期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：24
页码：13771-13782
DOI：10.1073/pnas.2000258117
出版社：The National Academy of Sciences of the United States of America
摘要：The nucleus accumbens (NAc), a central component of the midbrain dopamine reward circuit, exhibits disturbed circadian rhythms in the postmortem brains of depressed patients. We hypothesized that normal mood regulation requires proper circadian timing in the NAc, and that mood disorders are associated with dysfunctions of the NAc cellular circadian clock. In mice exhibiting stress-induced depression-like behavior (helplessness), we found altered circadian clock function and high nighttime expression of the core circadian clock component CRYPTOCHROME (CRY) in the NAc. In the NAc of helpless mice, we found that higher expression of CRY is associated with decreased activation of dopamine 1 receptor-expressing medium spiny neurons (D1R-MSNs). Furthermore, D1R-MSN–specific CRY-knockdown in the NAc reduced susceptibility to stress-induced helplessness and increased NAc neuronal activation at night. Finally, we show that CRY inhibits D1R-induced G protein activation, likely by interacting with the Gs protein. Altered circadian rhythms and CRY expression were also observed in human fibroblasts from major depressive disorder patients. Our data reveal a causal role for CRY in regulating the midbrain dopamine reward system, and provide a mechanistic link between the NAc circadian clock and vulnerability to depression.
