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bioRxiv · 10.1101/2025.07.30.667705

Sleep pressure is differentially regulated by molecularly distinct subtypes of Lhx6-positive and Lhx6-negative neurons of the zona incerta.

Chandler, P. W.·Lee, S. S.·Duncan, L.·Kim, D. W. T.·Wu, M.·Blackshaw, S.
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Abstract

Sleep pressure, the accumulating drive towards sleep during wakefulness, is shaped by Lhx6-positive GABAergic neurons in the zona incerta (ZI). Here, we show that these neurons are broadly activated both by spontaneous and experimentally-elevated sleep pressure, and remain active for hours into recovery sleep. Activation is stronger in anterior ZI and varies across molecularly defined subgroups: Nkx2-2-positive neurons respond vigorously, whereas Calb2-positive neurons respond weakly. We also identify Lhx6-negative/Slc32a1-positive GABAergic ZI neurons with distinct sleep pressure responses. Selective genetic ablation of Nkx2-2 in Lhx6-positive neurons reduces the number of Lhx6-positive neurons, alters their distribution, blunts sleep pressure-induced activation of both Lhx6-positive and negative cells, and increases sleep duration. These findings show that developmentally specified, molecularly heterogeneous Lhx6-positive ZI neurons form a key hub for regulating sleep homeostasis, and offer new insight into the circuitry that controls sleep pressure.

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Chandler, P. W., Lee, S. S., Duncan, L., Kim, D. W. T., Wu, M., Blackshaw, S.. 2025-08-01. Sleep pressure is differentially regulated by molecularly distinct subtypes of Lhx6-positive and Lhx6-negative neurons of the zona incerta.. https://doi.org/10.1101/2025.07.30.667705

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