Spinal Sensory Ganglia and Gut Sensation

项目摘要 肠道-脑轴，特别是脑-胃通讯，与情绪和认知过程有关，并经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、神经疾病和退行性疾病。虽然胃-大脑迷走神经通路上存在大量的研究，但对大脑和胃如何通过脊髓感觉通路进行交流的了解要少得多。此R01应用程序建议确定肠道神经脊神经感觉神经节的解剖、功能和回路。拟议的研究将检验最重要的假设，即胃肠道(GI)机械刺激类似于肌肉骨骼本体感觉，通过共享的脊髓感觉通路向大脑，特别是外侧网状核(LRN)发送信号。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、岛叶和眶前叶皮质。为了达到我们的目标，将使用最先进的方法，包括通过组合病毒注射进行器官特异性靶向，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新的外周治疗靶点，用于治疗与肠道-大脑通讯异常相关的情绪和心理社会障碍。此外，我们研究中描述的神经回路也可能针对缓解异常心理状态，包括胃肠道动力障碍典型的恶心、厌食和慢性疲劳。

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.