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Molecularly distinct subtypes of Lhx6-positive neurons of the zona incerta differentially regulate sleep pressure and recovery sleep

ABSTRACT: Sleep pressure is regulated not only by circadian rhythms, but also by sleep homeostasis, an activity-dependent process that dissipates during sleep. Recent work implicates Lhx6-positive GABAergic neurons of the zona incerta (ZI) in regulating sleep pressure, but their precise role remains unclear. Using sleep deprivation and HiPlex single-molecule fISH, we show that Lhx6-positive ZI neurons are broadly activated by both natural and induced increases in sleep pressure and remain active for more than three hours into recovery sleep. Anterior Lhx6-positive neurons showed stronger activation. Fos induction differed across molecularly distinct subpopulations, with Nkx2-2-positive cells showing robust responses and Calb2-positive cells showing reduced activation. We also identified distinct sleep pressure-responsive Lhx6-negative Slc32a1-positive GABAergic ZI subpopulations. Finally, intersectional genetic loss of Nkx2-2 reduced and redistributed Lhx6-positive neurons, blunted their activation, and increased total sleep time. These findings reveal a central, heterogeneous role for Lhx6-positive ZI neurons in sleep homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE324128 | GEO | 2026/03/15

REPOSITORIES: GEO

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Molecularly distinct subtypes of Lhx6-positive neurons of the zona incerta differentially regulate sleep pressure and recovery sleep

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