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 葡萄糖是大脑中的主要燃料。大脑中的葡萄糖感应神经元对葡萄糖的反应掉落 改变其发射活动，这会引发反调节反应以防止严重的低血糖。 腹侧下丘脑（VMH）是协调神经网络的关键组成部分 反调节。虽然大多数VMH神经元是谷氨酸能进行了很好的研究，但 VMH（VLVMH）的腹外侧细分中的神经元人数很少，因为它们表达了 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。我们发现其中大多数是抑制葡萄糖的（GI）神经元。自从 胃肠道神经元对低血糖反应的离子机制较少，这些Gi-vgatvlvmh 神经元提供了一个独特的机会来揭示脑胃肠道人群的机制和功能。 遵循试点观察，我们将结合光纤光度法，电生理学，光遗传学，斑块 - SEQ和CRISPR基因编辑，以检验VGATVLVMH神经元代表独特的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 回复。第一个目标是建立VGATVLVMH神经元在功能中的葡萄糖感应函数 动物并进一步确认它们在调节血糖水平的作用。第二，我们将确定是否 T型电压门控钙通道Cav3.2介导GI神经元的葡萄糖感应功能和 因此调节反调节。最后，我们将确定vGATVLVMH原始电路的调节电路 反调节。这些研究的完成可能会揭示新神经的重要功能 以前从未研究过的人口。我们还可能揭示葡萄糖感应的离子机制 胃肠道神经元的功能。此外，我们将描述一个新的分子靶标，用于脑葡萄糖感应和 反调节，这可能为开发新型治疗策略提供框架 血糖控制。