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

doi:10.1016/j.neuron.2016.01.007

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

Program in Biological Sciences

Research output: Contribution to journal › Article › peer-review

70 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 language	English (US)
Pages (from-to)	842-856
Number of pages	15
Journal	Neuron
Volume	89
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2016.01.007
State	Published - Feb 17 2016

Funding

We thank Melanie Pribisko, Alex Mack Cruz, Axel Dominguez, Sohini Khan, and Kenna Molinder for technical assistance. This work was supported by grants from the NIH (D.A.L.: NS084769; S. Chen: NS077842; A.F.S.: HL109625; D.A.P.: NS060996, NS070911, DA031367); the European Research Council Starting Grant and UCL Excellence Fellowship (J.R.); the High-Tech Fund of the Dana-Farber Cancer Institute and the Ellison Foundation (M.V.); and the Mallinckrodt, Rita Allen and the Brain and Behavior Research Foundations (D.A.P.). We declare no conflicts of interest.

ASJC Scopus subject areas

General Neuroscience

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Chiu, C. N., Rihel, J., Lee, D. A., Singh, C., Mosser, E. A., Chen, S., Sapin, V., Pham, U., Engle, J., Niles, B. J., Montz, C. J., Chakravarthy, S., Zimmerman, S., Salehi-Ashtiani, K., Vidal, M., Schier, A. F., & Prober, D. A. (2016). A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States. Neuron, 89(4), 842-856. https://doi.org/10.1016/j.neuron.2016.01.007

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title = "A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States",

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.",

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

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Chiu, CN, Rihel, J, Lee, DA, Singh, C, Mosser, EA, Chen, S, Sapin, V, Pham, U, Engle, J, Niles, BJ, Montz, CJ, Chakravarthy, S, Zimmerman, S, Salehi-Ashtiani, K, Vidal, M, Schier, AF & Prober, DA 2016, 'A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States', Neuron, vol. 89, no. 4, pp. 842-856. https://doi.org/10.1016/j.neuron.2016.01.007

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AU - Chiu, Cindy N.

AU - Rihel, Jason

AU - Lee, Daniel A.

AU - Singh, Chanpreet

AU - Mosser, Eric A.

AU - Chen, Shijia

AU - Sapin, Viveca

AU - Pham, Uyen

AU - Engle, Jae

AU - Niles, Brett J.

AU - Montz, Christin J.

AU - Chakravarthy, Sridhara

AU - Zimmerman, Steven

AU - Salehi-Ashtiani, Kourosh

AU - Vidal, Marc

AU - Schier, Alexander F.

AU - Prober, David A.

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

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