Our brain adapts to seasonal changes. Mis-adaptations may lead to seasonal patterns in several psychiatric disorders, but we know little regarding the underlying mechanisms. Our previous work identified two variants in the human circadian clock gene PERIOD3 (PER3), that is, P415A and H417R, which are associated with winter depression, but whether and how these variants lead to the disorder remain to be characterized. Here we find that male mice carrying human P415A and H417R display winter depression-like behaviours that are caused by the actions of P415A and H417R in the adrenal gland. Systemic corticosterone level is downregulated in adaptation to shortening of day length, while P415A and H417R eliminate this downregulation by increasing corticosterone synthesis. Enhanced glucocorticoid signalling represses the transcription of Tph2, which encodes the rate-limiting enzyme of serotonin synthesis, leading to increased depression-like behaviours. Taken together, our findings unveil a mechanism according to which human variants contribute to seasonal mood traits.

我们的大脑会适应季节变化。错误适应可能导致几种精神疾病的季节性模式，但我们对潜在机制知之甚少。我们之前的工作确定了人类生物钟基因 PERIOD3 （PER3） 中的两个变异，即 P415A 和 H417R，它们与冬季抑郁症有关，但这些变异是否以及如何导致这种疾病仍有待表征。在这里，我们发现携带人类 P415A 和 H417R 的雄性小鼠表现出冬季抑郁样行为，这是由 P415A 和 H417R 在肾上腺中的作用引起的。全身性皮质酮水平在适应日长缩短的过程中下调，而 P415A 和 H417R 通过增加皮质酮合成来消除这种下调。增强的糖皮质激素信号传导抑制了 Tph2 的转录，Tph2 编码 5-羟色胺合成的限速酶，导致抑郁样行为增加。综上所述，我们的研究结果揭示了一种机制，根据该机制，人类变异有助于季节性情绪特征。