Orexin neurons inhibit sleep to promote arousal

Roberto Luca, Stefano Nardone, Kevin P. Grace, Anne Venner, Michela Cristofolini, Sathyajit S. Bandaru, Lauren T. Sohn, Dong Kong, Takatoshi Mochizuki, Bianca Viberti, Lin Zhu, Antonino Zito, Thomas E. Scammell, Clifford B. Saper, Bradford B. Lowell, Patrick M. Fuller () and Elda Arrigoni ()
Additional contact information
Roberto Luca: Beth Israel Deaconess Medical Center and Harvard Medical School
Stefano Nardone: Diabetes and Metabolism. Beth Israel Deaconess Medical Center and Harvard Medical School
Kevin P. Grace: Beth Israel Deaconess Medical Center and Harvard Medical School
Anne Venner: Beth Israel Deaconess Medical Center and Harvard Medical School
Michela Cristofolini: Beth Israel Deaconess Medical Center and Harvard Medical School
Sathyajit S. Bandaru: Beth Israel Deaconess Medical Center and Harvard Medical School
Lauren T. Sohn: Beth Israel Deaconess Medical Center and Harvard Medical School
Dong Kong: F.M. Kirby Neurobiology Center. Children’s Hospital and Harvard Medical School
Takatoshi Mochizuki: Graduate School of Science and Engineering. University of Toyama
Bianca Viberti: Beth Israel Deaconess Medical Center and Harvard Medical School
Lin Zhu: Beth Israel Deaconess Medical Center and Harvard Medical School
Antonino Zito: Massachusetts General Hospital
Thomas E. Scammell: Beth Israel Deaconess Medical Center and Harvard Medical School
Clifford B. Saper: Beth Israel Deaconess Medical Center and Harvard Medical School
Bradford B. Lowell: Diabetes and Metabolism. Beth Israel Deaconess Medical Center and Harvard Medical School
Patrick M. Fuller: Beth Israel Deaconess Medical Center and Harvard Medical School
Elda Arrigoni: Beth Israel Deaconess Medical Center and Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31591-y

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