用逆行（突触后至突触前）狂犬病毒和顺行（突触前至突触后）狂犬病毒。 突触）单纯疱疹病毒追踪脑干和肠之间的单突触连接 感觉上皮细胞这一目标将建立一个解剖图，说明脑干如何连接到 神经足细胞 识别连接大脑和肠道的功能性神经回路将有助于理解 内脏敏感背后的机制我和我的指导团队一起设计了这个 项目为我提供必要的研究和专业培训，让我成为一名出色的 感觉神经胃肠病学领域的独立研究者。

ABSTRACT Functional gastrointestinal (GI) diseases are the most common diagnoses in gastroenterology. Such disorders, like irritable bowel syndrome or functional dyspepsia, are recognized by altered GI sensitivity and motility. Though the pathophysiology is complex, a conserved feature is the bidirectional alteration in brain- gut signaling. Thus, these are classified as disorders of brain-gut interaction. While the vagus nerve is the main brain-gut link, how the brain relays neural signals that modulate GI epithelial sensory function is unknown. My long-term career goal is to document how neural circuits originating from the brain alter the gut’s ability to sense nutrients. With the support of the NIH Mentored Research Scientist Development Award — K01, the objective of this proposal is to delineate a brain-to-gut neural circuit that could be used to alter sensory transduction at the gut epithelium. This will be accomplished in three aims: Aim 1. Determine the neurotransmitters and hormones released by intestinal sensory cells in response to excitatory neurotransmitter stimulation. An in vitro organoid and sorted single cell assay will be used to measure release in culture. This aim will demonstrate that an excitatory neurotransmitter can stimulate vesicular release in enteroendocrine cells. Aim 2. Pair vagal stimulation with sensory epithelial cell calcium imaging and electrophysiology to evaluate the functional connectivity of vagal neurons synapsing onto intestinal sensory cells. This aim will demonstrate a functional connection where neurons increase the excitability of sensory cells in the proximal small intestine. Aim 3. Utilize both retrograde (post- to pre-synapse) rabies virus and anterograde (pre- to post- synapse) herpes simplex virus to trace a mono-synaptic connection between the brainstem and intestinal sensory epithelial cells. This aim will establish an anatomical map for how the brainstem is connected to neuropod cells. Identifying functional neural circuits connecting the brain and the gut will enable the understanding of the mechanisms behind visceral hypersensitivity. Together with my mentoring team, we have designed this project to provide me with the necessary research and professional training for me to excel as an independent investigator in the field of sensory neurogastroenterology.