Sleep-promoting effects of threonine link amino acid metabolism in Drosophila neuron to GABAergic control of sleep drive

Abstract

Emerging evidence indicates the role of amino acid metabolism in sleep regulation. Here we demonstrate sleep-promoting effects of dietary threonine (SPET) in Drosophila. Dietary threonine markedly increased daily sleep amount and decreased the latency to sleep onset in a dose-dependent manner. High levels of synaptic GABA or pharmacological activation of metabotropic GABA receptors (GABAB-R) suppressed SPET. By contrast, synaptic blockade of GABAergic neurons or transgenic depletion of GABAB-R in the ellipsoid body R2 neurons enhanced sleep drive non-additively with SPET. Dietary threonine reduced GABA levels, weakened metabotropic GABA responses in R2 neurons, and ameliorated memory deficits in plasticity mutants. Moreover, genetic elevation of neuronal threonine levels was sufficient for facilitating sleep onset. Taken together, these data define threonine as a physiologically relevant, sleep-promoting molecule that may intimately link neuronal metabolism of amino acids to GABAergic control of sleep drive via the neuronal substrate of sleep homeostasis.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

Gene Expression and Alternative Splicing Dynamics Are Perturbed in Head Transcriptomes of Heterospecifically Mated Females

“…Although such pathways are not directly classi ed as behavioral or reproductive, some of their metabolic functions have been previously detected in conspeci c experiments in D. melanogaster [28,38]. These networks regulate energy balance [39,40] and nutritional uptake in brain tissues [41], and have been directly linked to several postcopulatory behaviors, including circadian rhythms [42,43], nutrient sensing, exploratory behavior for speci c nutrient source, consumption and posterior oviposition [26,27,75,76]. Consequently, mated D. melanogaster females experience a major switch in their diet following copulation [77], consuming more amino acids during the dark phase [26].…”

Growth regulation by amino acid transporters in Drosophila larvae

“…In Drosophila adults, nutrients and amino acids are also crucial since flies need food resources to regulate their life cycle, to survive, to have social interactions and to reproduce. In adults, the essential amino acid threonine promotes sleep via GABA neurons in the brain and three other amino acids ( l -Glutamate, l -Alanine and l -Aspartate) are able to directly stimulate DH44 + brain neurons to increase in food consumption via a putative amino acid transporter, CG13248 [ 53 , 54 ]. In adult females, nutrients play also an important role in germline stem cells development.…”

Modulation of sleep-courtship balance by nutritional status in Drosophila

“…Previous studies have identified several neuronal populations that mediate the effects of dietary protein and amino acids on adult Drosophila behavior. These include dopaminergic Wedge neurons, EB Ring5 neurons, and peptidergic neurons expressing diuretic hormone-44, insulin-like peptide-2, or leucokinin ( Brown et al, 2020 ; Ki and Lim, 2019 ; Liu et al, 2017 ; Murphy et al, 2016 ; Yang et al, 2018 ; Yurgel et al, 2019 ). It would be interesting to determine whether these neurons are involved in modulating the sleep-courtship balance by nutrition.…”