A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States

Cindy N. Chiu, Jason Rihel, Daniel A. Lee, Chanpreet Singh, Eric A. Mosser, Shijia Chen, Viveca Sapin, Uyen Pham, Jae Engle, Brett J. Niles, Christin J. Montz, Sridhara Chakravarthy, Steven Zimmerman, Kourosh Salehi-Ashtiani, Marc Vidal, Alexander F. Schier*, David A. Prober

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Neuromodulation of arousal states ensures that an animal appropriately responds to its environment and engages in behaviors necessary for survival. However, the molecular and circuit properties underlying neuromodulation of arousal states such as sleep and wakefulness remain unclear. To tackle this challenge in a systematic and unbiased manner, we performed a genetic overexpression screen to identify genes that affect larval zebrafish arousal. We found that the neuropeptide neuromedin U (Nmu) promotes hyperactivity and inhibits sleep in zebrafish larvae, whereas nmu mutant animals are hypoactive. We show that Nmu-induced arousal requires Nmu receptor 2 and signaling via corticotropin releasing hormone (Crh) receptor 1. In contrast to previously proposed models, we find that Nmu does not promote arousal via the hypothalamic-pituitary-adrenal axis, but rather probably acts via brainstem crh-expressing neurons. These results reveal an unexpected functional and anatomical interface between the Nmu system and brainstem arousal systems that represents a novel wake-promoting pathway. Video Abstract: Chiu et al. perform a genetic screen in zebrafish and identify Nmu as a regulator of sleep/wake behaviors. They show that Nmu overexpression activates brainstem Crh neurons and that Nmu-induced arousal requires Crh signaling, thus identifying a novel vertebrate arousal circuit.

Original languageEnglish (US)
Pages (from-to)842-856
Number of pages15
JournalNeuron
Volume89
Issue number4
DOIs
StatePublished - Feb 17 2016

ASJC Scopus subject areas

  • Neuroscience(all)

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