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: 10443455
• 负责人: Yanlin He
• 金额: $ 43.52万
• 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/10443455
• 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; Glucose; Glutamates; Hormones; Hypoglycemia; Hypothalamic structure; Impairment; Ion Channel; Lateral; Life; Medial; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Target; Monitor; Mus; Nature; 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; base; blood glucose regulation; counterregulation; diabetic; diabetic patient; falls; gamma-Aminobutyric Acid; glycemic control; in vivo; neural circuit; neural network; neurochemistry; novel; novel strategies; novel therapeutic intervention; optogenetics; patch sequencing; prevent; relating to nervous system; 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。大脑中的葡萄糖感应神经元通过以下方式对葡萄糖下降做出反应： 改变它们的放电活动，从而触发反调节反应以防止严重的低血糖。 腹内侧下丘脑（VMH）是协调神经网络的关键组成部分， 反调节虽然大多数VMH神经元是已被充分研究的多巴胺能神经元， VMH腹外侧亚部（vlVMH）中的一小部分神经元是GABA能的，因为它们表达 囊泡GABA转运体（Vgat）。这些Vgat神经元在vlVMH中的功能（VgatvlVMH神经元） 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。以来 GI神经元对低血糖反应的离子机制尚不明确，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，我们将结合联合收割机纤维光度学，电生理学，光遗传学，补丁- seq和CRISPR基因编辑，以测试VgatvlVMH神经元代表独特GI的一般假设。 在低血糖期间被激活并严重促进反调节的人群 反应第一个目的是建立功能性VgatvlVMH神经元的葡萄糖敏感功能， 动物，并进一步确认其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Cav3.2介导胃肠道神经元的葡萄糖敏感功能， 因此，调节反调节。最后，我们将确定VgatvlVMH起源的电路，调节 反调节这些研究的完成可能会揭示新型神经元的重要功能 这是以前从未被研究过的。我们还可以揭示葡萄糖敏感的离子机制 GI神经元的功能。此外，我们将描绘一个新的脑葡萄糖传感的分子靶点， 反调节，这可能为开发新的治疗策略提供框架， 血糖控制