Bonnefont Xavier, Albus Henk, Meijer Johanna H, van der Horst Gijsbertus T J
MGC, Department of Cell Biology and Genetics, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Novartis Found Symp. 2003;253:56-66; discussion 66-72, 102-9.
The mammalian master clock driving circadian rhythmicity in physiology, metabolism, and behaviour resides within the suprachiasmatic nuclei (SCN) of the anterior hypothalamus and is composed of intertwined negative and positive autoregulatory transcription-translation feedback loops. The Cryptochrome 1 and 2 gene products act in the negative feedback loop and are indispensable for molecular core oscillator function, as evident from the arrhythmic wheel running behaviour and absence of cyclic clock gene expression in mCry1/mCry2 double mutant mice in constant darkness. Recently, we have measured real-time multi-unit electrode activity recordings in hypothalamic slices from mCry-deficient mice kept in constant darkness and observed a complete lack of circadian oscillations in firing patterns. This proves that CRY proteins, and thus an intact circadian clock, are prerequisite for circadian rhythmicity in membrane excitability in SCN neurons. Strikingly, when mCry-deficient mice are housed in normal light-dark cycles, a single non-circadian peak in neuronal activity can be detected in SCN slices prepared two hours after the beginning of the day. This light-induced increase in electric activity of the SCN suggests that deletion of the mCry genes converts the core oscillator in an hour-glass-like timekeeper and may explain why in normal day-night cycles mCry-deficient mice show apparently normal behaviour.
驱动生理、新陈代谢和行为中昼夜节律的哺乳动物主时钟位于下丘脑前部的视交叉上核（SCN）内，由相互交织的负向和正向自动调节转录-翻译反馈环组成。隐花色素1和2基因产物在负反馈环中起作用，对于分子核心振荡器功能不可或缺，这在持续黑暗条件下mCry1/mCry2双突变小鼠的无节律转轮行为以及缺乏周期性时钟基因表达中得到了体现。最近，我们对持续黑暗饲养的mCry缺陷小鼠的下丘脑切片进行了实时多单位电极活动记录，并观察到放电模式完全缺乏昼夜节律振荡。这证明CRY蛋白以及完整的昼夜节律时钟是SCN神经元膜兴奋性昼夜节律的先决条件。引人注目的是，当mCry缺陷小鼠置于正常光暗周期中时，在一天开始两小时后制备的SCN切片中可检测到神经元活动的单个非昼夜峰值。SCN电活动的这种光诱导增加表明，mCry基因的缺失将核心振荡器转变为沙漏状计时器，这可能解释了为什么在正常昼夜周期中mCry缺陷小鼠表现出明显正常的行为。
