Ganglion Cell Function in Retinal Disease

项目总监/首席调查员(最后、第一、中间)： 项目摘要/摘要 这项研究的目标是了解调节发育的信号机制。 视觉功能和视网膜神经节细胞的空间组织，以及它们在视网膜疾病中是如何改变的。 正常的视觉始于视网膜，开始于光感受器对光的探测。并行的路径 信息流在光感受器和去极化和超极化之间的第一个突触启动 双极细胞，在暗适应和光适应下检测亮度增加和降低和/或视力 条件。结果，路径在强度上扩展了信息处理的动态范围 领域，并提高对显著环境特征的信息处理的专门化，例如运动， 方向和大小。这些回路中的信号通过视网膜外部和内部的抑制性输入而得到精炼 这些相互作用最终形成并定义了视网膜神经节细胞的感受野组织。这个 感受野是一种基本属性，存在于所有物种的所有感觉神经元中。它定义了类型和 每个细胞编码的环境刺激的范围。因此，了解接受性字段属性 发育是了解视网膜视觉功能的关键，而神经节细胞是至关重要的部分，因为它们 既代表了所有视网膜处理的顶峰，也代表了其余视觉处理的支架。 由于基本的射频空间组织在神经节细胞的视觉反应开始时就已经存在， 它们的发展过程一直相对难以调查。那种正常的视觉 需要通过去极化和超极化通路的信号由视觉充分地指示 先天性静止性夜盲(CSNB)患者和小鼠模型中出现的缺陷，其中 消除了去极化的双极电池处理。我们将推出三款独特的CSNB1鼠标模型 继续用来探测CSNB背后的突触电路，其中正常的光感受器功能是 保留。这三个脑区的自发和视觉诱发反应变化的本质 突变体为研究感受野组织和神经节细胞的发育提供了独特的机会 发信号。感受野组织的系统发育保守性表明，我们在小鼠身上的发现 将与灵长类外周视网膜处理相关。我们认为，这些小鼠的特征 模型代表了一个重要的机会，这是其他老鼠或脊椎动物模型所不能提供的，并代表了 了解CSNB1的疾病机制和正常视网膜发育的关键一步 和功能。 PHS 398/2590(11/07版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): PROJECT SUMMARY/ABSTRACT The goals of this research are focused on understanding signaling mechanisms that regulate the development of visual function and spatial organization of retinal ganglion cells and how they are altered in retinal disease. Normal vision begins in the retina and is initiated by photoreceptor detection of light. Parallel pathways of information flow are initiated at the first synapse between photoreceptors and depolarizing and hyperpolarizing bipolar cells, which detect luminance increases and decreases and/or vision under dark- and light-adapted conditions. As a result, the pathways extend the dynamic range of information processing in the intensity domain, and increase specialization of information processing for salient environmental features, e.g., motion, direction and size. Signaling within these circuits is refined by inhibitory inputs in the outer and inner retina and these interactions culminate in and define the receptive field organization of the retinal ganglion cells. The receptive field is a basic property, shared across all sensory neurons in all species. It defines the types and range of environmental stimuli that each cell encodes. Thus, understanding how receptive field properties develop is key to understanding visual function in the retina and the ganglion cells are a vital part because they represent both the culmination of all retinal processing and the scaffold for the rest of visual processing. Because basic RF spatial organization is already present at the onset of visual responses in ganglion cells, the processes underlying their development have been relatively intractable to investigation. That normal vision requires signaling through the depolarizing and hyperpolarizing pathways is amply indicated by the visual defects that occur in patients with and mouse models of congenital stationary night blindness (CSNB), where depolarizing bipolar cell processing is eliminated. We have three unique mouse models of CSNB1 that we will continue to use to probe the synaptic circuitry underlying CSNB, in which normal photoreceptor function is retained. The nature of the changes in spontaneous and visually-evoked responses across GCs in the three mutants provides a unique opening to study the development of receptive field organization and ganglion cell signaling. The phylogenetic conservation of receptive field organization suggests that our findings in the mouse will be relevant to primate peripheral retinal processing. We suggest that the characterization of these mouse models represents a significant opportunity, not afforded by other mouse or vertebrate models and represents a critical step in our understanding both the disease mechanisms in CSNB1 and normal retinal development and function. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page