LAUSR

The ventromedial hypothalamic nucleus (VMH) is a well-established hub for energy and glucose homeostasis. In particular, VMH neurons are thought to be important for initiating the counter-regulatory response to hypoglycaemia, and ex vivo electrophysiology and immunohistochemistry data indicate a clear role for VMH neurons in sensing glucose concentration. However, the temporal response of VMH neurons to physiologically relevant changes in glucose availability in vivo has been hampered by a lack of available tools for measuring neuronal activity over time. Since the majority of neurons within the VMH are glutamatergic and can be targeted using the vesicular glutamate transporter Vglut2, we expressed cre-dependent GCaMP7s in Vglut2 cre mice and examined the response profile of VMH to intraperitoneal injections of glucose, insulin, and 2-deoxyglucose (2DG). We show that reduced available glucose via insulin-induced hypoglycaemia and 2DG-induced glucoprivation, but not hyperglycaemia induced by glucose injection, inhibits VMH Vglut2 neuronal population activity in vivo. Surprisingly, this inhibition was maintained for at least 45 mins despite prolonged hypoglycaemia and initiation of a counter-regulatory response. Thus, although VMH stimulation, via pharmacological, electrical or optogenetic approaches, is sufficient to drive a counter-regulatory response, our data suggest VMH Vglut2 neurons are not the main drivers required to do so, since VMH Vglut2 neuronal population activity remains suppressed during hypoglycaemia and glucoprivation.