GABA neurons in the ventromedial hypothalamus contribute to the counterregulatory

下丘脑腹内侧的 GABA 神经元有助于反调节

• 批准号: 10328426
• 负责人: Yanlin He
• 金额: $ 18.81万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328426
• 关键词: Animals; Blood Glucose; Brain; Calcium Channel; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Electrophysiology (science); Equilibrium; Fiber; Genes; Glucose; Glutamates; Hypoglycemia; Hypothalamic structure; Mediating; Metabolic; Molecular; Neurons; Photometry; Play; Population; Role; Testing; counterregulation; falls; gamma-Aminobutyric Acid; glycemic control; neural network; novel; novel therapeutic intervention; optogenetics; prevent; relating to nervous system; response; single-cell RNA sequencing; vesicular GABA transporter; voltage

Glucose is the primary fuel in the brain. Glucose-sensing neurons in the brain respond to glucose fall by altering their firing activities, which trigger the counterregulatory responses to prevent severe hypoglycemia. The ventromedial hypothalamus (VMH) is a critical component of neural networks that coordinate the counterregulation. While the majority of VMH neurons are glutamatergic which have been well studied, a small population of neurons in the ventrolateral subdivision of VMH (vlVMH) are GABAergic as they express vesicular GABA transporter (Vgat). The functions of these Vgat neurons in the vlVMH (VgatvlVMH neurons) have never been studied. We found that the majority of these are glucose-inhibited (GI) neurons. Since the ionic mechanisms by which GI neurons respond to hypoglycemia are less defined, these GI-VgatvlVMH neurons provide a unique opportunity to reveal the mechanisms and functions of a brain GI population. Following upon our pilot observations, here we will combine the fiber photometry, electrophysiology, optogenetics, single cell RNA-seq and CRISPR gene editing to test a general hypothesis that VgatvlVMH neurons represent a unique population of neurons which are activated during hypoglycemia and critically contribute to the counterregulatory response. The first objective is to establish the glucose-sensing functions of VgatvlVMH neurons in functional animals and to further confirm their roles in regulating blood glucose levels. Second, we will determine if the T-type voltage-gated calcium channel mediates the glucose-sensing functions of GI-VgatvlVMH neurons and therefore regulate the counterregulation. Accomplishment of these studies may reveal the important functions of a novel neural population that has never been studied before. We may also reveal ionic mechanisms for glucose-sensing functions of GI neurons. In addition, we will delineate new molecular for the brain glucose-sensing and the counterregulation, which may provide a framework for the development novel therapeutic strategies for glycemic control.

葡萄糖是大脑的主要燃料。大脑中的葡萄糖感应神经元通过改变它们的放电活动来响应葡萄糖下降，这触发了反调节反应，以防止葡萄糖下降。 严重低血糖腹内侧下丘脑（VMH）是协调反调节的神经网络的重要组成部分。虽然大多数VMH神经元是已被充分研究的GABA能神经元，但VMH腹外侧亚部（vlVMH）中的一小部分神经元是GABA能神经元，因为它们表达囊泡GABA转运蛋白（Vgat）。 这些Vgat神经元在vlVMH（VgatvlVMH神经元）中的功能从未被研究过。我们发现，这些大多数是葡萄糖抑制（GI）神经元。由于离子 GI神经元对低血糖反应的机制还不太清楚，这些GI-VgatvlVMH神经元提供了一个独特的机会来揭示大脑GI神经元对低血糖反应的机制和功能。 人口在我们的试点观察之后，在这里，我们将联合收割机纤维光度学，电生理学，光遗传学，单细胞RNA-seq和CRISPR基因编辑来测试一个通用的 假设VgatvlVMH神经元代表了在低血糖期间被激活并对反调节反应起关键作用的独特神经元群体。第一个目标是在功能动物中建立VgatvlVMH神经元的葡萄糖敏感功能，并进一步证实它们在调节血糖水平中的作用。其次，我们将确定T型电压门控钙通道是否介导GI-VgatvlVMH神经元的葡萄糖敏感功能，从而调节反调节。完成这些 研究可能揭示一种以前从未研究过的新型神经群的重要功能。我们还可能揭示GI神经元葡萄糖敏感功能的离子机制。此外，我们将描绘新的分子的大脑葡萄糖传感和反调节，这可能会提供一个框架，开发新的治疗策略，血糖控制。