Mapping Stomach Autonomic Circuitry and Function for Neuromodulation of Gastric Disorders

两个系列的互补实验，由我们的11名研究人员组成的高素质团队进行 来自四个机构的八个最先进的实验室，将填补目前表征中的关键空白 控制胃功能的自主神经连接体。这些建议的协同解剖和 功能研究将形成神经调节协议所需的基础， 这是过去第一代生物电子试图改善和监测胃部疾病的缺点。 基于迷走神经回路映射的最新进展，我们的研究团队报告了许多，SA 1将完成 传出和传入终末表型的清单，分析它们的侧支特化，建立 它们的区域分布，并确定其靶组织的化学分类。我们还将比较 人（和猪，一种理想的大型动物临床前原理验证模型）胃的神经回路， 大鼠模型，以促进未来的翻译外推。SA 1的分析将使用一套 高清晰度神经追踪，免疫组织化学和分子协议，沿着先进的成像和 形态测量技术，我们的团队已经适应了自主电路。SA 1将侧重于这些要素 在胃神经网络中，可能与告知SA 2和识别 局部刺激的胃壁将具有很强的治疗潜力。在功能评估中，SA 2将确定高度选择性迷走神经刺激（VNS）和精确手术放置的最佳位置 在迷走神经从脑干的出口和胃壁内的轴突的靶位点之间， 将决定增强胃生理机能的最佳刺激方案。SA 2将使用最先进的 闭环刺激器技术、算法和电极（先前设计并通过 我们的研究团队的调查人员），并评估的可靠性，有效性和稳定性的VNS采用了 急性、短期和长期非侵入性终点组合（≥ 6）。该团队将使用数据存档， 所有研究和医学界都可普遍访问的资源共享平台。

Two series of complementary experiments, conducted by our exceptionally qualified team of 11 investigators from eight state-of-the-art laboratories at four institutions, will close critical gaps in the current characterization of the autonomic connectome controlling stomach function. These proposed synergistic anatomical and functional investigations will form the needed foundation for neuromodulation protocols that can correct shortcomings in past, first-generation bioelectronic attempts to ameliorate and monitor gastric disorders. Building on recent advances in mapping of vagal circuits, many reported by our research team, SA 1 will finish inventories of the efferent and afferent terminal phenotypes, analyze their collateral specializations, establish their regional distributions, and identify chemical taxonomies of their target tissues. We will also compare the neural circuitry of the human (and pig, an ideal large animal preclinical proof-of-principle model) stomach with that of the rat model to facilitate future translational extrapolations. The analyses of SA 1 will use a suite of high-definition neural tracing, immunohistochemical and molecular protocols, along with advanced imaging and morphometric techniques, that our team has adapted to autonomic circuits. SA 1 will focus on those elements in gastric neural network that may be most relevant to informing SA 2 and identify additional localized sites in the stomach wall where focal stimulation will have strong therapeutic potential. In functional assessments, SA 2 will identify optimal locations for both highly selective vagal stimulation (VNS) and precise surgical placement between the exit of the vagus from the brainstem and the target sites of the axons within the stomach wall and will determine the best stimulation protocols for augmenting gastric physiology. SA 2 will use state-of-the-art closed-loop stimulator technologies, algorithms, and electrodes (previously designed and robustly proven by investigators on our research team) and assess the reliability, validity, and stability of the VNS by employing a battery (≥ 6) of acute, short-term, and long-term non-invasive endpoints. The team will use data archiving and resource sharing platforms that are universally accessible to all research and medical communities.