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Serine metabolism in the brain regulates starvation-induced sleep suppression in Drosophila melanogaster.

ABSTRACT: Sleep and metabolism are physiologically and behaviorally intertwined; however, the molecular basis for their interaction remains poorly understood. Here, we identified a serine metabolic pathway as a key mediator for starvation-induced sleep suppression. Transcriptome analyses revealed that enzymes involved in serine biosynthesis were induced upon starvation in Drosophila melanogaster brains. Genetic mutants of astray (aay), a fly homolog of the rate-limiting phosphoserine phosphatase in serine biosynthesis, displayed reduced starvation-induced sleep suppression. In contrast, a hypomorphic mutation in a serine/threonine-metabolizing enzyme, serine/threonine dehydratase (stdh), exaggerated starvation-induced sleep suppression. Analyses of double mutants indicated that aay and stdh act on the same genetic pathway to titrate serine levels in the head as well as to adjust starvation-induced sleep behaviors. RNA interference-mediated depletion of aay expression in neurons, using cholinergic Gal4 drivers, phenocopied aay mutants, while a nicotinic acetylcholine receptor antagonist selectively rescued the exaggerated starvation-induced sleep suppression in stdh mutants. Taken together, these data demonstrate that neural serine metabolism controls sleep during starvation, possibly via cholinergic signaling. We propose that animals have evolved a sleep-regulatory mechanism that reprograms amino acid metabolism for adaptive sleep behaviors in response to metabolic needs.

SUBMITTER: Sonn JY

PROVIDER: S-EPMC6142195 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Serine metabolism in the brain regulates starvation-induced sleep suppression in Drosophila melanogaster.

Sonn Jun Young JY Lee Jongbin J Sung Min Kyung MK Ri Hwajung H Choi Jung Kyoon JK Lim Chunghun C Choe Joonho J

Proceedings of the National Academy of Sciences of the United States of America 20180618 27

Sleep and metabolism are physiologically and behaviorally intertwined; however, the molecular basis for their interaction remains poorly understood. Here, we identified a serine metabolic pathway as a key mediator for starvation-induced sleep suppression. Transcriptome analyses revealed that enzymes involved in serine biosynthesis were induced upon starvation in Drosophila melanogaster brains. Genetic mutants of astray (aay), a fly homolog of the rate-limiting phosphoserine ...[more]

PMID: 29915051

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Project description:Animal-associated microorganisms (microbiota) dramatically influence the nutritional and physiological traits of their hosts. To expand our understanding of such influences, we predicted bacterial genes that influence a quantitative animal trait by a comparative genomic approach, and we extended these predictions via mutant analysis. We focused on Drosophila melanogaster starvation resistance (SR). We first confirmed that D. melanogaster SR responds to the microbiota by demonstrating that bacterium-free flies have greater SR than flies bearing a standard 5-species microbial community, and we extended this analysis by revealing the species-specific influences of 38 genome-sequenced bacterial species on D. melanogaster SR. A subsequent metagenome-wide association analysis predicted bacterial genes with potential influence on D. melanogaster SR, among which were significant enrichments in bacterial genes for the metabolism of sulfur-containing amino acids and B vitamins. Dietary supplementation experiments established that the addition of methionine, but not B vitamins, to the diets significantly lowered D. melanogaster SR in a way that was additive, but not interactive, with the microbiota. A direct role for bacterial methionine metabolism genes in D. melanogaster SR was subsequently confirmed by analysis of flies that were reared individually with distinct methionine cycle Escherichia coli mutants. The correlated responses of D. melanogaster SR to bacterial methionine metabolism mutants and dietary modification are consistent with the established finding that bacteria can influence fly phenotypes through dietary modification, although we do not provide explicit evidence of this conclusion. Taken together, this work reveals that D. melanogaster SR is a microbiota-responsive trait, and specific bacterial genes underlie these influences.IMPORTANCE Extending descriptive studies of animal-associated microorganisms (microbiota) to define causal mechanistic bases for their influence on animal traits is an emerging imperative. In this study, we reveal that D. melanogaster starvation resistance (SR), a model quantitative trait in animal genetics, responds to the presence and identity of the microbiota. Using a predictive analysis, we reveal that the amino acid methionine has a key influence on D. melanogaster SR and show that bacterial methionine metabolism mutants alter normal patterns of SR in flies bearing the bacteria. Our data further suggest that these effects are additive, and we propose the untested hypothesis that, similar to bacterial effects on fruit fly triacylglyceride deposition, the bacterial influence may be through dietary modification. Together, these findings expand our understanding of the bacterial genetic basis for influence on a nutritionally relevant trait of a model animal host.

