GABA neurons in the ventromedial hypothalamus contribute to the counterregulatory

葡萄糖是大脑的主要燃料。大脑中的葡萄糖敏感神经元通过改变它们的放电活动来对葡萄糖下降做出反应，这触发了反调节反应，以防止 严重低血糖。下丘脑腹内侧核(VMH)是协调逆调节的神经网络的重要组成部分。虽然大多数VMH神经元是谷氨酸能的，但VMH腹外侧区(VlVMH)的一小部分神经元是GABA能的，因为它们表达囊泡状GABA转运体(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。因为爱奥尼亚 GI神经元对低血糖的反应机制尚不明确，这些GI-VgatvlVMH神经元为揭示大脑GI的机制和功能提供了一个独特的机会 人口。根据我们的初步观察，我们将在这里结合纤维光度学、电生理学、光遗传学、单细胞rna-seq和crispr基因编辑来测试一种通用的 假设VgatvlVMH神经元代表一组独特的神经元，这些神经元在低血糖时被激活，并对反调节反应起关键作用。第一个目标是在功能动物中建立VgatvlVMH神经元的血糖感知功能，并进一步确认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了Gi-VgatvlVMH神经元的葡萄糖敏感功能，从而调节了反向调节。实现这些目标 研究可能会揭示一种以前从未被研究过的新型神经细胞群体的重要功能。我们还可能揭示GI神经元的血糖敏感功能的离子机制。此外，我们还将为大脑的葡萄糖感应和反向调节提供新的分子，这可能为开发新的血糖控制治疗策略提供框架。

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.