International Institutes for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki, Japan; Research and Development Center for Precision Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Life Science Research Center, Technology Research Laboratory, Shimadzu Corporation, Kyoto, Japan.
Neurosci Res. 2022 Apr;177:16-24. doi: 10.1016/j.neures.2021.11.008. Epub 2021 Nov 29.
Sleep pressure, the driving force of the homeostatic sleep regulation, is accumulated during wakefulness and dissipated during sleep. Sleep deprivation (SD) has been used as a method to acutely increase animal's sleep pressure for investigating the molecular changes under high sleep pressure. However, SD induces changes not only reflecting increased sleep pressure but also inevitable stresses and prolonged wake state itself. The Sik3 mutant mice (Sleepy) exhibit constitutively high sleep pressure despite sleeping longer, and have been useful as a model of increased sleep pressure. Here we conducted a cross-comparison of brain metabolomic profiles between SD versus ad lib slept mice, as well as Sleepy mutant versus littermate wild-type mice. Targeted metabolome analyses of whole brains quantified 203 metabolites in total, of which 43 metabolites showed significant changes in SD, whereas three did in Sleepy mutant mice. The large difference in the number of differential metabolites highlighted limitations of SD as methodology. The cross-comparison revealed that a decrease in betaine and an increase in imidazole dipeptides are associated with high sleep pressure in both models. These metabolites may be novel markers of sleep pressure at the whole-brain level. Furthermore, we found that intracerebroventricular injection of imidazole dipeptides increased subsequent NREM sleep time, suggesting the possibility that imidazole dipeptides may participate in the regulation of sleep in mice.
睡眠压力是维持睡眠稳态调节的驱动力，它在清醒时积累，在睡眠时释放。睡眠剥夺 (SD) 已被用作一种急性增加动物睡眠压力的方法，以研究高睡眠压力下的分子变化。然而，SD 不仅会引起反映睡眠压力增加的变化，还会引起不可避免的应激和延长清醒状态本身的变化。Sik3 突变小鼠（Sleepy）尽管睡眠时间更长，但表现出持续的高睡眠压力，已被用作增加睡眠压力的模型。在这里，我们对 SD 与自由睡眠小鼠、Sleepy 突变体与同窝野生型小鼠之间的大脑代谢组学图谱进行了交叉比较。对整个大脑的靶向代谢组学分析总共定量了 203 种代谢物，其中 43 种代谢物在 SD 中显示出显著变化，而 3 种在 Sleepy 突变体小鼠中显示出显著变化。差异代谢物数量的巨大差异突出了 SD 作为方法的局限性。交叉比较表明，两种模型中甜菜碱的减少和咪唑二肽的增加与高睡眠压力有关。这些代谢物可能是大脑整体水平睡眠压力的新标志物。此外，我们发现脑室内注射咪唑二肽可增加随后的 NREM 睡眠时间，这表明咪唑二肽可能参与了小鼠睡眠的调节。
