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）视觉功能有深远的影响，包括昼夜节律、睡眠、情绪、体温和瞳孔光反射。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，即经典光感受器、视杆细胞和视锥细胞以及表达光色素黑视素的内在光敏视网膜神经节细胞（ipRGCs）。作为神经节细胞，ipRGCs将视杆/视锥细胞输入与自身固有的基于黑视素的光导结合起来，作为唯一的通道，将光信息信号传递到对这些NIF功能重要的大脑区域。然而，iprgc这个看似“同质”的群体是如何将来自杆状细胞和视锥细胞的外部光输入与它们自身基于黑视素的内在光反应结合起来协调各种行为的，目前尚不清楚。这种竞争性更新的总体目标是在三个层面上解决这个基本问题。在Aim I中，我们将确定在iprgc中整合杆状细胞、视锥细胞和黑视素信号以驱动NIF功能的功能电路。最近，我们发现ipRGCs比以前认为的更加多样化，由多种形态和电生理上不同的亚型组成。此外，ipRGCs在视网膜神经节细胞中似乎是独特的，因为它们共同表达两种神经递质，谷氨酸和神经肽PACAP。因此，在Aim II中，我们将定义谷氨酸能和多肽能神经传递对不同NIF功能的相对贡献。在Aim III中，我们将阐明单个ipRGC亚型对NIF功能的功能贡献。这些研究将促进我们目前对iprgc在控制光介导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.