Chandler Parris Washington, Lee Sang Soo, Duncan Leighton H, Kim Dong Won, Wu Mark N, Blackshaw Seth
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
bioRxiv. 2025 Aug 1:2025.07.30.667705. doi: 10.1101/2025.07.30.667705.
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 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.
睡眠压力是清醒期间逐渐积累的睡眠驱动力，由未定带（ZI）中表达Lhx6的γ-氨基丁酸能神经元塑造。在此，我们表明，这些神经元在自发和实验性升高的睡眠压力下均被广泛激活，并在恢复睡眠中持续活跃数小时。ZI前部的激活更强，且在分子定义的亚组中有所不同：Nkx2-2阳性神经元反应强烈，而Calb2阳性神经元反应较弱。我们还鉴定出具有不同睡眠压力反应的Lhx6阴性/Slc32a1阳性γ-氨基丁酸能ZI神经元。对Lhx6阳性神经元进行选择性基因消融会减少Lhx6阳性神经元的数量，改变其分布，减弱睡眠压力诱导的Lhx6阳性和阴性细胞的激活，并增加睡眠时间。这些发现表明，发育上特定的、分子异质性的Lhx6阳性ZI神经元形成了调节睡眠稳态的关键枢纽，并为控制睡眠压力的神经回路提供了新的见解。
