title: 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.
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Chanpreet
authors.initials: C
authors.lastname: Singh
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: Grigorios
authors.initials: G
authors.lastname: Oikonomou
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States.
authors.forename: David A
authors.identifier: http://orcid.org/0000-0002-7371-4675
authors.initials: DA
authors.lastname: Prober
mesh_terms: D000818:Animals; D001143:Arousal / Q000187:drug effects*; D001342:Autonomic Nervous System Diseases; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000172:deficiency / Q000378:metabolism*; D000068797:Orexins / Q000378:metabolism*; D014851:Wakefulness / Q000187:drug effects*; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*
chemical_list: D000068797:Orexins; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine
keywords: hypocretin; neuroscience; noradrenaline; norepinephrine; orexin; sleep; zebrafish