Normal sleep bouts are not essential for C. elegans survival and FoxO is important for compensatory changes in sleep

Abstract

BackgroundSleep deprivation impairs learning, causes stress, and can lead to death. Notch and JNK-1 pathways impact C. elegans sleep in complex ways; these have been hypothesized to involve compensatory sleep. C. elegans DAF-16, a FoxO transcription factor, is required for homeostatic response to decreased sleep and DAF-16 loss decreases survival after sleep bout deprivation. Here, we investigate connections between these pathways and the requirement for sleep after mechanical stress.ResultsReduced function of Notch ligand LAG-2 or JNK-1 kinase resulted in increased time in sleep bouts during development. These animals were inappropriately easy to arouse using sensory stimulation, but only during sleep bouts. This constellation of defects suggested that poor quality sleep bouts in these animals might activate homeostatic mechanisms, driving compensatory increased sleep bouts. Testing this hypothesis, we found that DAF-16 FoxO function was required for increased sleep bouts in animals with defective lag-2 and jnk-1, as loss of daf-16 reduced sleep bouts back to normal levels. However, loss of daf-16 did not suppress arousal thresholds defects. Where DAF-16 function was required differed; in lag-2 and jnk-1 animals, daf-16 function was required in neurons or muscles, respectively, suggesting that disparate tissues can drive a coordinated response to sleep need. Sleep deprivation due to mechanical stimulation can cause death in many species, including C. elegans, suggesting that sleep is essential. We found that loss of sleep bouts in C. elegans due to genetic manipulation did not impact their survival, even in animals lacking DAF-16 function. However, we found that sleep bout deprivation was often fatal when combined with the concurrent stress of mechanical stimulation.ConclusionsTogether, these results in C. elegans confirm that Notch and JNK-1 signaling are required to achieve normal sleep depth, suggest that DAF-16 is required for increased sleep bouts when signaling decreases, and that failure to enter sleep bouts is not sufficient to cause death in C. elegans, unless paired with concurrent mechanical stress. These results suggest that mechanical stress may directly contribute to death observed in previous studies of sleep deprivation and/or that sleep bouts have a uniquely restorative role in C. elegans sleep.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0408-1) contains supplementary material, which is available to authorized users.

A salt-induced kinase (SIK) is required for the metabolic regulation of sleep

“…Central nervous system neurons control sleep in a top-down fashion [85, 86], but bottom-up metabolic signals from glia [17, 24, 87, 88], muscle cells [32, 88-90] and adipocytes [91, 92] affect activity of sleep regulating neurons. While several gene products have been reported to regulate both metabolism and sleep [4, 9, 21-23, 25, 26, 32, 41, 89, 90, 93, 94], the mechanism of the metabolic regulation of sleep has heretofore remained opaque.…”

A wake-active locomotion circuit depolarizes a sleep-active neuron to switch on sleep

“…Like its mammalian counterparts, RIS depolarizes at sleep onset. RIS is crucial for sleep induction because its ablation leads to a virtually complete loss of detectable sleep bouts [25][26][27]. The small, invariant nervous system, its mapped connectome, and the transparency of C. elegans facilitate neural circuit analysis [28].…”

Genetic sleep deprivation: using sleep mutants to study sleep functions

“…One of the strongest mutations in Drosophila is sleepless with > 80% sleep reduction [105]. Caenorhabditis elegans physiological sleep during lethargus is reduced by about 80% in hyperactive mutants (egl-30gf [127] or acy-1gf [128]) as well as in ALA mutant ceh-17(À) (locomotion quiescence 20 min after heat shock) [35] and is virtually abolished across several physiological conditions (reduction here displayed as 99%) by aptf-1 À/À or ablation of the sleep-active RIS neuron [124,134,139].…”

“…Sleep bouts become undetectable in these “RIS mutants” during many life stages and physiological conditions. aptf‐1 mutant worms show no severe hyperactivity during wake, indicating that they are not strongly hyperaroused following sleep loss and that sleep loss is likely not a consequence of increased arousal . Thus, during many physiological conditions, RIS inactivation in C. elegans presents both a virtually complete as well as a highly specific model for sleeplessness (Fig ).…”