Modeling feedback loops of the mammalian circadian oscillator
Modeling feedback loops of the mammalian circadian oscillator
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DOI：
10.1529/biophysj.104.040824
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发表时间：
2004-11-01
影响因子：
3.4
通讯作者：
Kramer, A
中科院分区：
文献类型：
--
作者：
Becker-Weimann, S;Wolf, J;Kramer, A
视交叉上核控制着哺乳动物生理和行为的日常变化。在单个神经元内，互锁的转录/翻译反馈回路在分子水平上产生昼夜节律。我们提出了一个数学模型，反映了哺乳动物的昼夜节律振荡器的基本特征来表征负反馈和正反馈回路的不同作用。所获得的振荡有一个24小时的周期，并对参数的变化是强大的，即使是由一个不断表达的激活剂取代的正反馈。这表明了负反馈对节奏生成的关键作用。此外，它还解释了Rev-erbalpha（-/-）突变小鼠的节律表型，其中缺少正反馈。消极和积极反馈的相互作用揭示了一种复杂的动态。特别是，该模型解释了Per 2（Brdm 1）/Cry 2（-/-）双突变小鼠（Per 2（Brdm 1）单突变小鼠是心律失常的）的昼夜节律振荡的意外拯救。这里，与Per 2基因突变相关的正反馈强度的降低被同时降低负反馈强度的Cry 2（-/-）突变补偿。最后，该模型使我们对分子和行为表型进行了可测试的预测：当将哺乳动物Per 2（Brdm 1）突变小鼠与Rev-erbalpha（-/-）突变小鼠杂交时，应该挽救昼夜节律振荡。
The suprachiasmatic nucleus governs daily variations of physiology and behavior in mammals. Within single neurons, interlocked transcriptional/translational feedback loops generate circadian rhythms on the molecular level. We present a mathematical model that reflects the essential features of the mammalian circadian oscillator to characterize the differential roles of negative and positive feedback loops. The oscillations that are obtained have a 24-h period and are robust toward parameter variations even when the positive feedback is replaced by a constantly expressed activator. This demonstrates the crucial role of the negative feedback for rhythm generation. Moreover, it explains the rhythmic phenotype of Rev-erbalpha(-/-) mutant mice, where a positive feedback is missing. The interplay of negative and positive feedback reveals a complex dynamics. In particular, the model explains the unexpected rescue of circadian oscillations in Per2(Brdm1)/Cry2(-/-) double-mutant mice (Per2(Brdm1) single-mutant mice are arrhythmic). Here, a decrease of positive feedback strength associated with mutating the Per2 gene is compensated by the Cry2(-/-) mutation that simultaneously decreases the negative feedback strength. Finally, this model leads us to a testable prediction of a molecular and behavioral phenotype: circadian oscillations should be rescued when arrhythmic Per2(Brdm1) mutant mice are crossed with Rev-erbalpha(-/-) mutant mice.