A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States
Open accessAbstract
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.
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eQTL, PheWAS, and model organism evidence support the hypothesis that introgressed alleles downregulate NMUR2 in the brain leading to increased morningness.
“In the Supplemental Text, we describe eQTL, PheWAS, and model organism evidence supporting the hypothesis that introgressed alleles downregulate NMUR2 in the brain leading to increased morningness61–65.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [64]
The Results section reports that adult zebrafish lacking nmur2 have reduced activity, with the strongest effect around morning light onset; the Discussion links Nmu to the transition from nighttime sleep to daytime wakefulness (page not available in our copy). This supplies model-organism evidence that the pathway affects morning arousal, but it does not establish that reduced NMUR2 increases morningness. The eQTL, PheWAS, and introgressed-allele components are not findings of this source. (LLM, conf=0.86)
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“This pattern of expression accords with nmu expression in the adult mammalian CNS in hypothalamus, brainstem, and spinal cord (Austin et al., 1994; Fujii et al., 2000; Graham et al., 2003; Howard et al., 2000; Ivanov et al., 2002; Nogueiras et al., 2006; Szekeres et al., 2000).”
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- Authors
- 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.
- Affiliations
- California Institute of Technology (US)
- Harvard University (US)
- Corresponding author
- Schier, Alexander F.
- Prober, David A.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 89
- Issue
- 4
- Pages
- 842-856
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4851465
- OpenAlex
- W2273790468
- Cited by
- 101
- References
- 58
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 5 · 2023: 10 · 2022: 11 · 2021: 12 · 2020: 14 · 2019: 9 · 2018: 8 · 2017: 9 · 2016: 5
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- edoc (University of Basel) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL109625, R01HL109525)
- National Institute on Drug Abuse (DA-031367, R01DA031367)
- National Institute of Neurological Disorders and Stroke (NS060996, R01NS101158, F31NS077842, NS-070911, R01NS070911, F32NS084769, NS084769, R00NS060996, NS077842, K99NS060996)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- neuromedin U, sleep-wake regulation, arousal, zebrafish larvae, corticotropin-releasing hormone receptor 1, hyperactivity, brainstem neurons, hypothalamic-pituitary-adrenal axis
- MeSH terms
- Age Factors, Aniline Compounds, Animals, Brain Stem, Gene Expression Regulation, Humans, Hypothalamo-Hypophyseal System, Larva, Mice, Transgenic, Motor Activity, Neurons, Neuropeptides, Pituitary-Adrenal System, Pyrimidines, Sleep, Wakefulness, Zebrafish, Signal Transduction, Receptors, Complement 3b, Receptors, Neurotransmitter, Zebrafish Proteins
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