Neurofibromin 1 mediates sleep depth in Drosophila

Abstract

Neural regulation of sleep and metabolic homeostasis are critical in many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic function. The RAS GTPase-activating gene Neurofibromin (Nf1) has been implicated in the regulation of sleep and metabolic rate, raising the possibility that it serves to integrate these processes, but the effects on sleep consolidation and physiology remain poorly understood. A key hallmark of sleep depth in mammals and flies is a reduction in metabolic rate during sleep. Here, we use indirect calorimetry to define the role of Nf1 on sleep-dependent changes in metabolic rate. Flies lacking Nf1 fail to suppress metabolic rate during sleep, raising the possibility that loss of Nf1 prevents flies from integrating sleep and metabolic state. Sleep of Nf1 mutant flies is fragmented with a reduced arousal threshold in Nf1 mutants, suggesting Nf1 flies fail to enter deep sleep. The effects of Nf1 on sleep can be localized to a subset of neurons expressing the GABA receptor Rdl. Selective knockdown of Nf1 in Rdl-expressing neurons increases gut permeability and reactive oxygen species (ROS) in the gut, suggesting a critical role for deep sleep in gut homeostasis. Together, these findings suggest Nf1 acts in GABA-sensitive neurons to modulate sleep depth in Drosophila.

Neurofibromin 1 regulates early developmental sleep in Drosophila

“…Moreover, both children and adults with NF1 exhibit disturbed sleep and poor sleep quality ( Licis et al, 2013 ; Johnson et al, 2005 ; Leschziner et al, 2013 ). Studies in Drosophila Nf1 mutants in mature adulthood have likewise demonstrated disruptions to both sleep and rest:activity circadian rhythms ( Williams et al, 2001 ; Bai et al, 2018 ; Bai and Sehgal, 2015 ; Brown et al, 2022 ; Machado Almeida et al, 2021 ). Specifically, adult Nf1 mutants exhibit loss of rest:activity rhythms under constant conditions, and a reduction in sleep duration with associated sleep fragmentation.…”