The circadian geneCryptochrome 2influences stress‐induced brain activity and depressive‐like behavior in mice

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Abstract 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 ofCry2−/−andCry2+/+mice. Compared toCry2+/+mice, we found thatCry2−/−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 betweenCry2−/−andCry2+/+mice. These findings are consistent with other studies showing thatCry2is 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.

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