Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior
Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior
复制标题
NRF2抗氧化通路的季节性变化调节冬季抑郁样行为
DOI：
10.1073/pnas.2000278117
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发表时间：
2020-04-28
影响因子：
11.1
通讯作者：
Yoshimura, Takashi
中科院分区：
文献类型：
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作者：
Nakayama, Tomoya;Okimura, Kousuke;Yoshimura, Takashi
环境的季节性变化会导致人类和动物出现类似抑郁的行为。然而，潜在的机制尚不清楚。我们观察到暴露在冬季条件下的青冈鱼社交能力下降，焦虑样行为增加。全脑代谢分析揭示了68种代谢物的季节性变化，包括与抑郁症相关的神经递质和抗氧化剂。转录组分析确定了3306个差异表达的转录本，包括炎症标志物、黑素蛋白和生物钟基因。进一步的分析揭示了与抑郁症有关的多个信号通路的季节性变化，包括核因子红系衍生2-样2(NRF2)抗氧化途径。广谱化学屏幕显示，雷公藤红素(一种传统中药)独特地逆转了冬天的行为。NRF2是一种雷公藤红素靶标，表达于缰核(Hb)，在抑郁症的病理生理学中起关键作用。另一种NRF2化学激活剂表现出这些效应，一个NRF2突变体表现出社交能力下降。我们的研究为冬季抑郁症提供了重要的见解，并提供了涉及NRF2的潜在治疗靶点。
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.