Orexin neurons inhibit sleep to promote arousal

Roberto De 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, Elda Arrigoni
Nature Communications (2022)


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 wakestabilizing 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.