Project description:Animals respond to changes in food availability by adjusting sleep and foraging strategies to optimize their fitness. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation resistance that are dependent on geographic location, food availability and evolutionary history. How behaviors that include sleep and feeding vary in Drosophila with increased starvation resistance is unclear. We have generated starvation-resistant flies through experimental evolution to investigate the relationship between foraging behaviors and starvation resistance. Outbred populations of D. melanogaster were selected for starvation resistance over 60 generations. This selection process resulted in flies with a threefold increase in total lipids that survive up to 18 days without food. We tested starvation-selected (S) flies for sleep and feeding behaviors to determine the effect that selection for starvation resistance has had on foraging behavior. Flies from three replicated starvation-selected populations displayed a dramatic reduction in feeding and prolonged sleep duration compared to fed control (F) populations, suggesting that modified sleep and feeding may contribute to starvation resistance. A prolonged larval developmental period contributes to the elevated energy stores present in starvation-selected flies. By preventing S larvae from feeding longer than F larvae, we were able to reduce energy stores in adult S flies to the levels seen in adult F flies, thus allowing us to control for energy storage levels. However, the reduction of energy stores in S flies fails to generate normal sleep and feeding behavior seen in F flies with similar energy stores. These findings suggest that the behavioral changes observed in S flies are due to genetic regulation of behavior rather than elevated lipid levels. Testing S-F hybrid individuals for both feeding and sleep revealed a lack of correlation between food consumption and sleep duration, indicating further independence in genetic factors underlying the sleep and feeding changes observed in S flies. Taken together, these findings provide evidence that starvation selection results in prolonged sleep and reduced feeding through a mechanism that is independent of elevated energy stores. These findings suggest that changes in both metabolic function and behavior contribute to the increase in starvation resistance seen in flies selected for starvation resistance.

Project description:How to respond to starvation determines fitness. One prominent behavioral response is increased locomotor activities upon starvation, also known as Starvation-Induced Hyperactivity (SIH). SIH is paradoxical as it promotes food seeking but also increases energy expenditure. Despite its importance in fitness, the genetic contributions to SIH as a behavioral trait remains unexplored. Here, we examined SIH in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association studies. We identified 23 significant loci, corresponding to 14 genes, significantly associated with SIH in adult Drosophila. Gene enrichment analyses indicated that genes encoding ion channels and mRNA binding proteins (RBPs) were most enriched in SIH. We are especially interested in RBPs because they provide a potential mechanism to quickly change protein expression in response to environmental challenges. Using RNA interference, we validated the role of syp in regulating SIH. syp encodes Syncrip (Syp), an RBP. While ubiquitous knockdown of syp led to semi-lethality in adult flies, adult flies with neuron-specific syp knockdown were viable and exhibited decreased SIH. Using the Temporal and Regional Gene Expression Targeting (TARGET) system, we further confirmed the role of Syp in adult neurons in regulating SIH. To determine how syp is regulated by starvation, we performed RNA-seq using the heads of flies maintained under either food or starvation conditions. RNA-seq analyses revealed that syp was alternatively spliced under starvation while its expression level was unchanged. We further generated an alternatively-spliced-exon-specific knockout (KO) line and found that KO flies showed reduced SIH. Together, this study demonstrates a significant genetic contribution to SIH as a behavioral trait, identifies syp as a SIH gene, and highlights the significance of RBPs and post-transcriptional processes in the brain in regulating behavioral responses to starvation.

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Serine metabolism in the brain regulates starvation-induced sleep suppression in Drosophila melanogaster.

Publications

Serine metabolism in the brain regulates starvation-induced sleep suppression in <i>Drosophila melanogaster</i>.

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