Kavli Affiliate: Seth Blackshaw
| Authors: Parris Washington Chandler, Sang Soo Lee, Leighton Duncan, Dong Won Thomas Kim, Mark Wu and Seth Blackshaw
| Summary:
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.