Department of Neuroscience, Robert J. and Nancy D. Carney Institute for Brain Science, Brown University, Providence, Rhode Island 02912.
Department of Ecology and Evolution, Brown University, Providence, Rhode Island 02912.
Genetics. 2018 Dec;210(4):1369-1381. doi: 10.1534/genetics.118.301551. Epub 2018 Oct 15.
An essential characteristic of sleep is heightened arousal threshold, with decreased behavioral response to external stimuli. The molecular and cellular mechanisms underlying arousal threshold changes during sleep are not fully understood. We report that loss of UNC-7 or UNC-9 innexin function dramatically reduced sleep and decreased arousal threshold during developmentally timed sleep in UNC-7 function was required in premotor interneurons and UNC-9 function was required in motor neurons in this paradigm. Simultaneous transient overexpression of UNC-7 and UNC-9 was sufficient to induce anachronistic sleep in adult animals. Moreover, loss of UNC-7 or UNC-9 suppressed the increased sleep of EGL-4 gain-of-function animals, which have increased cyclic-GMP-dependent protein kinase activity. These results suggest gap junctions may act downstream of previously identified sleep regulators. In other paradigms, the NCA cation channels act upstream of gap junctions. Consistent with this, diminished NCA channel activity in robustly increased arousal thresholds during sleep bouts in L4-to-adult developmentally timed sleep. Total time in sleep bouts was only modestly increased in animals lacking NCA channel auxiliary subunit UNC-79, whereas increased channel activity dramatically decreased sleep. Loss of EGL-4 or innexin proteins suppressed UNC-79 loss-of-function sleep and arousal defects. In , the ion channel narrow abdomen, an ortholog of the NCA channels, drive the pigment dispersing factor (PDF) neuropeptide release, regulating circadian behavior. However, in , we found that loss of the PDF receptor PDFR-1 did not suppress gain-of-function sleep defects, suggesting an alternative downstream pathway. This study emphasizes the conservation and importance of neuronal activity modulation during sleep, and unequivocally demonstrates that gap junction function is critical for normal sleep.
睡眠的一个重要特征是觉醒阈值升高，对外界刺激的行为反应减弱。睡眠期间觉醒阈值变化的分子和细胞机制尚未完全了解。我们报告说，UNC-7 或 UNC-9 连接蛋白功能的丧失显著减少了发育时间睡眠中的睡眠，并降低了觉醒阈值；在这种范式中，UNC-7 功能在运动前中间神经元中是必需的，UNC-9 功能在运动神经元中是必需的。UNC-7 和 UNC-9 的同时瞬时过表达足以诱导成年动物出现不合时宜的睡眠。此外，UNC-7 或 UNC-9 的缺失抑制了 EGL-4 功能获得动物的睡眠增加，而 EGL-4 动物具有增加的环鸟苷酸依赖性蛋白激酶活性。这些结果表明间隙连接可能作用于先前鉴定的睡眠调节剂的下游。在其他范式中，NCA 阳离子通道作用于间隙连接的上游。与这一致的是，在 L4 到成年的发育时间睡眠中，NCA 通道活性的减弱导致睡眠期间的觉醒阈值显著增加。在缺乏 NCA 通道辅助亚基 UNC-79 的动物中，睡眠发作的总时间仅略有增加，而通道活性的增加则显著减少了睡眠。EGL-4 或连接蛋白的缺失抑制了 UNC-79 功能丧失引起的睡眠和觉醒缺陷。在 中，离子通道瘦腰，一种 NCA 通道的同源物，驱动色素分散因子 (PDF) 神经肽的释放，调节生物钟行为。然而，在 中，我们发现 PDF 受体 PDFR-1 的缺失并没有抑制功能获得性睡眠缺陷，这表明存在替代的下游途径。这项研究强调了神经元活动调节在睡眠中的保守性和重要性，并明确表明间隙连接功能对于正常睡眠至关重要。
