GABA neurons in the ventromedial hypothalamus contribute to the counterregulatory response

下丘脑腹内侧的 GABA 神经元有助于反调节反应

• 批准号: 10597219
• 负责人: Yanlin He
• 金额: $ 42.32万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597219
• 关键词: Address; Amygdaloid structure; Animals; Blood Glucose; Brain; CRISPR/Cas technology; Calcium; Calcium Channel; Closure by clamp; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; Data; Development; Electrophysiology (science); Equilibrium; Estrogen Receptor alpha; Event; Failure; Fiber; Genes; Genetic; Glucose; Glutamates; Hormones; Hyperinsulinism; Hypoglycemia; Hypothalamic structure; Impairment; Ion Channel; Lateral; Life; Maps; Medial; Mediating; Mediator; Modeling; Molecular; Molecular Target; Monitor; Mus; Nature; Neuroanatomy; Neurons; Photometry; Physiological; Play; Population; Property; Reporting; Role; SF1; Slice; Structure of nucleus infundibularis hypothalami; Structure of paraventricular nucleus of thalamus; Subgroup; Substantia nigra structure; Testing; Work; blood glucose regulation; counterregulation; diabetic; diabetic patient; falls; gamma-Aminobutyric Acid; glycemic control; in vivo; neural; neural circuit; neural network; neurochemistry; novel; novel strategies; novel therapeutic intervention; optogenetics; patch sequencing; prevent; response; type I diabetic; ventromedial hypothalamic nucleus; vesicular GABA transporter; voltage

Project Summary 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) is 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 our pilot observations, we will combine fiber photometry, electrophysiology, optogenetics, Patch- seq, and CRISPR gene editing to test a general hypothesis that VgatvlVMH neurons represent a unique GI population that 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 Cav3.2 mediates the glucose-sensing functions of GI neurons and therefore regulate the counterregulation. Finally, we will identify VgatvlVMH-originated circuits that regulate the counterregulation. The 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 the glucose-sensing functions of GI neurons. Further, we will delineate a new molecular target for brain glucose-sensing and the counterregulation, which may provide a framework for the development of novel therapeutic strategies for glycemic control.

项目摘要 葡萄糖是大脑的主要燃料。大脑中的葡萄糖感觉神经元对葡萄糖下降的反应 改变它们的激发活动，从而触发反调节反应，以防止严重的低血糖。 下丘脑腹内侧核(VMH)是神经网络的重要组成部分，它协调 反监管。虽然大多数VMH神经元是谷氨酸能的，这一点已经得到了很好的研究，但 VMH腹外侧区(VlVMH)的少量神经元是GABA能的 囊泡型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，这些神经元中的大多数是葡萄糖抑制(GI)神经元。自.以来 GI神经元对低血糖反应的离子机制还不是很清楚，这些GI-VgatvlVMH 神经元提供了一个独特的机会来揭示大脑GI群体的机制和功能。 在我们的初步观察之后，我们将结合纤维光度学、电生理学、光遗传学、贴片- SEQ和CRISPR基因编辑，以检验VgatvlVMH神经元代表独特GI的一般假设 在低血糖期间被激活并对反调节起关键作用的人群 回应。第一个目标是建立VgatvlVMH神经元的糖感受功能。 并进一步确认它们在调节血糖水平方面的作用。第二，我们将确定是否 T型电压门控钙通道Cav3.2介导GI神经元的葡萄糖敏感功能 因此，应对反规制进行规范。最后，我们将识别VgatvlVMH起源的电路，这些电路调节 反监管。这些研究的完成可能会揭示一种新的神经的重要功能 以前从未被研究过的人口。我们还可能揭示葡萄糖传感的离子机制。 胃肠道神经元的功能。此外，我们将描绘一个新的分子靶点，用于大脑的葡萄糖传感和 反调节，这可能为开发新的治疗策略提供一个框架 血糖控制。