Orphan nuclear receptor nr4a1 regulates winter depression-like behavior in medaka

•Nr4a1 was suppressed in the medaka brain under winter conditions.•Cytosporone B reversed winter depression-like behavior under winter conditions.•Nr4a1 mutant fish showed decreased sociability under summer conditions.•Seasonal regulation of nr4a1 regulates winter depression-like behavior. About 10% of the population suffers from depression in winter at high latitude. Although it has become a serious public health issue, its underlying mechanism remains unknown and new treatments and therapies are required. As an adaptive strategy, many animals also exhibit depression-like behavior in winter. Previously, it has been reported that celastrol, a traditional Chinese medicine, can rescue winter depression-like behavior in medaka, an excellent model of winter depression. Nuclear receptor subfamily 4 group A member 1 (nr4a1, also known as nur77) is a known target of celastrol, and the signaling pathway of nr4a1 was suggested to be inactive in medaka brain during winter, implying the association of nr4a1 and winter depression-like behavior. However, the direct evidence for its involvement in winter depression-like behavior remains unclear. The present study found that nr4a1 was suppressed in the medaka brain under winter conditions. Cytosporone B, nr4a1 chemical activator, reversed winter depression-like behavior under winter conditions. Additionally, nr4a1 mutant fish generated by CRISPR/Cas9 system showed decreased sociability under summer conditions. Therefore, our results demonstrate that the seasonal regulation of nr4a1 regulates winter depression-like behavior and offers potential therapeutic target.