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Published August 21, 2019 | Accepted Version + Supplemental Material
Journal Article Open

The Serotonergic Raphe Promote Sleep in Zebrafish and Mice


The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents.

Additional Information

© 2019 Elsevier Inc. Received 20 September 2018, Revised 11 April 2019, Accepted 22 May 2019, Available online 24 June 2019. Data and Code Availability: The datasets generated and analyzed in this study are available from the corresponding author upon request. We thank the Gradinaru and Prober labs for helpful discussions; Viveca Sapin, Uyen Pham, Hannah Hurley, and Tasha Cammidge for zebrafish husbandry assistance; Chanpreet Singh for generating the Tg(aanat2:ChR2-YFP) line; Elisha D. Mackey for supervising mouse breeding; Andres Collazo for advice on 2-photon laser ablation; Justin S. Bois for advice on statistics; and Catherine M. Oikonomou for critical reading of the manuscript. This work was supported by the NIH (F32NS082010 to G.O.; NIH BRAIN RF1MH117069 to V.G.; and R01NS070911, R01NS101158, R01NS095824, and R01NS101665 to D.A.P.), Center for Molecular and Cellular Neuroscience of the Chen Institute (to V.G.) and the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (to V.G.). G.M.C. is supported by a PGS-D from the National Science and Engineering Research Council (NSERC) of Canada. V.G. is a Heritage Principal Investigator supported by the Heritage Medical Research Institute. Author Contributions: G.O., M.A., D.A.P., and V.G. designed experiments. G.O. performed zebrafish experiments. M.A. performed mouse experiments. R.Z. performed zebrafish electrophysiology. G.M.C. performed mouse histology and quantification. C.M. isolated the zebrafish tph2 promoter. V.G. supervised rodent aspects of the project. D.A.P. supervised zebrafish aspects of the project. G.O., M.A., V.G., and D.A.P. wrote the paper with input from R.Z. and G.M.C. The authors declare no competing interests.

Attached Files

Accepted Version - nihms-1530614.pdf

Supplemental Material - 1-s2.0-S089662731930491X-mmc1.pdf


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August 22, 2023
October 20, 2023