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Cited by 130Sleep and Wakefulness ResearchCircadian rhythm and melatoninNeuroscience of respiration and sleep

Orexin neurons inhibit sleep to promote arousal

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De Luca, Roberto, Nardone, Stefano, Grace, Kevin P., Venner, Anne, Cristofolini, Michela, Bandaru, Sathyajit S., Sohn, Lauren T., Kong, Dong +9 more·2022·Nature Communications
DOI 10.1038/s41467-022-31591-yPMC PMC9293990
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Abstract

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state.

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Cited by

Sorted by citations

Authors
De Luca, R., Nardone, S., Grace, K. P., Venner, A., Cristofolini, M., Bandaru, S. S., Sohn, L. T., Kong, D., Mochizuki, T., Viberti, B., Zhu, L., Zito, A., Scammell, T. E., Saper, C. B., Lowell, B. B., Fuller, P. M., & Arrigoni, E.
Affiliations
  • Beth Israel Deaconess Medical Center (US)
  • Harvard University (US)
  • University of Toyama (JP)
Corresponding author
  • Fuller, Patrick M.
  • Arrigoni, Elda
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-07-18
Volume
13
Issue
1
Pages
4163-4163
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-31591-y
PMC
PMC9293990
OpenAlex
W4285727802
Cited by
130
References
5
Citations by year
2026: 42 · 2025: 29 · 2024: 38 · 2023: 15 · 2022: 5 · 2020: 1
FWCI
11.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (5r01ns122589-03, DK057521, DK089044, DK046200, NS073613, NS072337)
  • National Heart, Lung, and Blood Institute (P01HL149630)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, R01DK075632, R01DK089044, R01DK108797, P30DK046200, R01DK096010, R01DK122976)
  • National Institute of Neurological Disorders and Stroke (R01NS107315, R01NS072337, R01 NS122589, R01NS085477, R01NS103161, R01NS073613)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098056)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
Keywords
orexin neurons, sleep-wake regulation, wakefulness, arousal, ventrolateral preoptic nucleus, sleep-promoting neurons, feedforward circuits, glutamate co-release, sleep attacks, daytime sleepiness
MeSH terms
Orexins, Animals, Arousal, Humans, Neurons, Sleep, Wakefulness

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