Melatonin’s role in the timing of sleep onset is conserved in nocturnal mice

Melatonin supplementation strengthens non‐restorative sleep rhythms and its temporal alignment in both humans and night-active rodents. Of note, although the sleep cycle is reversed in day-active and night-active (nocturnal) mammals, both, produce melatonin at night under the control of the circadian clock. The effects of exogenous melatonin on sleep and sleepiness are relatively clear, but its endogenous role in sleep, particularly, in timing sleep onset (SO), remains poorly understood. We show in nocturnal mice that the increases in mid-nighttime sleep episodes, and the mid-nighttime decline in activity, are coupled to nighttime melatonin signaling. Furthermore, we show that endogenous melatonin modulates SO by reducing the threshold for wake-to-sleep transitioning. Such link between melatonin and SO timing may explain phenomena such as increased sleep propensity in circadian rhythm sleep disorders and chronic insomnia in patients with severely reduced nocturnal melatonin levels. Our findings demonstrate that melatonin’s role in sleep is evolutionarily conserved, effectively challenging the argument that melatonin cannot play a major role in sleep regulation in nocturnal mammals, where the main activity phase coincides with high melatonin levels.