Cryptochrome 2 (Cry2) is a core clock gene important for circadian regulation. It has also been associated with anxiety and depressive‐like behaviors in mice, but the previous findings have been conflicting in terms of the direction of the effect. To begin to elucidate the molecular mechanisms of this association, we carried out behavioral testing, PET imaging, and gene expression analysis of Cry2^−/− and Cry2^+/+ mice. Compared to Cry2^+/+ mice, we found that Cry2^−/− mice spent less time immobile in the forced swim test, suggesting reduced despair‐like behavior. Moreover, Cry2^−/− mice had lower saccharin preference, indicative of increased anhedonia. In contrast, we observed no group differences in anxiety‐like behavior. The behavioral changes were accompanied by lower metabolic activity of the ventro‐medial hypothalamus, suprachiasmatic nuclei, ventral tegmental area, anterior and medial striatum, substantia nigra, and habenula after cold stress as measured by PET imaging with a glucose analog. Although the expression of many depression‐associated and metabolic genes was upregulated or downregulated by cold stress, we observed no differences between Cry2^−/− and Cry2^+/+ mice. These findings are consistent with other studies showing that Cry2 is required for normal emotional behavior. Our findings confirm previous roles of Cry2 in behavior and extend them by showing that the effects on behavior may be mediated by changes in brain metabolism.

中文翻译：

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昼夜节律基因隐花色素 2 影响小鼠应激诱导的大脑活动和抑郁样行为

Cryptochrome 2 ( Cry2 ) 是一种对昼夜节律调节很重要的核心时钟基因。它也与小鼠的焦虑和抑郁样行为有关，但之前的发现在影响的方向上一直存在矛盾。为了阐明这种关联的分子机制，我们对Cry2 ^-/-和Cry2 ^+/+小鼠进行了行为测试、PET 成像和基因表达分析。与Cry2 ^+/+小鼠相比，我们发现Cry2 ^-/-小鼠在强迫游泳测试中不动的时间更少，这表明绝望样行为减少。此外，Cry2 ^-/-小鼠对糖精的偏好较低，表明快感缺失增加。相比之下，我们没有观察到焦虑样行为的组别差异。行为变化伴随着下丘脑腹内侧、视交叉上核、腹侧被盖区、前部和内侧纹状体、黑质和缰核的代谢活性降低，通过使用葡萄糖类似物的 PET 成像测量。尽管冷应激导致许多抑郁相关基因和代谢基因的表达上调或下调，但我们观察到Cry2 ^-/-和Cry2 ^+/+小鼠之间没有差异。这些发现与其他表明Cry2是正常情绪行为所必需的。我们的研究结果证实了 Cry2 在行为中的先前作用，并通过表明对行为的影响可能由大脑代谢的变化介导来扩展它们。