GABA neurons in the ventromedial hypothalamus contribute to the counterregulatory response

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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.