Brain Circuits Involved in the Sympathetic Control of the Liver

自主神经系统在肝脏代谢调节中起着重要作用。 肝脏交感神经的激活增加了肝脏葡萄糖的产生(HGP)和糖原分解，以及 HGP升高在2型糖尿病的发病机制中起重要作用。因此，如果没有完整的 要了解参与肝脏调节的神经回路，还有一个障碍需要发展 通过脑-肝途径控制血糖水平的策略。这项提议的总体长期目标是 阐明中枢自主神经控制与肝脏碳水化合物的基本关系 新陈代谢。下丘脑室旁核(PVN)是一个重要的指挥中枢 自主神经流出，从而影响血糖和能量的动态平衡。由于血糖受损 糖尿病患者的动态平衡涉及控制自主神经输出的中枢回路，这是当前的目标 这项建议的目的是研究交感神经前核、肝脏相关的室旁核和腹侧脑干的作用。 使用体内和体外方法来维持神经元对HGP和胰岛素的作用。我们的预赛 饮食诱导肥胖(DIO)小鼠的观察显示，肝脏相关的兴奋作用总体上发生了转变 交感前核室旁核神经元与胰岛素对兴奋性神经传递的抑制作用 腹侧脑干投射PVN神经元。此外，我们的数据还表明，与肝脏相关的脑干 神经元接受下丘脑室旁核神经元的兴奋性输入。这些观察结果导致了一个中心假设 交感前、肝脏相关的PVN和腹侧脑干神经元之间的单突触联系是 是调节肝脏碳水化合物代谢所必需的。拟议的研究将界定 下丘脑和腹侧脑干回路参与逆行控制肝脏的交感神经 病毒追踪和环路标测结合免疫染色。电生理学研究将 测定对照组和DIO小鼠肝脏相关神经元的细胞特性。功能连接 PVN和肝脏相关的腹侧脑干神经元之间的联系将用光遗传学来揭示。建议中的 活体研究将确定肝脏相关神经元对肝脏葡萄糖产生和胰岛素的贡献 行动。对神经元的药物遗传刺激和抑制将与 清醒、完整和肾上腺切除小鼠的高胰岛素-正常血糖钳夹研究。富有同情心 活动将在各种器官和组织中进行评估。拟议研究的结果将确定 下丘脑和腹侧脑干环路在肝脏碳水化合物代谢中的作用 我们对交感神经控制肝脏的了解，可能会为改善 糖尿病患者通过自主神经控制的血糖状态。

The autonomic nervous system plays a significant role in the regulation of hepatic metabolism. Activation of hepatic sympathetic nerves increases hepatic glucose production (HGP) and glycogenolysis, and increased HGP largely contributes to the pathogenesis of type 2 diabetes mellitus. Therefore, without a full understanding of the neural circuits involved in the regulation of the liver, there is a barrier to develop strategies to control glucose levels via the brain-liver pathway. The overall long-term goal of this proposal is to elucidate the fundamental relationship between central autonomic control and hepatic carbohydrate metabolism. The paraventricular nucleus (PVN) of the hypothalamus is a critical command center controlling autonomic outflow and, thereby, influencing glucose and energy homeostasis. Since impaired glucose homeostasis in diabetic patients involves central circuits controlling autonomic output, the immediate objective of this proposal is to investigate the contribution of pre-sympathetic, liver-related PVN and ventral brainstem neurons to the maintenance of HGP and insulin action using in vivo and in vitro approaches. Our preliminary observations from diet-induced obese (DIO) mice demonstrate an overall shift toward excitation in liver-related PVN neurons and a diminished suppression of excitatory neurotransmission by insulin in pre-sympathetic ventral brainstem projecting PVN neurons. Furthermore, our data also show that liver-related brainstem neurons receive excitatory inputs from PVN neurons. These observations lead to the central hypothesis that monosynaptic connections between pre-sympathetic, liver-related PVN and ventral brainstem neurons are necessary for the regulation of hepatic carbohydrate metabolism. The proposed studies will define hypothalamic and ventral brainstem circuits involved in the sympathetic control of the liver using retrograde viral tracing and circuit mapping in combination with immunostaining. The electrophysiological studies will determine the cellular properties of liver-related neurons in control and DIO mice. Functional connections between PVN and liver-related ventral brainstem neurons will be revealed with optogenetics. The proposed in vivo studies will determine the contribution of liver-related neurons to hepatic glucose production and insulin action. Pharmacogenetic stimulation and inhibition of neurons will be used in combination with hyperinsulinemic-euglycemic clamp studies in conscious intact and adrenalectomized mice. Sympathetic activity will be assessed in a variety of organs and tissues. The outcomes of the proposed studies will establish the contribution of hypothalamic and ventral brainstem circuits to hepatic carbohydrate metabolism, advance our knowledge of sympathetic control of the liver, and may provide new strategies for the improvement of glycemic status in diabetic patients via autonomic control.