BACKGROUND: We have previously reported that the expression of circadian clock-genes increases in the cerebral cortex after sleep deprivation (SD) and that the sleep rebound following SD is attenuated in mice deficient for one or more clock-genes. We hypothesized that besides generating circadian rhythms, clock-genes also play a role in the homeostatic regulation of sleep. Here we follow the time course of the forebrain changes in the expression of the clock-genes period (per)-1, per2, and of the clock-controlled gene albumin D-binding protein (dbp) during a 6 h SD and subsequent recovery sleep in three inbred strains of mice for which the homeostatic sleep rebound following SD differs. We reasoned that if clock genes are functionally implicated in sleep homeostasis then the SD-induced changes in gene expression should vary according to the genotypic differences in the sleep rebound. RESULTS: In all three strains per expression was increased when animals were kept awake but the rate of increase during the SD as well as the relative increase in per after 6 h SD were highest in the strain for which the sleep rebound was smallest; i.e., DBA/2J (D2). Moreover, whereas in the other two strains per1 and per2 reverted to control levels with recovery sleep, per2 expression specifically, remained elevated in D2 mice. dbp expression increased during the light period both during baseline and during SD although levels were reduced during the latter condition compared to baseline. In contrast to per2, dbp expression reverted to control levels with recovery sleep in D2 only, whereas in the two other strains expression remained decreased. CONCLUSION: These findings support and extend our previous findings that clock genes in the forebrain are implicated in the homeostatic regulation of sleep and suggest that sustained, high levels of per2 expression may negatively impact recovery sleep.
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机译:背景:我们先前曾报道,睡眠不足(SD)后,大脑皮层中昼夜节律时钟基因的表达增加,并且在缺乏一种或多种时钟基因的小鼠中,SD后的睡眠反弹减弱。我们假设,时钟基因除了产生昼夜节律外,还在睡眠的体内稳态调节中起作用。在这里,我们按照前脑变化的时程变化,在6小时的SD和随后的恢复过程中,时钟基因周期(per)-1,per2和时钟控制基因白蛋白D结合蛋白(dbp)的表达在三种自交系小鼠的睡眠中,SD后稳态睡眠反弹不同。我们认为,如果时钟基因在功能上与睡眠稳态有关,那么SD诱导的基因表达变化应根据睡眠反弹的基因型差异而变化。结果:在所有三种菌株中,当动物保持清醒时,每种表达均增加,但是在SD中,睡眠反弹最小的菌株中SD的增加速率以及6 h SD之后的相对表达最高。即DBA / 2J(D2)。而且,在其他两个品系中,per1和per2通过恢复睡眠恢复到对照水平,而在D2小鼠中,per2的表达仍然保持特定水平。 dbp的表达在光照期间在基线和SD期间均增加,尽管与基线相比,后者的水平降低了。与per2相反,只有D2中dbp的表达恢复到对照水平,并且恢复睡眠,而其他两个菌株中的表达保持下降。结论:这些发现支持并扩展了我们先前的发现,即前脑中的时钟基因与睡眠的体内调节有关,并表明持续高水平的per2表达可能对恢复睡眠产生负面影响。
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