The functional impact of pancreatic islet innervation

周围自主神经系统的三个组成部分，即副交感神经、交感神经和 感觉神经，共同努力，防止危及生命的葡萄糖稳态波动。他们这样做是在 部分是通过调节胰岛的激素分泌。电极刺激自主神经 最近被认为是一种潜在的治疗疾病的方法(神经调节)。鉴于它在 与糖代谢和糖尿病有关，胰岛被认为是神经调节的主要靶点。至 建议电刺激神经治疗糖尿病，然而，了解胰岛是如何 神经影响胰岛β细胞的胰岛素分泌。此应用程序的目标是确定 神经用来控制胰腺激素分泌的机制。最近的解剖学研究表明 详细说明自主神经如何支配胰岛，但自主神经到底是如何影响激素分泌的 从小岛上来的还不知道。我们假设副交感、肠道和感觉神经通路起作用。 通过胰腺内神经节调节局部胆碱能调控胰岛细胞功能。该计划的基本原理 建议的研究是，有必要了解自主神经控制的局部机制 胰岛的激素分泌，这与美国国立卫生研究院的任务有关。根据初步数据，我们的 假说将通过追求两个特定的目标来检验：(1)胰腺感觉神经支配在 调节胰岛功能，以及(2)胰腺内神经节作为控制胰岛的信号中枢的作用 功能。在第一个目标下，我们将测试胰岛的迷走神经支配参与一种 迷走神经回路调节胰岛激素分泌。我们将有选择地刺激胰岛细胞 化学发生途径和通过靶向重组获得激活神经元的遗传途径 活跃种群(陷阱)系统。我们将结合陷阱和工具来标记、跟踪、记录和 由胰岛细胞刺激激活的脑干操纵性神经元。在第二个目标下，我们将测试 胰腺内神经节整合来自副交感传出神经、肠神经和 感觉轴突计算肠道和大脑输入的执行摘要以调整局部胆碱能控制 它们作用于胰岛细胞。我们将刺激前神经节的副交感、肠道和感觉神经支配。 在体内和体内使用化学发生和光遗传工具，并测量对胰腺内神经元的影响。 我们将进一步研究操纵胰腺内神经元活动如何影响胰岛功能和血糖。 代谢(胰岛素、血浆水平和血糖)。我们希望应用我们的新方法来衡量 操纵胰腺神经活动将产生有关神经如何影响胰岛生物学的重要信息。 这一贡献意义重大，因为它将提供将完成和修改的基础知识 自主神经对胰腺内分泌功能影响的模型。曾经的功能图 胰岛神经支配是可行的，我们将能够提出神经调节来改善糖尿病患者的胰岛功能。

The three components of the peripheral autonomic nervous system, the parasympathetic, sympathetic and sensory nerves, work together to prevent life-threatening fluctuations in glucose homeostasis. They do so in part by regulating hormone secretion from the pancreatic islet. Stimulating autonomic nerves with electrodes has recently been recognized as a potential way to treat diseases (neuromodulation). Given its central role in glucose metabolism and diabetes, the pancreatic islet is considered a primary target for neuromodulation. To propose electrical stimulation of nerves to treat diabetes, however, it is essential to understand how islet nerves impact insulin secretion from the beta cell. The objective of this application is to determine the mechanisms nerves use to control hormone secretion from the pancreas. Recent anatomical studies show in detail how autonomic nerves innervate the islet, but how exactly autonomic nerves impact hormone secretion from the islet is not known. We hypothesize that parasympathetic, enteric, and sensory neural pathways act through intrapancreatic ganglia to modulate local cholinergic control of islet cell function. The rationale for the proposed research is that there is a need to understand the local mechanisms of autonomic nerve control of hormone secretion from the islet, which is relevant to the mission of the NIH. Guided by preliminary data, our hypothesis will be tested by pursuing two specific aims: (1) the role of pancreas sensory innervation in regulating islet function, and (2) the role of the intrapancreatic ganglion as a signaling hub controlling islet function. Under the first aim, we will test that the vagal sensory innervation of the islet participates in a vagovagal neuronal circuit regulating islet hormone secretion. We will selectively stimulate islet cells with a chemogenetic approach and gain genetic access to activated neurons with the Targeted Recombination in Active Populations (TRAP) system. We will combine TRAP with tools for labeling, tracing, recording, and manipulating neurons in the brainstem activated by islet cell stimulation. Under the second aim, we will test that intrapancreatic ganglia integrate signals from parasympathetic efferent nerves, enteric neurons, and sensory axons to compute an executive summary of gut and brain inputs to adjust the local cholinergic control they exert on islet cells. We will stimulate parasympathetic, enteric and sensory innervation of the ganglion ex vivo and in vivo with chemogenetic and optogenetic tools and measure the effects in intrapancreatic neurons. We will further study how manipulating intrapancreatic neuronal activity affects islet function and glucose metabolism (insulin plasma levels and glycemia). We expect that applying our novel approaches to measure and manipulate pancreas nerve activity will yield important information about how nerves affect islet biology. This contribution is significant because it will provide fundamental knowledge that will complete and revise models about the influence of autonomic nerves on endocrine pancreas function. Once a functional map of islet innervation is available, we will be able to propose neuromodulation to improve islet function in diabetes.