Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior

Proc Natl Acad Sci U S A. 2020 Apr 28;117(17):9594-9603. doi: 10.1073/pnas.2000278117. Epub 2020 Apr 10.


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.

Keywords: chemical genomics; circadian rhythm; medaka; seasonal affective disorder; winter depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Depression / metabolism*
  • Dimethyl Sulfoxide / toxicity
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Genome
  • Mutation
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oryzias / physiology*
  • Seasons*


  • NF-E2-Related Factor 2
  • Dimethyl Sulfoxide