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

Abstract

Summary 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 corticotrophin-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 likely 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.

Familial Aggregation of Insomnia

“…40 Recently, a sleep-regulating gene (neuromedin U [Nmu]) was associated with a severe form of insomnia, characterized by substantial reductions in sleep time, increased sleep latency, and increased wake time in zebrafish. 41 Given the high rate of familial aggregation of insomnia, the present findings corroborate the relevance of conducting future studies related to the genetic component of insomnia.…”

An LHX1-Regulated Transcriptional Network Controls Sleep/Wake Coupling and Thermal Resistance of the Central Circadian Clockworks

“…Components of this transcriptional module like Ankfn1 (the murine homolog of Drosophila wide awake ) and Nms (a member of the sleep-regulating neuromedin family) may contribute to light control of sleep [44,53,54]. Furthermore, localization of these and many other VIP-independent, LHX1-regulated transcripts in the SCN core and central domains give insight into the SCN circuitry underlying regulation of sleep timing by light.…”

Synaptic transmission parallels neuromodulation in a central food-intake circuit

“…This complexity, however, only underlines the use of numerically smaller nervous systems such as Drosophila 's to generate a foundation to build upon. Moreover, NMU/NMU-like systems may have similar functions not just in mammals and Drosophila but also other vertebrates such as fish (Chiu et al, 2016; Li et al, 2015) and other invertebrates such as C. elegans (Maier et al, 2010). In summary, our findings should encourage research in other organisms, such as the involvement of NMU and NMU homologs in relaying chemosensory information onto endocrine systems, and more ambitiously, to elucidate their connectomes in order to allow comparative analyses of the underlying network architecture.…”

“…Among these, neuromedinU (NMU) is known for its profound effects on feeding behavior and activity; NMU inhibits feeding behavior (Howard et al, 2000), promotes physical activity (Novak et al, 2007; Chiu et al, 2016), and is involved in energy homeostasis (Nakazato et al, 2000; Ivanov et al, 2002) and stress response (Hanada et al, 2001; Zeng et al, 2006). Hugin is a member of the pyrokinin/PBAN (pheromone biosynthesis activating neuropeptide) peptide family and a Drosophila homolog of NMU that has recently gained traction due to similar effects on behavior in the fly: increased hugin signaling inhibits food intake and promotes locomotion (Melcher et al., 2006; Schoofs et al, 2014; Bader et al, 2007b).…”