Biology of Photosensitive Ganglion Cells

这个项目的长期目标是探索内在的生理和功能作用， 光敏视网膜神经节细胞（ipRGC）。目前的建议是调查的相互作用， ipRGC与发育中的视网膜中的关键过程。ipRGC是第一个有功能的光感受器 在视杆细胞和视锥细胞之前一个多星期， 光感受器足够成熟以影响视网膜输出。在这个年龄，神经节细胞轴突已经 建立和完善他们的中央投射到大脑的视觉中心。这个过程是 被认为依赖于视网膜活动，特别是扫过视网膜的电活动波。 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 由胆碱能（星状）无长突细胞网络驱动，这些细胞相互兴奋，也兴奋神经节 细胞通过烟碱受体。这些<$Stage II <$视网膜波被认为是免疫的 由于经典光感受器的不成熟而引起的光影响。然而，我们的初步 有证据表明，事实上，光确实调节II期视网膜波的行为， 需要黑视素，ipRGC的色素。作为回报，波激发ipRGC。这些 视网膜波和ipRGC之间的双向相互作用是出乎意料的，并且具有显著的 对视觉系统发育的影响。此次更新申请的中心重点是探索 ipRGC之间双向相互作用的性质、机制和功能意义 和II期视网膜波。该提案的具体目标是：1）确定突触 波激发黑视素神经节细胞的机制以及波如何塑造中央神经节细胞 ipRGC的投射;以及2）评估ipRGC对视网膜波的影响， 负责这些影响，以及它们对视网膜投射到中央视觉系统的发展的影响。 目标的拟议的研究将在野生型和转基因小鼠中进行， 视网膜神经元的体外记录和药理学操作;基因表达谱;以及 追踪离视网膜投射。这些研究将有助于记录一个重要的和新颖的 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的影响。他们将完善我们对光驱动的作用的理解 活动在视觉系统的发展，并可能促使重新考虑可能的影响 光照环境对人类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.