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

Abstract

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.

Light and Hormones in Seasonal Regulation of Reproduction and Mood

“…It is very likely that animals across multiple taxa, including human lineages, exhibit similar seasonality in physiology and behaviors, such as retinal sensitivity and winter depression. In addition, the underlying molecular basis could also be shared among various species, as exemplified by the aforementioned TSH–TH signal transduction machinery associated with seasonal reproduction and the involvement of NRF2 antioxidant pathway in winter depression in both medaka ( 67 ) and humans ( 82 ). Despite the substantial differences between humans and other vertebrates, many biological functions are conserved, making animal models invaluable tools for the scientific community.…”

“…These analyses revealed seasonal changes in multiple metabolites (eg, serotonin and glutamate), gene expression (eg, circadian clock genes), and signaling pathways (eg, glucocorticoid receptor signaling and estrogen receptor signaling) previously implicated in depression ( Fig. 2 ) ( 67 ). To further understand the underlying mechanism of winter depression–like behavior, Nakayama et al employed a chemical genomics approach to screen an existing drug library and identified a NRF2 pathway–activating drug, celastrol, that alleviated the social withdrawal of winter medaka.…”

“…Interestingly, winter depression- and anxiety-like behaviors are widely observed in animals ( 65 ), including medaka, which exhibit reduced sociability and increased anxiety-like behaviors under winter conditions ( 66 , 67 ). Nuptial coloration, in which animals (especially males) undergo rapid color changes and ornamentation, functions as a type of social signaling to attract mates during the breeding season ( 68 ).…”

“…Treatment with another structurally different NRF2 activator, dimethyl fumarate, also reversed the depression-like behavior in winter medaka. Moreover, NRF2 -knockout medaka exhibited decreased sociability even under summer conditions ( 67 ). All of these findings imply the involvement of NRF2 antioxidant pathway in the regulation of winter depression–like behavior in medaka.…”

“…The inactivation of multiple signaling pathways under winter conditions were identified by transcriptomic and metabolomic analyses. A chemical genomics approach revealed that seasonal changes in the NRF2-mediated antioxidant pathways regulate winter depression–like behavior ( 67 ).…”