Biology of Photosensitive Ganglion Cells

这个项目的长期目标是探索人的内在生理和功能作用 光敏视网膜神经节细胞(IpRGCs)。目前的建议是调查以下因素之间的相互作用 IpRGCs与视网膜发育中的关键过程有关。IpRGCs是第一个具有功能的光感受器 哺乳动物的视网膜，在视杆细胞和视锥细胞之前一个多星期产生光的电反应 光感受器已经足够成熟，可以影响视网膜的输出。在这个年龄，神经节细胞轴突已经 建立和完善他们对大脑视觉中心的中央投射。这个过程是 视视网膜活动而定的被认为依赖于视网膜活动的，尤指横扫的电波 内层视网膜。在关键的发育阶段(小鼠出生后第一周)，视网膜波是 由相互兴奋的胆碱能(星爆型)无长突细胞和神经节网络驱动 通过尼古丁受体传递给细胞。这些“二期”视网膜波被认为对 由于经典光感受器的不成熟而造成的光影响。然而，我们的初步调查 有证据表明，事实上，光确实调节了第二阶段视网膜波的行为，而这种影响 需要黑色素，即ipRGC的感光色素。作为回报，电波刺激ipRGC。这些 视网膜波和ipRGC之间的双向相互作用是意想不到的，并具有显著的 对视觉系统发展的影响。此续订申请的中心重点是探索 IpRGC间双向相互作用的性质、机制及其功能意义 和II期视网膜波。该提案的具体目的是：1)确定突触 波刺激黑素神经节细胞的机制以及波如何塑造中央 和2)评估ipRGCs对视网膜波的影响，其机制 对这些效应负责，以及它们对视网膜向中央视觉的投射发展的影响 目标。拟议的研究将在野生型和转基因小鼠身上进行，并将涉及 视网膜神经元的体外记录和药理学操作；基因表达谱；以及 视网膜脱离投射的追踪。这些研究将有助于记录一项重要而新颖的 神经节细胞光感受器的功能作用，并将阐明其机制 对其他视网膜神经元产生令人惊讶的影响。它们将完善我们对光驱动的作用的理解 在视觉系统开发中的活动，并可能促使重新考虑可能的影响 光照环境对早产儿视觉系统发育的影响。

The long term goal of this project is to explore the physiology and functional roles of the intrinsically photosensitive retinal ganglion cells (ipRGCs). The present proposal is to investigate the interactions of ipRGCs with key processes in the developing retina. The ipRGCs are the first functional photoreceptors of the mammalian retina, generating electrical responses to light more than a week before rod and cone photoreceptors are mature enough to affect retinal output. At this age, ganglion cell axons are already establishing and refining their central projections to the visual centers of the brain. This process is thought to be dependent on retinal activity, especially the waves of electrical activity that sweep across the inner retina. During a critical developmental stage (first postnatal week in mice), retinal waves are driven by a network of cholinergic (starburst) amacrine cells which excite each other as well as ganglion cells through nicotinic receptors. These ¿Stage II¿ retinal waves have been considered immune from photic influence due to the immaturity of the classical photoreceptors. However, our preliminary evidence shows that light does, in fact, modulate the behavior of Stage II retinal waves and this influence requires melanopsin, the photopigment of ipRGCs. In return, the waves excite ipRGCs. These bidirectional interactions between retinal waves and ipRGCs are unexpected, and have significant implications for visual system development. The central focus of this renewal application is to explore the nature, mechanisms and functional implications of the bidirectional interactions between ipRGCs and Stage II retinal waves. The specific aims of the proposal are: 1) to determine the synaptic mechanisms by which waves excite melanopsin ganglion cells and how the waves shape the central projections of ipRGCs; and 2) to assess the impact of ipRGCs on retinal waves, the mechanisms responsible for these effects, and their impact on development of retinal projections to central visual targets. Proposed studies will be conducted in wildtype and genetically modified mice and will involve in vitro recordings and pharmacological manipulation of retinal neurons; gene expression profiling; and tracing of retinofugal projections. These studies will help to document an important and novel functional role for ganglion cell photoreceptors, and will clarify mechanisms responsible for their surprising influence on other retinal neurons. They will refine our understanding of the role of lightdriven activity in visual system development and may prompt a reconsideration of the possible impact of lighting environments on visual system development in premature human infants.