Brain Circuits Involved in the Sympathetic Control of the Liver

参与肝脏交感神经控制的脑回路

• 批准号: 10379952
• 负责人: Andrei Derbenev
• 金额: $ 57.26万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379952
• 关键词: Achievement; Adrenal Glands; Autonomic nervous system; Brain; Brain Stem; Cells; Conscious; Data; Electrophysiology (science); Glucose; Glucose Clamp; Goals; Hepatic; Homeostasis; Hypothalamic structure; Impairment; In Vitro; Injections; Insulin; Knowledge; Label; Lead; Light; Liver; Location; Maintenance; Measures; Mus; Nerve; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obese Mice; Organ; Outcome; Output; Pathogenesis; Pathway interactions; Pharmacogenetics; Phenotype; Physiological; Plasma; Play; Prevalence; Property; Public Health; Regulation; Research; Role; Site; Slice; Spinal Cord; Sympathetic Nervous System; Techniques; Testing; Tissues; Tracer; Viral; awake; blood glucose regulation; carbohydrate metabolism; diabetic patient; diet-induced obesity; glucose production; glucose tolerance; glycogenolysis; improved; in vivo; lipid metabolism; liver metabolism; nerve supply; neural circuit; neurochemistry; neuromechanism; neurotransmission; novel strategies; optogenetics; paraventricular nucleus; patch clamp; postsynaptic; prevent; response

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.

自主神经系统在肝脏代谢的调节中起着重要的作用。 肝交感神经的激活增加肝葡萄糖产生（HGP）和糖原分解， 增加的HGP在很大程度上促成了2型糖尿病的发病机制。因此，如果没有完整的 了解参与肝脏调节的神经回路，有一个障碍， 通过脑-肝途径控制葡萄糖水平的策略。本提案的总体长期目标是 阐明中枢自主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心， 自主流出，从而影响葡萄糖和能量稳态。由于血糖受损 糖尿病患者的体内平衡涉及控制自主输出的中央回路， 本研究的目的是探讨交感神经前、肝相关PVN和腹侧脑干的作用 神经元的HGP和胰岛素的作用的维持使用在体内和体外的方法。我们的初步 从饮食诱导的肥胖（DIO）小鼠的观察表明，肝脏相关的兴奋的整体转变， PVN神经元和减少抑制兴奋性神经传递的胰岛素在交感神经前 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 神经元接收来自PVN神经元的兴奋性输入。这些观察导致了一个中心假设， 交感神经前、肝相关PVN和腹侧脑干神经元之间的单突触连接是 调节肝脏碳水化合物代谢所必需的。拟议的研究将确定 下丘脑和腹侧脑干回路参与肝脏的交感神经控制， 病毒追踪和电路作图结合免疫染色。电生理研究将 确定对照和DIO小鼠中肝脏相关神经元的细胞特性。功能连接 PVN与肝相关腹侧脑干神经元之间的关系将通过光遗传学来揭示。的拟定 体内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 行动上神经元的药物遗传学刺激和抑制将与以下药物联合使用： 在清醒的完整和肾上腺切除小鼠中的高胰岛素-正葡萄糖钳夹研究。交感 将在各种器官和组织中评估活性。拟议研究的结果将确定 下丘脑和腹侧脑干回路对肝脏碳水化合物代谢作用研究进展 我们对肝脏交感神经控制的认识，并可能为改善肝脏的功能提供新的策略。 糖尿病患者通过自主控制的血糖状态。