Cellular Stress Induces a Protective Sleep-like State in C. elegans

Abstract

Summary Sleep is recognized to be ancient in origin, with vertebrates and invertebrates experiencing behaviorally quiescent states that are regulated by conserved genetic mechanisms[1, 2]. Despite its conservation throughout phylogeny the function of sleep remains debated. Hypotheses for the purpose of sleep include nervous system-specific functions such as modulation of synaptic strength and clearance of metabolites from the brain[3, 4], and more generalized cellular functions such as energy conservation and macromolecule biosynthesis[5]. These models are supported by the identification of synaptic and metabolic processes that are perturbed during prolonged wakefulness. It remains to be seen whether perturbations of cellular homeostasis in turn drive sleep. Here we show that under conditions of cellular stress, including noxious heat, cold, hypertonicity, and tissue damage, the nematode Caenorhabditis elegans engages a behavioral quiescence program. The stress-induced quiescent state displays properties of sleep and is dependent on the ALA neuron, which mediates the conserved soporific effect of Epidermal Growth Factor (EGF) ligand overexpression. We characterize heat-induced quiescence in detail and show that it is indeed dependent on components of EGF signaling, providing physiological relevance to the behavioral effects of EGF family ligands. We find that following noxious heat exposure, quiescence-defective animals show elevated expression of cellular stress reporter genes and are impaired for survival, demonstrating the benefit of stress-induced behavioral quiescence. These data provide evidence that cellular stress can induce a protective sleep-like state in C. elegans and suggest that a deeply conserved function of sleep is to mitigate disruptions of cellular homeostasis.

Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory inAplysia

“…Sleep, through discrete mechanisms, occurs either developmentally during the quiescent periods between larval stages or following the induction of cellular stress with the amount of sleep correlated to the degree of the stressful stimulus. 22,[77][78][79][80] Thus, the timing of developmental sleep and the stress-induced sleep during adulthood in C. elegans make it more difficult to study the interactions of sleep with memory. To determine the persistence of sleep deprivation on shortterm memory, animals were sleep deprived for 9 h and allowed to recover for 24 or 48 h prior to learning that food is inedible (LFI) training.…”

Sleep and Development in Genetically Tractable Model Organisms

“…Cessation of locomotion and feeding can also be induced in adult C. elegans by satiety, stress, or genetic manipulations. Examples of the latter include heat-shock-induced activation of epidermal growth factor signaling (Van Buskirk and Sternberg 2007), mutations affecting cGMP, cAMP, or TGF-b signaling You et al 2008;Iwanir et al 2013), specific rescue of a peptidergic or insulin/insulin-like signaling pathway (Driver et al 2013;Hill et al 2014;Nagy et al 2014;Nelson et al 2014), or optogenetic activation of an avoidance response-promoting neuron (Cho and Sternberg 2014). Such findings potentially decouple worm sleep from molting.…”

A Conserved GEF for Rho-Family GTPases Acts in an EGF Signaling Pathway to Promote Sleep-like Quiescence inCaenorhabditis elegans

“…Further, we demonstrate that activation of VAV-1 is sufficient to induce quiescence behavior in active adult animals. Moreover, we discovered that VAV-1 requires GEF activity and acts in the neurosecretory ALA interneuron, a neuron previously shown to be critical for sleep-like behavior, to mediate behavioral quiescence (Van Buskirk and Sternberg 2007;Hill et al 2014). We also found that VAV-1 regulates the protein levels of two critical ALA signaling molecules, LET-23/EGFR and IDA-1/phogrin, required for ALA function (Van Buskirk and Sternberg 2007;Zhou et al 2007;Van Buskirk and Sternberg 2010).…”

“…The sleeplike behavioral quiescence induced by cellular stress results in an initial short-lived quiescent state (1 hr) followed by brief recovery and a second, prolonged quiescent state (several hours) . Hill et al (2014) proposed that the prolonged bout of quiescence is critical for regulating cellular homeostasis. From our analyses, we have found that while vav-1 mutants are defective in both cellular stressinduced sleep-like behavioral quiescence periods, we observed complete rescue of the second bout only on wild-type vav-1 expression from either its 59 cis-regulatory control element or the ALA-specific 59 cis-regulatory element.…”

“…The ALA interneuron and LET-23/EGFR were previously found to be required for lethargus and cellular stressand EGF-induced sleep-like quiescence (Van Buskirk and Sternberg 2007;Hill et al 2014). Because we have found consistent expression of vav-1 in ALA (Figure 1) and altered accumulation of LET-23/EGFR in ALA of vav-1 mutants (Figure 2, A and B), we hypothesized that VAV-1 is involved in behavioral sleep-like quiescence.…”