Melatonin Is Required for the Circadian Regulation of Sleep
Sleep is an evolutionarily conserved behavioral state whose regulation is poorly understood. A classical model posits that sleep is regulated by homeostatic and circadian mechanisms. Several factors have been implicated in mediating the homeostatic regulation of sleep, but molecules underlying the circadian mechanism are unknown. Here we use animals lacking melatonin due to mutation of arylalkylamine N-acetyltransferase 2 (aanat2) to show that melatonin is required for circadian regulation of sleep in zebrafish. Sleep is dramatically reduced at night in aanat2 mutants maintained in light/dark conditions, and the circadian regulation of sleep is abolished in free-running conditions. We find that melatonin promotes sleep downstream of the circadian clock as it is not required to initiate or maintain circadian rhythms. Additionally, we provide evidence that melatonin may induce sleep in part by promoting adenosine signaling, thus potentially linking circadian and homeostatic control of sleep.
© 2015 Elsevier Inc. Received: April 14, 2014; Revised: December 15, 2014; Accepted: January 27, 2015; Published: March 5, 2015. We thank Jason Rihel, Kathy Tamai, Michael Rosbash, Daniel Lee, Catherine Oikonomou, and Chanpreet Singh for critical reading of the manuscript and Melanie Pribisko Yen for assistance with melatonin isolation. This work was supported by a Della Martin postdoctoral fellowship (E.M.), NIH grants (G.O.: F32NS082010; D.A.P.: NS060996, NS070911 and DA031367), the Mallinckrodt Foundation, the Rita Allen Foundation, and the Brain and Behavior Research Foundation (D.A.P.). Author Contributions: A.V.G. performed all experiments except circadian rhythm and ELISA assays (E.A.M.) and arousal threshold assays (G.O.). A.V.G., E.A.M., G.O., and D.A.P. analyzed the data and wrote the manuscript.
Supplemental Material - mmc1.pdf