A novel brain-to-pancreatic islet neural circuit regulates glucose homeostasis

项目摘要 大脑中的葡萄糖感觉神经元通过改变它们的放电活动来对葡萄糖下降做出反应，这触发了 预防严重低血糖的反调节反应。中枢神经系统的一个基本过程 系统中维持血糖水平是通过对胰岛的调节。腹内侧 下丘脑(VMH)是调节血糖的神经网络的重要组成部分。神经元表达 囊泡型GABA转运体(Vgat)集中在VMH的腹外侧部(VlVMH)。我们发现， 这些VgatvlVMH神经元大多是葡萄糖抑制(GI)神经元。这些Gi-VgatvlVMH神经元的激活 在低血糖条件下会减少胰岛素分泌以提高血糖。跟随我们的飞行员 观察，我们将结合神经回路映射、纤维光度学、电生理学、光遗传学和 VgatvlVMH神经元通过改变VgatvlVMH神经元调节血糖稳态的化学遗传学 胰岛素和胰升糖素通过脑到胰岛的途径分泌。目标1将建立 VgatvlVMH神经元在不同条件(如高血糖、肥胖、 和糖尿病)，并进一步确认它们在调节血糖水平方面的作用。目标2将决定是否 VgatvlVMH起源的神经回路通过调节胰岛功能参与血糖稳态。在……里面 目的3、我们将鉴定VgatvlVMH神经元通过交感神经胰腺投射调节血糖。 酪氨酸羟基酶(TH)神经元。这些研究的完成可能会揭示出 一种新的脑-胰岛神经回路调节胰岛素分泌，这是以前从未研究过的。 更重要的是，我们将描绘一个新的葡萄糖动态平衡的分子靶点，这可能提供一个 开发治疗糖尿病和肥胖症的新治疗策略的框架。

Project Summary Glucose-sensing neurons in the brain respond to glucose fall by altering their firing activities, which trigger the counterregulatory responses to prevent severe hypoglycemia. One essential process of the central nervous system in the maintenance of blood glucose levels is through the regulation of pancreatic islets. The ventromedial hypothalamus (VMH) is a critical component of neural networks that regulate blood glucose. Neurons express vesicular GABA transporter (Vgat) are concentrated in the ventrolateral part of VMH (vlVMH). We found that the majority of these VgatvlVMH neurons are glucose-inhibited (GI) neurons. Activation of these GI-VgatvlVMH neurons will reduce insulin secretion to increase blood glucose under hypoglycemia conditions. Following our pilot observations, we will combine neural circuits mapping, fiber photometry, electrophysiology, optogenetics, and chemogenetics to test the hypothesis that VgatvlVMH neurons regulates glucose homeostasis by changing insulin and glucagon secretion via the brain-to-pancreatic islet pathway. Aim 1 will establish the physiological functions of VgatvlVMH neurons in animals under different conditions (e.g. hyperglycemic, obesity, and diabetes) and further confirm their roles in regulating blood glucose levels. Aim 2 will determine if the VgatvlVMH-originated neural circuits contribute to glucose homeostasis via regulating pancreatic islet function. In aim 3, we will identify the VgatvlVMH neurons that regulate blood glucose via sympathetic pancreatic-projecting tyrosine hydroxylase (TH) neurons. The accomplishment of these studies may reveal the important functions of a novel brain-to-pancreatic islet neural circuit in regulating insulin secretion that has never been studied before. More importantly, we will delineate a new molecular target for glucose homeostasis, which may provide a framework for the development of novel therapeutic strategies for diabetes and obesity.