Conservation of sleep: insights from non-mammalian model systems

Abstract

The past 10 years have seen new approaches to elucidating genetic pathways regulating sleep. The emerging theme is that sleep-like states are conserved in evolution, with similar signaling pathways playing a role in animals as distantly related as flies and humans. We review the evidence for the presence of sleep states in non-mammalian species including zebrafish (Danio rerio), fruitflies (Drosophila melanogaster) and roundworms (Caenorhabditis elegans). We describe conserved sleep-regulatory molecular pathways with a focus on cAMP and epidermal growth factor signaling; neurotransmitters with conserved effects on sleep and wake regulation, including dopamine and GABA; and a conserved molecular response to sleep deprivation involving the chaperone protein BiP/GRP78.

Figure 1

Schematic showing pathways that have been identified by more than one model systems as having an impact on sleep. (a) The cAMP–CREB pathway has been shown to impact sleep /wake behavior in the fly, worm, and mammalian systems. Mutations of genes which code for the enzymes adenylate cyclase and cyclic AMP phosphodiesterase in Drosophila melanogaster and in Caenorhabditis elegans have led to the following conclusions: elevation of cAMP promotes wake behavior and reduction of cAMP, at least in the fly, promotes sleep. Over expression of a murine cAMP dependent kinase and expression of an activated form of CREB in the fly leads to decreased sleep. Mice lacking the α and δ isoforms of CREB have low CREB activity and decreased wakefulness. Therefore CREB activity is involved in the maintenance of wakefulness in both the mouse and the fly. (b) The Epidermal Growth Factor Receptor (EGFR). EGFR ligands increased sleep and suppressed activity in both mammals and fruit flies. Mice with reduced EGFR function have increased quiescence. Phosphorylation of an extracellular signal-regulated kinase (ERK) is a downstream event correlated with the sleep induction by EGF in the fly. In the worm, mutants with reduced EGFR function show increased activity during the sleep-like state of lethargus and over expression of the single EGF ligand, LIN-3, causes quiescence during periods of normal activity. This LIN-3 effect requires phospholipase C-γ. Steps in each of the pathways are labeled by the enzyme or receptor; substrates of enzymatic reactions are connected by black arrows next to the enzyme responsible for the step; large grey arrows indicate binding and/or activation; a circled F indicates evidence from Drosophila, a circled W indicates evidence from C. elegans, a circled M indicates evidence from a mammalian system, and a circled P indicates phosphorylation.