LAUSR

To maintain metabolic homeostasis, motivated behaviors are driven by neuronal circuits that process information encoding the animal's energy state. Such circuits likely include ventromedial hypothalamus (VMH) glutamatergic neurons that project throughout the brain to drive food intake and energy expenditure. Targets of VMH glutamatergic neurons include proopiomelanocortin (POMC) neurons in the arcuate nucleus which, when activated, inhibit food intake. While an energy-state-sensitive, glutamate circuit between the VMH and POMC neurons has been previously indicated, the significance and details of this circuit have not been fully elucidated. This, the goal of the present work was to add to the understanding of this circuit. Using a knockout strategy, the data show that the VMH glutamateàPOMC neuron circuit is important for the inhibition of food intake. Conditional deletion of the vesicular glutamate transporter (VGLUT2) in the VMH results in increased bodyweight and increased food intake following a fast in both male and female mice. Additionally, the targeted blunting of glutamate release from the VMH resulted in an approximately 32% reduction in excitatory inputs to POMC cells suggesting that this circuit may respond to changes in energy state to affect POMC activity. Indeed, we found that glutamate release is increased at VMH-to-POMC synapses during feeding and POMC AMPA receptors switch from a calcium-permeable state to a calcium-impermeable state during fasting. Collectively, these data indicate that there is an energy-balance-sensitive VMH-to-POMC circuit conveying excitatory neuromodulation onto POMC cells at both pre- and post-synaptic levels, that may contribute to maintaining appropriate food intake and body mass.