Tomoya Nakayama, Kousuke Okimura, Jiachen Shen, Ying-Jey Guh, T. Katherine Tamai, Akiko Shimada, Souta Minou, Yuki Okushi, Tsuyoshi Shimmura, Yuko Furukawa, Naoya Kadofusa, Ayato Sato, Toshiya Nishimura, Minoru Tanaka, Kei Nakayama, Nobuyuki Shiina, Naoyuki Yamamoto, Andrew S. Loudon, Taeko Nishiwaki-Ohkawa, Ai Shinomiya, Toshitaka Nabeshima, Yusuke Nakane, Takashi Yoshimura
Proceedings of the National Academy of Sciences 117 (17) 9594 - 9603 0027-8424 2020/04/28
Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an NRF2 mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2.