GABA neurons in the ventromedial hypothalamus contribute to the counterregulatory

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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.