Qiao Sheng-Nan, Zhou Wei, Liu Lei-Lei, Zhang Dao-Qi, Zhong Yong-Mei
Institutes of Brain Science, Fudan University, Shanghai, China.
Eye Research Institute, Oakland University, Rochester, Michigan, United States.
Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4712-4721. doi: 10.1167/iovs.17-21835.
The neuropeptides orexin-A and orexin-B are widely expressed in the vertebrate retina; however, their role in visual function is unclear. This study investigates whether and how orexins modulate signal transmission to dopaminergic amacrine cells (DACs) from both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (melanopsin-expressing intrinsically photosensitive retinal ganglion cells [ipRGCs]).
A whole-cell voltage-clamp technique was used to record light-induced responses from genetically labeled DACs in flat-mount mouse retinas. Rod and cone signaling to DACs was confirmed pharmacologically (in wild-type retinas), whereas retrograde melanopsin signaling to DACs was isolated either pharmacologically (in wild-type retinas) or by genetic deletion of rod and cone function (in transgenic mice).
Orexin-A attenuated rod/cone-mediated light responses in the majority of DACs and inhibited all DACs that exhibited melanopsin-based light responses, suggesting that exogenous orexin suppresses signal transmission from rods, cones, and ipRGCs to DACs. In addition, orexin receptor 1 antagonist SB334867 and orexin receptor 2 antagonist TCS OX229 enhanced melanopsin-based DAC responses, indicating that endogenous orexins inhibit signal transmission from ipRGCs to DACs. We further found that orexin-A inhibits melanopsin-based DAC responses via orexin receptors on DACs, whereas orexin-A may modulate signal transmission from rods and cones to DACs through activation of orexin receptors on DACs and their upstream neurons.
Our results suggest that orexins could influence visual function via the dopaminergic system in the mammalian retina.
神经肽食欲素A和食欲素B在脊椎动物视网膜中广泛表达；然而，它们在视觉功能中的作用尚不清楚。本研究调查食欲素是否以及如何调节从视网膜外层光感受器（视杆细胞和视锥细胞）和视网膜内层光感受器（表达黑视蛋白的内在光敏视网膜神经节细胞[ipRGCs]）到多巴胺能无长突细胞（DACs）的信号传递。
采用全细胞膜片钳技术记录平铺的小鼠视网膜中基因标记的DACs的光诱导反应。视杆细胞和视锥细胞向DACs的信号传递通过药理学方法（在野生型视网膜中）得到证实，而逆行性黑视蛋白向DACs的信号传递则通过药理学方法（在野生型视网膜中）或通过视杆细胞和视锥细胞功能的基因缺失（在转基因小鼠中）进行分离。
食欲素A减弱了大多数DACs中视杆细胞/视锥细胞介导的光反应，并抑制了所有表现出基于黑视蛋白的光反应的DACs，这表明外源性食欲素抑制了从视杆细胞、视锥细胞和ipRGCs到DACs的信号传递。此外，食欲素受体1拮抗剂SB334867和食欲素受体2拮抗剂TCS OX229增强了基于黑视蛋白的DAC反应，表明内源性食欲素抑制了从ipRGCs到DACs的信号传递。我们进一步发现，食欲素A通过DACs上的食欲素受体抑制基于黑视蛋白的DAC反应，而食欲素A可能通过激活DACs及其上游神经元上的食欲素受体来调节从视杆细胞和视锥细胞到DACs的信号传递。
我们的结果表明，食欲素可能通过哺乳动物视网膜中的多巴胺能系统影响视觉功能。
