The systems biology of sleep: toward integrative understanding of molecular and circuit-based mechanisms of sleep

Sleep, a universal biological phenomenon, is regulated by multiscale processes, from molecular mechanisms to cellular networks. While the underlying mechanisms, particularly those governing sleep homeostasis, were poorly understood, recent technological breakthroughs have facilitated the identification of molecular and circuit-based mechanisms. Advances in mouse genetics, including next-generation genetics that bypass the need for crossing and postnatal gene knockout methods, enable the comprehensive identification of molecular components for sleep regulation by combining them with noninvasive, large-scale sleep measurements. Elucidated mechanisms include Ca 2+ -related and protein kinase/phosphatase-mediated signaling, supporting the phosphorylation hypothesis of sleep. The molecular signaling forms ‘cellular sleepiness’ in sleep regulatory neurons to modulate neuronal activity. These integrated understandings of multiscale mechanisms will lead to a system-level understanding of sleep regulation. • Sleep is an emerging topic for research in systems biology. • Advances in mouse genetics facilitate the identification of sleep-regulatory genes. • Intracellular signaling affecting the neuronal activity may serve as ‘cellular sleepiness’. • Molecular mechanisms of sleep are now being integrated with circuit-level mechanisms. • Principles of sleep regulation provide hints for controlling and engineering sleep.