Spinal Sensory Ganglia and Gut Sensation

项目摘要 肠-脑轴，特别是脑-胃通信，与情绪和认知过程有关，通常与许多神经系统疾病有关，包括心理社会功能障碍，药物滥用，神经系统疾病和变性。虽然胃-脑迷走神经通路存在大量的工作，但对大脑和胃如何通过脊髓感觉通路进行通信的了解要少得多。该R 01申请旨在确定肠道神经支配脊髓感觉神经节的解剖结构、功能和靶向电路。拟议的研究将测试总体假设，即与肌肉骨骼本体感受类似，胃肠道（GI）机械刺激通过共享的脊髓感觉通路向大脑发出信号，特别是外侧网状核（LRN）。此外，该提案将确定胃-脊髓-脑通路对大脑功能的功能影响，包括奖励行为和大脑回路，包括顶叶、岛叶和眶额皮质。为了实现我们的目标，将使用最先进的方法，包括通过组合病毒注射的器官特异性靶向，包括光学引导的光遗传学，清醒小鼠的体内电生理学，计算机操作的管腔内球囊扩张，以及使用光片显微镜的全脑c-Fos图。我们的研究可能揭示与异常肠脑交流相关的情绪和心理社会障碍的新的外周治疗靶点。此外，在我们的研究中描述的神经回路也可以有针对性地减轻异常的心理状态，包括恶心，厌食症和慢性疲劳典型的胃肠道动力障碍。

Project Summary The gut-brain axis, and in particular brain-stomach communication, are implicated in emotional and cognitive processing and often linked to many nervous system disorders, including psychosocial dysfunction, substance abuse, neurological diseases, and degeneration. While a large body of work exists on stomach-brain vagal pathways, much less is known about how the brain and the stomach may communicate through the spinal sensory pathways. This R01 application proposes to determine the anatomy, function, and circuitry targeted by gut-innervating spinal sensory ganglia. The proposed studies will test the overarching hypothesis that, similarly to musculoskeletal proprioception, gastrointestinal (GI) mechanical stimuli are signaled to the brain, specifically the lateral reticular nucleus (LRN), via shared spinal sensory pathways. In addition, the proposal will determine the functional impact of the gastric-spinal-brain pathways on brain functions including reward behaviors and brain circuitries including the parietal, insular, and orbitofrontal cortices. To address our aims, state-of-the-art methodology will be used including organ-specific targeting by combinatorial viral injection, optogenetics including optically guided, in vivo electrophysiology in awake mice, computer-operated intraluminal balloon distension, and whole-brain c-Fos maps using light-sheet microscopy. Our studies may reveal novel peripheral therapeutical targets for emotional and psychosocial disorders associated with abnormal gut-brain communication. Moreover, the neural circuitries to be described in our studies may also be targeted to alleviate abnormal psychological states, including the nausea, anorexia, and chronic fatigue typical of GI motility disorders.