A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions

Abstract

Dysregulation of sleep and feeding has widespread health consequences. Despite extensive epidemiological evidence for interactions between sleep and metabolic function, little is known about the neural or molecular basis underlying the integration of these processes. Drosophila melanogaster potently suppress sleep in response to starvation, and powerful genetic tools allow for mechanistic investigation of sleep-metabolism interactions. We have previously identified neurons expressing the neuropeptide leucokinin (Lk) as being required for starvation-mediated changes in sleep. Here, we demonstrate an essential role for Lk neuropeptide in metabolic regulation of sleep. Further, we find that the activity of Lk neurons is modulated by feeding state and circulating nutrients, with reduced activity in response to glucose and increased activity under starvation conditions. Both genetic silencing and laser-mediated microablation localize Lk-mediated sleep regulation to a single pair of Lk neurons within the lateral horn (LHLK) that project near primary sleep and metabolic centers of the brain. A targeted screen identified a critical role for AMP-activated protein kinase (AMPK) in starvation-modulated changes in sleep. Disruption of AMPK function in Lk neurons suppresses sleep and increases LHLK activity in fed flies, phenocopying the starvation state. Taken together, these findings localize feeding state-dependent regulation of sleep to a single pair of neurons within the fruit fly brain and provide a system for investigating the cellular basis of sleep-metabolism interactions.