Mice lacking circadian clock components display different mood-related behaviors and do not respond uniformly to chronic lithium treatment

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.基因组学研究表明，生物钟基因与人类双相情感障碍（bipolar disorder，BD）及锂盐治疗应答存在相关性。据此，我们针对携带多种生物钟基因突变的小鼠，在强迫游泳实验（forced swim test，FST，一种用于评估啮齿类动物类抑郁状态的经典行为学测试）中开展了锂盐处理前后的行为学检测。我们发现，锂盐处理会改变Per2、Cry1及Rev-erbα等生物钟核心组分的表达水平，因此这些生物钟组分可能参与介导锂盐治疗的获益效应。特别值得关注的是，我们观察到Cry1在每日特定时段对传递锂盐介导的生物学效应至关重要。有趣的是，调控强迫游泳实验中行为表现与锂盐应答的Per2与Cry1相关通路并非完全一致：该结论可通过锂盐处理后糖原合成激酶3β（glycogen synthase kinase 3β，GSK3β）的磷酸化变化，以及纹状体多巴胺水平的调控差异得到验证。此外，我们在Cry1基因敲除小鼠中同时观测到抑郁样与躁狂样症状，这一表型与双相情感障碍患者所见的所谓“混合状态”高度相似。综上，本研究结果进一步强化了这一认知：存在功能缺陷的生物钟计时系统，可直接或间接影响情绪相关行为。