Role of mammalian retinal photoreceptors in non-image-forming visual functions

描述（由申请人提供）：进入我们眼睛的光不仅仅为我们提供形成图像的视觉信息。光还影响非图像形成（NIF）视觉功能，例如通过光（昼夜光诱导）对生物钟的日常调节、光对情绪和警觉性的直接影响以及瞳孔收缩。这些视觉功能需要眼睛，但在缺乏经典的光感受器杆和锥的“盲”哺乳动物中被保留下来，这些细胞被认为是唯一能够检测光信号的细胞。在哺乳动物视网膜中发现了负责检测NIF光的第三种感光器。该新系统表达推定的色素黑视蛋白，并且令人惊讶地在视网膜神经节细胞（RGC）的子集（约1 - 2%）中发现。黑视素RGC接收来自视杆和/或视锥的输入。表达黑视素的RGC投射到大脑中对NIF功能重要的区域，例如分别负责昼夜光诱导和瞳孔光反射的视交叉上核和橄榄顶盖前核。在缺乏黑视蛋白的情况下，黑视蛋白细胞的固有光敏性丧失，并且NIF视觉功能的光检测受损。视杆/视锥系统部分补偿了动物对NIF视觉功能的光响应能力。在具体目标I中，我们将通过使用瞳孔收缩、昼夜光诱导和直接光对行为的影响来确定视杆细胞、视锥细胞和黑视蛋白细胞对NIF视觉的个体贡献。在具体的目标II中，我们将鉴定投射到脑中的NIF中心的非黑视素神经节细胞的横向和数量，使用经工程化以通过白喉毒素A亚基在这些细胞中特异性表达而失去所有黑视素RGC的动物。在具体目标III中，我们将解决杆/锥细胞如何向大脑中的NIF视觉中心发出信号的基本问题。它们是只通过黑视素神经节细胞向大脑传递光信息，还是使用其他不表达黑视素的神经节细胞？我们将使用目标II中创造的动物，并使用目标I中的行为分析来测试光反应。这些研究将阐明三类视网膜光感受器如何相互作用并协调NIF功能的光检测，最重要的是确定每个光感受器对单个NIF功能的单独贡献。我相信这些研究将有助于确定光信号如何传递到大脑，以影响我们的情绪，警觉性和我们的睡眠/觉醒周期。

DESCRIPTION (provided by applicant): Light entering our eyes does much more than provide us with image-forming visual information. Light also affects non-image-forming (NIF) visual functions such as daily adjustments of the biological clock by light (circadian photoentrainment), direct effects of light on mood and alertness and pupil constriction. These visual functions require the eyes but are preserved in "blind" mammals lacking the classical photoreceptors rods and cones, which were thought to be the only cells capable of detecting light signals. A third type of photoreceptor responsible for detecting light for NIF was discovered in the mammalian retina. This new system expresses a putative photopigment melanopsin and is found, surprisingly, in a subset (-1-2%) of retinal ganglion cells (RGCs). The melanopsin RGCs receive input from rods and/or cones. The melanopsin expressing RGCs project to areas in the brain important for NIF functions such as the suprachiasmatic nucleus and the olivary pretectal nucleus responsible for circadian photoentrainment and pupillary light reflex, respectively. In the absence of melanopsin, the intrinsic photosensitivity of the melanopsin cells is lost and light detection for NIF visual functions is compromised. The rod/cone system partially compensates for the animals' ability to respond to light for the NIF visual functions. In specific aim I, we will determine the individual contribution of rods, cones and melanopsin cells to NIF vision by using pupil constriction, circadian photoentrainment and direct light effects on behavior. In specific aim II, we will identify the laterally and number of non-melanopsin ganglion cells that project to the NIF centers in the brain using an animal engineered to lose all melanopsin RGCs through diphtheria toxin A subunit expression specifically in these cells. In specific aim III, we will address the fundamental question of how rods/cones signal to the NIF visual centers in the brain. Do they signal light information to the brain only through the melanopsin ganglion cells or do they use other ganglion cells that do not express melanopsin? We will use the animals created in aim II and test light responses using the behavioral assays in aim I. These studies will elucidate how the three classes of retinal photoreceptors interact and coordinate light detection for NIF functions and most importantly determine the individual contribution of each photoreceptor to individual NIF functions. I believe that these studies will be instrumental in defining how light signals are conveyed to the brain to influence our mood, alertness and our sleep/wake cycles.