Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signalling.

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.