Biology of Photosensitive Ganglion Cells

描述(申请人提供)：该项目的长期目标是探索固有的光敏性视网膜神经节细胞(IpRGCs)的生理和功能作用。目前的建议是研究ipRGC与视网膜发育中的关键过程的相互作用。IpRGCs是哺乳动物视网膜的第一个功能性光感受器，在视杆细胞和视锥细胞成熟到足以影响视网膜输出之前一个多星期就会对光产生电反应。在这个年龄段，神经节细胞轴突已经建立和完善了它们到大脑视觉中心的中央投射。这一过程被认为依赖于视网膜的活动，特别是横扫视网膜内部的电波。在发育的关键阶段(小鼠出生后第一周)，视网膜波由胆碱能(星状爆发式)无长突细胞和神经节细胞组成的网络相互兴奋，神经节细胞通过烟碱受体驱动。由于经典光感受器的不成熟，这些“第二阶段”视网膜波被认为不受光的影响。然而，我们的初步证据表明，事实上，光确实调节了第二阶段视网膜波的行为，这种影响需要黑色素，即ipRGC的光色素。作为回报，电波刺激ipRGC。视网膜波和ipRGC之间的这种双向相互作用是意想不到的，对视觉系统的发展具有重要意义。这一更新应用的中心焦点是探索ipRGC和II期视网膜波之间双向相互作用的性质、机制和功能意义。该提案的具体目的是：1)确定波刺激黑素神经节细胞的突触机制以及波如何塑造ipRGCs的中央投射；2)评估ipRGCs对视网膜波的影响，这些影响的机制，以及它们对视网膜向中央视觉目标投射的影响。拟议的研究将在野生型和转基因小鼠身上进行，涉及视网膜神经元的体外记录和药理学操作；基因表达谱；以及视黄醇投射的追踪。这些研究将有助于证明神经节细胞光感受器的重要和新的功能作用，并将澄清它们对其他视网膜神经元产生惊人影响的机制。它们将加深我们对光驱动活动在视觉系统发育中的作用的理解，并可能促使我们重新考虑光环境对早产儿视觉系统发育的可能影响。 与公众健康相关：该项目将评估光对发育中的视网膜的电活动的影响，以及新发现的光敏视网膜细胞在这一过程中的作用。这种活动对大脑视觉区域的正常发育和功能至关重要，因此，这一过程中的障碍，如早产儿可能发生的，可能会对视觉系统的健康产生负面影响。

DESCRIPTION (provided by applicant): 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 wild type 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 light driven 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. PUBLIC HEALTH RELEVANCE: This project will assess the effects of light on electrical activity in the developing retina and the role of a newly discovered light-sensitive retinal cell in this process. Such activity is crucial for the normal development and function of the visual regions of the brain, so disturbances in this process, as may occur in premature infants, could have negative effects on the health of the visual system.