Modeling and Validating Chronic Pharmacological Manipulation of Circadian Rhythms
Modeling and Validating Chronic Pharmacological Manipulation of Circadian Rhythms
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DOI：
10.1038/psp.2013.34
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发表时间：
2013-07-01
影响因子：
3.5
通讯作者：
Walton, K. M.
中科院分区：
文献类型：
--
作者：
Kim, J. K.;Forger, D. B.;Walton, K. M.
昼夜节律可以由明暗(LD)循环引起，也可以通过药物重置，例如，CK1增量/epsilon抑制剂PF-670462。在这里，我们确定这两个独立的信号是如何从分子水平到行为水平影响昼夜节律的。通过建立一个系统药理学模型，我们预测并实验验证了在LD周期的早期几个小时慢性抑制CK1d/e可以产生恒定的稳定的节律延迟。然而，在白天晚些时候或在较长光照间隔的情况下长期服药，预计不会产生复杂的节律。我们还提出了一种基于相响应曲线(PRCs)的简单方法，该方法可以预测LD周期和长期服用昼夜节律药物的影响。这项工作表明，必须仔细考虑给药时机和环境信号，才能准确地对昼夜节律进行药理学操作。
Circadian rhythms can be entrained by a light-dark (LD) cycle and can also be reset pharmacologically, for example, by the CK1 delta/epsilon inhibitor PF-670462. Here, we determine how these two independent signals affect circadian timekeeping from the molecular to the behavioral level. By developing a systems pharmacology model, we predict and experimentally validate that chronic CK1d/e inhibition during the earlier hours of a LD cycle can produce a constant stable delay of rhythm. However, chronic dosing later during the day, or in the presence of longer light intervals, is not predicted to yield an entrained rhythm. We also propose a simple method based on phase response curves (PRCs) that predicts the effects of a LD cycle and chronic dosing of a circadian drug. This work indicates that dosing timing and environmental signals must be carefully considered for accurate pharmacological manipulation of circadian phase.