Neuromedin U2 receptor signaling mediates alteration of sleep–wake architecture in rats

Ahnaou, A.; Drinkenburg, Wilhelmus

doi:10.1016/j.npep.2011.01.004

Cited by 12 publications

(10 citation statements)

References 52 publications

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“…Nmu overexpression consolidates waking bouts into periods of prolonged hyperactivity and shortens and reduces initiations to sleep, similar to insomnia. The effect of Nmu on sleep/wake architecture has not been extensively examined in other species, but our results are consistent with the short-term effect of acute intracerebroventricular injection of Nmu in rats, namely prolonged wakefulness and disrupted sleep (Ahnaou and Drinkenburg, 2011). …”

Section: Discussionsupporting

confidence: 88%

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

Chiu

Rihel

Lee

et al. 2016

Neuron

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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.

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Section: Discussionsupporting

confidence: 88%

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

Chiu

Rihel

Lee

et al. 2016

Neuron

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“…The mammalian orthologue of Hugin, Neuromedian U (NMU) (Melcher et al, 2006), has been previously implicated in sleep regulation. While NMU injection in rats does not change total sleep time, it changes sleep architecture (Ahnaou & Drinkenburg, 2011). NMU overexpression decreases sleep in zebrafish (Chiu et al, 2016), which is in contrast to our finding that hugin CRISPR mutants exhibit decreased baseline sleep.…”

Section: Discussioncontrasting

confidence: 99%

Hugin⁺neurons link the sleep homeostat to circadian clock neurons

Schwarz

King

Hsu

et al. 2020

Preprint

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Sleep is controlled by homeostatic mechanisms, which drive sleep following periods of wakefulness, and a circadian clock, which regulates sleep timing in a daily cycle. Homeostatic sleep drive sometimes overrides the clock, such that recovery sleep after deprivation occurs outside the normal circadian rest period. However, mechanisms underlying this effect are unknown. We find that sleep-promoting dorsal fan-shaped body (dFB) neurons, effectors of homeostatic sleep in Drosophila, are presynaptic to hugin+ neurons, previously identified as circadian output neurons regulating locomotor activity rhythms. Sleep deprivation decreases hugin+ neuronal activity, which likely suppresses circadian control to promote recovery sleep driven by dFB neurons. Indeed, removal of hugin+ neurons increases sleep-promoting effects of dFB neurons. Trans-synaptic mapping reveals that hugin+ neurons feed back onto s-LNv central clock neurons, which also show Hugin-dependent decreased activity upon sleep loss.These findings identify a circuit-based mechanism through which sleep drive modulates the circadian system to promote recovery sleep following deprivation.

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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SUMMARY The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals. It is entrained by light, but resistant to temperature shifts that entrain peripheral clocks [1–5]. The SCN expresses many functionally important neuropeptides including vasoactive intestinal peptide (VIP), which drives light entrainment, synchrony, and amplitude of SCN cellular clocks, and organizes circadian behavior [5–16]. The transcription factor LHX1 drives SCN Vip expression, and cellular desynchrony in Lhx1-deficient SCN largely results from Vip loss [17,18]. LHX1 regulates many genes other than Vip, yet activity rhythms in Lhx1-deficient mice are similar to Vip−/− mice under light-dark cycles, and only somewhat worse in constant conditions. We suspected that LHX1 targets other than Vip have circadian functions overlooked in previous studies. In this study, we compared circadian sleep and temperature rhythms of Lhx1 and Vip-deficient mice, and found loss of acute light control of sleep in Lhx1 but not Vip mutants. We also found loss of circadian resistance to fever in Lhx1 but not Vip mice, which was partially recapitulated by heat application to cultured Lhx1-deficient SCN. Having identified VIP-independent functions of LHX1, we mapped the VIP-independent transcriptional network downstream of LHX1, and a largely separable VIP-dependent transcriptional network. The VIP-independent network does not affect core clock amplitude and synchrony, unlike the VIP-dependent network. . These studies identify Lhx1 as the first gene required for temperature resistance of the SCN clockworks, and demonstrate that acute light control of sleep is routed through the SCN and its immediate output regions.

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Neuromedin U2 receptor signaling mediates alteration of sleep–wake architecture in rats

Cited by 12 publications

References 52 publications

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

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

Hugin⁺neurons link the sleep homeostat to circadian clock neurons

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

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Neuromedin U2 receptor signaling mediates alteration of sleep–wake architecture in rats

Cited by 12 publications

References 52 publications

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

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

Hugin+neurons link the sleep homeostat to circadian clock neurons

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

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Hugin⁺neurons link the sleep homeostat to circadian clock neurons