Identifying Sleep Regulatory Genes Using a<i>Drosophila</i>Model of Insomnia

Seugnet, Laurent; Suzuki, Yasuko; Thimgan, Matthew S.; Donlea, Jeffrey M.; Gimbel, Sarah I.; Gottschalk, Laura; Duntley, Stephen P.; Shaw, Paul J.

doi:10.1523/jneurosci.5629-08.2009

Cited by 107 publications

(87 citation statements)

References 56 publications

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“…It is possible that genetic changes result in modified regulation of fatbody-secreted proteins, thereby modulating sleep independently of triglyceride levels. Short-sleeping selected flies have a reduced lifespan and elevated levels of the sleep-suppressing neurotransmitter dopamine (Seugnet et al, 2009). Interestingly, both the S flies described in this study and the short-sleeping selected flies have elevated lipid levels.…”

Section: Research Articlementioning

confidence: 58%

Altered regulation of sleep and feeding contribute to starvation resistance in Drosophila

Mašek

Reynolds

Bollinger

et al. 2014

Journal of Experimental Biology

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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.

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Section: Research Articlementioning

confidence: 58%

Altered regulation of sleep and feeding contribute to starvation resistance in Drosophila

Mašek

Reynolds

Bollinger

et al. 2014

Journal of Experimental Biology

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“…Sleep is thought to be an essential biological function, since sleep deprivation can lead to death (Rechtschaffen et al, 1983;Shaw et al, 2002). In addition, several previously identified sleep mutants have decreased lifespans, suggesting that sleep and organismal lifespan may be linked (Shaw et al, 2002;Cirelli et al, 2005;Seugnet et al, 2009) (but also see Kume et al, 2005 (Fig. 3C), and 12.81 Ϯ 0.48 d for females (data not shown).…”

Section: Sleep Is Correlated With Levels Of Sra Proteinmentioning

confidence: 78%

Calcineurin and Its Regulator Sra/DSCR1 Are Essential for Sleep inDrosophila

Nakai

Horiuchi²,

Tsuda³

et al. 2011

J. Neurosci.

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Sleep is a fundamental biological process for all animals. However, the molecular mechanisms that regulate sleep are still poorly understood. Here we report that sleep-like behavior in Drosophila is severely impaired by mutations in sarah (sra), a member of the Regulator of Calcineurin (RCAN) family of genes. Sleep reduction in sra mutants is highly correlated with decreases in Sra protein levels. Pan-neural expression of sra rescues this behavioral phenotype, indicating that neuronal sra function is required for normal sleep. Since Sra regulates calcineurin (CN), we generated and examined the behavior of knock-out mutants for all Drosophila CN genes: CanA-14F, Pp2B-14D, and CanA1 (catalytic subunits), and CanB and CanB2 (regulatory subunits). While all mutants show at least minor changes in sleep, CanA-14F KO and CanB KO have striking reductions, suggesting that these are the major CN subunits regulating sleep. In addition, neuronal expression of constitutively active forms of CN catalytic subunits also significantly reduces sleep, demonstrating that both increases and decreases in CN activity inhibit sleep. sra sleep defects are suppressed by CN mutations, indicating that sra and CN affect sleep through a common mechanism. Our results demonstrate that CN and its regulation by Sra are required for normal sleep in Drosophila and identify a critical role of Ca 2ϩ /calmodulin-dependent signaling in sleep regulation.

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“…The lack of a homeostatic response seen in for R flies may represent either an adaptation that allows animals to better withstand the negative effects of waking, or it may indicate that foraging disrupts regulatory processes, thereby preventing flies from obtaining needed sleep. Because deficits in short-term memory are a robust consequence of sleep loss (13,22,23), we evaluated short-term memory (STM) using aversive phototaxic suppression (APS) in for R , for s , and for s2 flies following 12 h of SD. In the APS, flies are individually placed in a T maze and allowed to choose between a lighted and darkened chamber (13,24).…”

Section: Resultsmentioning

confidence: 99%

“…SD is known to result in robust cognitive impairments in humans (10), rodents (11), bees (12), and flies (13,14). However, the extent to which prolonged waking will result in cognitive impairments is strongly influenced by the environmental context.…”

mentioning

confidence: 99%

foraging alters resilience/vulnerability to sleep disruption and starvation in Drosophila

Donlea

Leahy

Thimgan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Recent human studies suggest that genetic polymorphisms allow an individual to maintain optimal cognitive functioning during sleep deprivation. If such polymorphisms were not associated with additional costs, selective pressures would allow these alleles to spread through the population such that an evolutionary alternative to sleep would emerge. To determine whether there are indeed costs associated with resiliency to sleep loss, we challenged natural allelic variants of the foraging gene (for) with either sleep deprivation or starvation. Flies with high levels of Protein Kinase G (PKG) (for R ) do not display deficits in short-term memory following 12 h of sleep deprivation. However, short-term memory is significantly disrupted when for R flies are starved overnight. In contrast, flies with low levels of PKG (for s , for s2 ) show substantial deficits in short-term memory following sleep deprivation but retain their ability to learn after 12 h of starvation. We found that for R phenotypes could be largely recapitulated in for s flies by selectively increasing the level of PKG in the α/β lobes of the mushroom bodies, a structure known to regulate both sleep and memory. Together, these data indicate that whereas the expression of for may appear to provide resilience in one environmental context, it may confer an unexpected vulnerability in other situations. Understanding how these tradeoffs confer resilience or vulnerability to specific environmental challenges may provide additional clues as to why an evolutionary alternative to sleep has not emerged.A lthough sleep is a behavioral state that is conserved across a diverse range of species, the biological functions of sleep remain unknown. Sleep deprivation (SD) has been shown to negatively impact cognition, but individual responses to sleep loss can vary significantly within a population (1). Recent studies suggest that a portion of this variability may be influenced by genetic factors (2). For example, polymorphisms for PERIOD 3 (PER3), a circadian clock gene, can predict the magnitude of cognitive impairment and sleep homeostasis in response to a night of SD in humans (2). Although these genetic contributions may attenuate impairments following SD, the tradeoffs associated with resistance to sleep loss remain unknown. Presumably, the potential costs must be substantial. Thus, it is likely that the price of protection from sleep loss that can be conferred by allelic variation in one environment may induce a cost when manifested in a different environment. To date, putative costs of resiliency to sleep loss have not been identified in humans or any model organism.foraging (for), which codes for Protein Kinase G (PKG), is maintained in wild-type populations as a genetic polymorphism that results in either higher or lower levels of PKG activity (3). The allele associated with higher levels of PKG ("rover"; for R ) results in larvae with longer foraging trails between food patches, whereas the allele associated with lower levels of PKG ("sitter"; for s ) results i...

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Identifying Sleep Regulatory Genes Using aDrosophilaModel of Insomnia

Cited by 107 publications

References 56 publications

Altered regulation of sleep and feeding contribute to starvation resistance in Drosophila

Altered regulation of sleep and feeding contribute to starvation resistance in Drosophila

Calcineurin and Its Regulator Sra/DSCR1 Are Essential for Sleep inDrosophila

foraging alters resilience/vulnerability to sleep disruption and starvation in Drosophila

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