Porcu Alessandra, Vaughan Megan, Nilsson Anna, Arimoto Natsuko, Lamia Katja, Welsh David K
Research Service, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161;
Department of Psychiatry, University of California San Diego, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2020 Jun 16;117(24):13771-13782. doi: 10.1073/pnas.2000258117. Epub 2020 Jun 2.
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.
伏隔核（NAc）是中脑多巴胺奖赏回路的核心组成部分，在抑郁症患者的尸检大脑中表现出昼夜节律紊乱。我们假设正常的情绪调节需要NAc中适当的昼夜节律定时，并且情绪障碍与NAc细胞生物钟功能障碍有关。在表现出应激诱导的抑郁样行为（无助）的小鼠中，我们发现NAc中的生物钟功能改变以及核心生物钟成分隐花色素（CRY）的夜间高表达。在无助小鼠的NAc中，我们发现CRY的高表达与表达多巴胺1受体的中等棘状神经元（D1R-MSNs）的激活减少有关。此外，NAc中D1R-MSN特异性CRY敲低降低了对应激诱导的无助的易感性，并增加了夜间NAc神经元的激活。最后，我们表明CRY可能通过与Gs蛋白相互作用来抑制D1R诱导的G蛋白激活。在重度抑郁症患者的人成纤维细胞中也观察到昼夜节律和CRY表达的改变。我们的数据揭示了CRY在调节中脑多巴胺奖赏系统中的因果作用，并提供了NAc生物钟与抑郁症易感性之间的机制联系。
