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Published September 16, 2015 | Published
Journal Article Open

Norepinephrine is required to promote wakefulness and for hypocretin-induced arousal in zebrafish

Abstract

Pharmacological studies in mammals suggest that norepinephrine (NE) plays an important role in promoting arousal. However, the role of endogenous NE is unclear, with contradicting reports concerning the sleep phenotypes of mice lacking NE due to mutation of dopamine β-hydroxylase (dbh). To investigate NE function in an alternative vertebrate model, we generated dbh mutant zebrafish. In contrast to mice, these animals exhibit dramatically increased sleep. Surprisingly, despite an increase in sleep,dbh mutant zebrafish have a reduced arousal threshold. These phenotypes are also observed in zebrafish treated with small molecules that inhibit NE signaling, suggesting that they are caused by the lack of NE. Using genetic overexpression of hypocretin (Hcrt) and optogenetic activation of hcrt-expressing neurons, we also find that NE is important for Hcrt-induced arousal. These results establish a role for endogenous NE in promoting arousal and indicate that NE is a critical downstream effector of Hcrt neurons.

Additional Information

© 2015 The authors. Copyright Singh et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. We thank Mike Walsh for assistance with the optogenetic and tapping assays, Andres Collazo for imaging assistance, Viveca Sapin and Jae Engle for genotyping assistance, and Catherine Oikonomou for critical reading of the manuscript. This work was supported by grants from the NIH (GO: F32NS082010; DAP: NS060996, NS070911 and DA031367), the Mallinckrodt Foundation, the Rita Allen Foundation and the Brain and Behavior Research Foundation (D.A.P.). We declare no competing interests.

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