Schnell Anna, Sandrelli Federica, Ranc Vaclav, Ripperger Jürgen A, Brai Emanuele, Alberi Lavinia, Rainer Gregor, Albrecht Urs
a Department of Biology, Unit of Biochemistry , University of Fribourg , Fribourg , Switzerland .
b Department of Biology , University of Padova , Padova , Italy .
Chronobiol Int. 2015;32(8):1075-89. doi: 10.3109/07420528.2015.1062024. Epub 2015 Aug 28.
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-erbα, 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 GSK3β 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.
基因组研究表明，昼夜节律时钟基因与人类双相情感障碍（BD）及锂反应之间存在关联。因此，我们在强迫游泳试验（FST）中对锂治疗前后的各种时钟基因敲除小鼠进行了测试，FST是一种用于评估啮齿动物抑郁样状态的行为测试。我们发现，包括Per2、Cry1和Rev-erbα在内的昼夜节律时钟成分的表达受锂治疗影响，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Cry1在一天中的特定时间对传递锂介导的效应很重要。有趣的是，涉及Per2和Cry1的途径在调节FST行为和对锂的反应方面是不同的，锂治疗后GSK3β的磷酸化以及纹状体中多巴胺水平的调节证明了这一点。此外，我们在Cry1基因敲除小鼠中观察到抑郁和躁狂样症状并存，这类似于BD患者中出现的所谓混合状态。综上所述，我们的结果强化了这样一个概念，即昼夜节律计时系统缺陷可能直接或间接影响与情绪相关的行为。
