Biology of Photosensitive Ganglion Cells

光敏神经节细胞的生物学

• 批准号: 8187478
• 负责人: David M. Berson
• 金额: $ 36.45万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8187478
• 关键词: Acetylcholine; Address; Affect; Age; Amacrine Cells; Axon; Behavior; Biology; Brain; Brain region; Cells; Development; Environment; Gene Expression Profiling; Goals; Health; Immune; In Vitro; Lateral Geniculate Body; Light; Lighting; Mediating; Mus; Nature; Neonatal Intensive Care; Nicotinic Receptors; Output; Pattern; Photoreceptors; Physiology; Premature Infant; Process; Retina; Retinal; Retinal Cone; Retinal Ganglion Cells; Retinal Photoreceptors; Role; Shapes; Signal Transduction; Staging; Synapses; Vision; Visual; Visual Pathways; Visual system structure; Work; cholinergic; ganglion cell; light effects; melanopsin; novel; postnatal; response; retinal neuron; retinal rods; segregation; spatiotemporal; superior colliculus Corpora quadrigemina; vision development

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.

描述（由申请人提供）：该项目的长期目标是探索本质光敏视网膜神经节细胞（ipRGC）的生理学和功能作用。目前的提议是研究 ipRGC 与视网膜发育中关键过程的相互作用。 ipRGC 是哺乳动物视网膜第一个有功能的光感受器，在视杆细胞和视锥细胞光感受器成熟到足以影响视网膜输出的一周多之前，它会产生对光的电反应。在这个年龄，神经节细胞轴突已经建立并完善了它们对大脑视觉中心的中央投射。这个过程被认为依赖于视网膜活动，尤其是扫过视网膜内部的电活动波。在关键的发育阶段（小鼠出生后第一周），视网膜电波由胆碱能（星爆）无长突细胞网络驱动，这些细胞相互兴奋，并通过烟碱受体兴奋神经节细胞。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影响。然而，我们的初步证据表明，光确实可以调节 II 期视网膜电波的行为，而这种影响需要黑视蛋白（ipRGC 的感光色素）。作为回报，这些波会激发 ipRGC。视网膜电波和 ipRGC 之间的这些双向相互作用是出乎意料的，并且对视觉系统的发育具有重要意义。这一更新应用的中心重点是探索 ipRGC 和 II 期视网膜波之间双向相互作用的性质、机制和功能含义。该提案的具体目标是：1）确定波激发黑视蛋白神经节细胞的突触机制以及波如何塑造 ipRGC 的中心投影； 2) 评估 ipRGC 对视网膜电波的影响、造成这些影响的机制以及它们对视网膜投射到中央视觉目标的影响。拟议的研究将在野生型和转基因小鼠中进行，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；和视网膜投影的追踪。这些研究将有助于记录神经节细胞感光细胞的重要而新颖的功能作用，并将阐明其对其他视网膜神经元产生令人惊讶的影响的机制。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，并可能促使人们重新考虑照明环境对早产儿视觉系统发育的可能影响。 公共健康相关性：该项目将评估光对发育中视网膜电活动的影响以及新发现的光敏视网膜细胞在此过程中的作用。这种活动对于大脑视觉区域的正常发育和功能至关重要，因此这一过程中的干扰（如早产儿可能发生的情况）可能会对视觉系统的健康产生负面影响。