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

描述（由申请人提供）：光对许多非成像（NIF）视觉功能具有深远的影响，包括昼夜节律、睡眠、情绪、体温和瞳孔对光反射。在哺乳动物中，光通过三种视网膜光感受器影响这些NIF功能，即经典的光感受器、视杆和视锥以及表达色素黑视蛋白的固有光敏视网膜神经节细胞（ipRGC）。作为神经节细胞，ipRGC将视杆/视锥输入与其自身的内在的基于黑视素的光转导整合，以充当将光信息信号传递到对这些NIF功能重要的脑区域的唯一管道。然而，ipRGC，一个看似“同质”的群体，如何整合来自视杆细胞和视锥细胞的外源性光输入与其自身内在的基于黑视素的光响应，以协调不同的行为，目前还知之甚少。这次竞争性更新的总体目标是在三个层面解决这个基本问题。在目的I中，我们将确定视杆细胞、视锥细胞和基于黑视蛋白的信号被整合到ipRGC中以驱动NIF功能的功能电路。最近，我们发现ipRGC比以前认识到的更加多样化，由多种形态学和电生理学上不同的亚型组成。此外，ipRGC在视网膜神经节细胞中似乎是独特的，因为它们共表达两种神经递质谷氨酸和神经肽PACAP。因此，在目标II中，我们将定义不同的NIF功能的谷氨酸能和肽能神经传递的相对贡献。在目的III中，我们将阐明单个ipRGC亚型对NIF功能的功能贡献。这些研究将推进我们目前对ipRGC在控制光介导的行为中的作用的理解，这些行为对人类健康和更好的生活质量至关重要。

DESCRIPTION (provided by applicant): Light has profound influences on many non-image forming (NIF) visual functions including circadian rhythms, sleep, mood, body temperature and the pupillary light reflex. In mammals, light influences these NIF functions through three retinal photoreceptors, namely the classical photoreceptors, rods and cones, and the intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin. As ganglion cells, ipRGCs integrate rod/cone input with their own intrinsic melanopsin-based phototransduction to serve as the sole conduits to signal light information to brain regions important for these NIF functions. However, how ipRGCs, a seemingly "homogeneous" population, integrate extrinsic light input from rods and cones with their own intrinsic melanopsin-based light responses to coordinate diverse behaviors is poorly understood. The overall goal of this competitive renewal is to address this fundamental question at three levels. In Aim I, we will determine the functional circuits by which rod, cone and melanopsin-based signals are integrated in ipRGCs to drive NIF functions. Recently, we found that ipRGCs are much more diverse than previously appreciated, consisting of multiple morphologically and electrophysiologically distinct subtypes. Additionally, ipRGCs appear to be unique among retinal ganglion cells in that they co-express two neurotransmitters, glutamate and a neuropeptide, PACAP. Thus, in Aim II, we will define the relative contribution of glutamatergic and peptidergic neurotransmission to diverse NIF functions. In Aim III, we will elucidate the functional contribution of individual ipRGC subtypes to NIF functions. These studies will advance our current understanding of the role of ipRGCs in controlling light- mediated behaviors that are essential to human health and a better quality of life.