Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment
Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment
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DOI：
10.3109/07420528.2015.1062024
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发表时间：
2015-01-01
影响因子：
2.8
通讯作者：
Albrecht, Urs
中科院分区：
文献类型：
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作者：
Schnell, Anna;Sandrelli, Federica;Albrecht, Urs
基因组研究表明，生物钟基因与人类的双相情感障碍(BD)和锂反应有关。因此，我们在强迫游泳试验(FST)中测试了锂治疗前后各种时钟基因突变的小鼠，强迫游泳试验是一种用于评估抑郁状态的啮齿动物行为测试。我们发现，包括PER2、Cry1和Rev-erbα在内的生物钟成分的表达受到锂治疗的影响，因此，这些时钟成分可能有助于锂治疗的有益效果。特别是，我们观察到，在一天中的特定时间段，Cry1对于传递锂介导的效应是重要的。有趣的是，涉及PER2和Cry1的调控FST中的行为和对锂的反应的通路是不同的，锂处理后GSK3β的磷酸化和纹状体中多巴胺水平的调节就是明证。此外，我们观察到在Cry1基因敲除小鼠中抑郁和躁狂样症状共存，这类似于在BD患者中看到的所谓混合状态。综上所述，我们的结果强化了这样一个概念，即有缺陷的昼夜节律系统可能直接或间接地影响与情绪相关的行为。
Genomic studies suggest an association of circadian clock genes with bipolar disorder (BD) and lithium response in humans. Therefore, we tested mice mutant in various clock genes before and after lithium treatment in the forced swim test (FST), a rodent behavioral test used for evaluation of depressive-like states. We find that expression of circadian clock components, including Per2, Cry1 and Rev-erb alpha, is affected by lithium treatment, and thus, these clock components may contribute to the beneficial effects of lithium therapy. In particular, we observed that Cry1 is important at specific times of the day to transmit lithium-mediated effects. Interestingly, the pathways involving Per2 and Cry1, which regulate the behavior in the FST and the response to lithium, are distinct as evidenced by the phosphorylation of GSK3 beta after lithium treatment and the modulation of dopamine levels in the striatum. Furthermore, we observed the co-existence of depressive and mania-like symptoms in Cry1 knock-out mice, which resembles the so-called mixed state seen in BD patients. Taken together our results strengthen the concept that a defective circadian timing system may impact directly or indirectly on mood-related behaviors.