Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice.
Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice.
复制标题
DOI：
10.3389/fnbeh.2013.00152
复制
发表时间：
2013
影响因子：
3
通讯作者：
Valjent E
中科院分区：
文献类型：
--
作者：
De Bundel D;Gangarossa G;Biever A;Bonnefont X;Valjent E
生物钟包括一组参与细胞自主转录反馈回路的基因，这些基因协调一系列下游基因的表达，从而驱动昼夜行为模式。认知功能障碍、心境障碍、焦虑症和物质滥用障碍与昼夜节律和生物钟基因的破坏有关，但这些关联的因果关系仍然知之甚少。在本研究中，我们通过删除核心基因隐花色素的两个旁系同源物（Cry 1和Cry 2）来研究生物钟遗传破坏的影响。缺乏Cry 1和Cry 2（Cry 1 −/− Cry 2 −/−）的小鼠表现出减弱的暗相和新奇诱导的运动活动。此外，他们表现出受损的识别记忆，但完整的恐惧记忆。强迫游泳测试或蔗糖偏好测试中的抑郁相关行为不受影响，但Cry 1 −/− Cry 2 −/−小鼠在开放场地和高架十字迷宫测试中表现出焦虑增加。最后，在Cry 1 −/− Cry 2 −/−小鼠中，由单次可卡因给药诱导的细胞外信号调节激酶（ERK）的过度运动和纹状体磷酸化强烈减少。有趣的是，在缺乏Cry 1或Cry 2的小鼠中，只有一些行为指标受到影响。值得注意的是，Cry 1 −/− Cry 2 +/+和Cry 1 +/+ Cry 2 −/−小鼠的识别记忆都受损。此外，我们进一步观察到Cry 1 −/− Cry 2 +/+和Cry 1 +/+ Cry 2 −/−小鼠的焦虑升高。我们的数据表明，隐花色素基因除了控制昼夜节律外，还直接影响认知功能、焦虑相关行为和对精神兴奋剂药物的敏感性。
The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2). Mice lacking Cry1 and Cry2 (Cry1−/−Cry2−/−) displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1−/−Cry2−/− mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK) induced by a single cocaine administration are strongly reduced in Cry1−/−Cry2−/− mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1−/−Cry2+/+ and Cry1+/+Cry2−/− mice. Moreover, we further observed elevated anxiety in Cry1−/−Cry2+/+ and Cry1+/+Cry2−/− mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.
登录
查看更多内容
DOI：
10.1002/ajmg.b.30602
发表时间：
2008-04-05
影响因子：
2.8
作者：
Kissling, Christian;Retz, Wolfgang;Thome, Johannes
通讯作者：
Thome, Johannes
DOI：
10.1038/nrn2881
发表时间：
2010-08
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Gerstner JR;Yin JC
通讯作者：
Yin JC
DOI：
10.1073/pnas.0703615105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Gonzalez, M. M. C.;Aston-Jones, G.
通讯作者：
Aston-Jones, G.
影响因子：
2.8
作者：
Kovanen, Leena;Saarikoski, Sirkku T.;Partonen, Timo
通讯作者：
Partonen, Timo
影响因子：
2.7
作者：
Fonken, Laura K.;Finy, M. Sima;Nelson, Randy J.
通讯作者：
Nelson, Randy J.