Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
Department of Neuroscience and the Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Neuron. 2014 Apr 2;82(1):151-66. doi: 10.1016/j.neuron.2014.01.040. Epub 2014 Mar 13.
How the circadian clock regulates the timing of sleep is poorly understood. Here, we identify a Drosophila mutant, wide awake (wake), that exhibits a marked delay in sleep onset at dusk. Loss of WAKE in a set of arousal-promoting clock neurons, the large ventrolateral neurons (l-LNvs), impairs sleep onset. WAKE levels cycle, peaking near dusk, and the expression of WAKE in l-LNvs is Clock dependent. Strikingly, Clock and cycle mutants also exhibit a profound delay in sleep onset, which can be rescued by restoring WAKE expression in LNvs. WAKE interacts with the GABAA receptor Resistant to Dieldrin (RDL), upregulating its levels and promoting its localization to the plasma membrane. In wake mutant l-LNvs, GABA sensitivity is decreased and excitability is increased at dusk. We propose that WAKE acts as a clock output molecule specifically for sleep, inhibiting LNvs at dusk to promote the transition from wake to sleep.
昼夜节律钟如何调节睡眠时机还不甚清楚。在这里，我们鉴定到一个果蝇突变体，wide awake（wake），其在黄昏时表现出明显的睡眠起始延迟。在一组促觉醒的生物钟神经元，即大型腹外侧神经元（l-LNvs）中丧失 wake 会损害睡眠起始。WAKE 水平呈周期性波动，在黄昏时达到峰值，并且 l-LNvs 中的 WAKE 表达受 Clock 依赖性调控。显著的是，Clock 和 cycle 突变体也表现出严重的睡眠起始延迟，这种延迟可以通过在 LNvs 中恢复 WAKE 表达来挽救。WAKE 与 GABA A 受体抗二氯苯（RDL）相互作用，上调其水平并促进其定位于质膜。在 wake 突变体 l-LNvs 中，黄昏时 GABA 敏感性降低，兴奋性增加。我们提出，WAKE 作为一种专门针对睡眠的生物钟输出分子起作用，在黄昏时抑制 LNvs，以促进从清醒到睡眠的转变。
