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

描述(申请人提供)：进入我们眼睛的光不仅仅是为我们提供成像视觉信息。光还会影响非成像(NIF)视觉功能，如光对生物钟的日常调节(昼夜节律光夹带)、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，但在缺乏经典光感受器杆和锥体的“盲目”哺乳动物中得到保护，这些杆和锥被认为是唯一能够检测光信号的细胞。在哺乳动物的视网膜中发现了第三种类型的光感受器，负责探测NIF的光。这个新系统表达一种可能的黑色素，令人惊讶的是，在视网膜神经节细胞(RGC)的一个子集(-1-2%)中发现了它。黑素视素RGC接受来自视杆和/或视锥的输入。表达黑素的RGCs投射到大脑中对NIF功能重要的区域，如负责昼夜光携带和瞳孔光反射的视交叉上核和顶盖前橄榄核。在没有黑素的情况下，黑素细胞的内在光敏性会丧失，NIF视觉功能的光检测也会受到影响。视杆/视锥系统部分补偿了动物对光的NIF视觉功能的反应能力。在具体目标I中，我们将通过利用瞳孔收缩、昼夜节律光携带和直接光对行为的影响来确定视杆细胞、视锥细胞和黑素细胞对NIF视觉的个体贡献。在特定的目标II中，我们将使用一种通过白喉毒素A亚单位特异性表达而失去所有黑色素RGC的动物来鉴定投射到大脑中NIF中心的非黑素神经节细胞的侧向和数量。在特定的目标III中，我们将解决杆/锥如何向大脑中的NIF视觉中心发送信号的基本问题。它们是只通过黑素神经节细胞向大脑发送光信息，还是使用其他不表达黑素的神经节细胞？我们将使用AIM II中创建的动物，并使用AIM I中的行为分析测试光反应。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，从而影响我们的情绪、警觉性和睡眠/醒来周期。

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.