The absence of melanopsin alters retinal clock function and dopamine regulation by light
The absence of melanopsin alters retinal clock function and dopamine regulation by light
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DOI：
10.1007/s00018-013-1338-9
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发表时间：
2013-09-01
影响因子：
8
通讯作者：
Cooper, Howard M.
中科院分区：
文献类型：
--
作者：
Dkhissi-Benyahya, Ouria;Coutanson, Christine;Cooper, Howard M.
视网膜生物钟对视网膜生理和功能的最佳调节至关重要，但其在哺乳动物中的细胞位置仍存在争议。我们使用激光显微解剖研究了野生型和黑视素敲除(Opn（4)(-/-)）小鼠视网膜分离的外（杆/锥）和内（核和神经节细胞层）区域光诱导时钟基因表达和周期基因的昼夜节律谱和相位关系。在野生型小鼠中，所有的时钟基因都在感光层有节奏地表达，而不是在视网膜内。对于在两个视网膜隔室中都有节律的时钟基因来说，昼夜节律谱是不同步的。这些结果与光感受器是昼夜节律产生的潜在位点的观点一致。在缺乏黑视素的小鼠中，我们意外地发现时钟基因节律和Per1-Per2 mrna的光诱导仅在外层视网膜中丢失。由于已知黑视素神经节细胞为多巴胺能细胞提供光信息的反馈信号通路，我们进一步研究了Opn(4)（-/-）小鼠的多巴胺（DA）合成。黑视素的缺乏阻止了酪氨酸羟化酶（TH） mRNA和DA的光依赖性增加，并且在持续的黑暗中，导致这两种成分的水平相对较高。这些结果表明，黑视素是视网膜分子时钟功能和DA调节所必需的，并且光对周期基因的诱导是由黑视素依赖的、DA驱动的信号作用于视网膜光感受器介导的。
The retinal circadian clock is crucial for optimal regulation of retinal physiology and function, yet its cellular location in mammals is still controversial. We used laser microdissection to investigate the circadian profiles and phase relations of clock gene expression and Period gene induction by light in the isolated outer (rods/cones) and inner (inner nuclear and ganglion cell layers) regions in wild-type and melanopsin-knockout (Opn (4) (-/-) ) mouse retinas. In the wild-type mouse, all clock genes are rhythmically expressed in the photoreceptor layer but not in the inner retina. For clock genes that are rhythmic in both retinal compartments, the circadian profiles are out of phase. These results are consistent with the view that photoreceptors are a potential site of circadian rhythm generation. In mice lacking melanopsin, we found an unexpected loss of clock gene rhythms and of the photic induction of Per1-Per2 mRNAs only in the outer retina. Since melanopsin ganglion cells are known to provide a feed-back signalling pathway for photic information to dopaminergic cells, we further examined dopamine (DA) synthesis in Opn (4) (-/-) mice. The lack of melanopsin prevented the light-dependent increase of tyrosine hydroxylase (TH) mRNA and of DA and, in constant darkness, led to comparatively high levels of both components. These results suggest that melanopsin is required for molecular clock function and DA regulation in the retina, and that Period gene induction by light is mediated by a melanopsin-dependent, DA-driven signal acting on retinal photoreceptors.