Structure, function, and adaptability of parallel pathways in mammalian retina

项目总结/摘要 为了恢复视力，我们必须了解信息在成熟的视网膜中是如何处理的， 结构和功能组织在退化期间受到影响。信号的分歧， 视觉系统中的第一个突触，其中单个锥体向10-12种锥体双极提供输入 细胞，提供了一个独特的机会来研究平行途径的起源。这个突触还表现出 会聚，其中每种类型的视锥双极细胞接收来自固定数量的视锥的输入。 我们最近的工作表明，三种类型的锥双极细胞建立了他们独特的模式， 根据不同的策略与突触前锥体光感受器的结构接触， 隔离的时间线然而，我们对这些差异如何转化为功能性差异知之甚少。 在成熟的赛道上。此外，锥双极细胞类型如何响应于 疾病期间的光受体尚不清楚。拟议工作的长期目标是了解 视觉信息如何在视网膜中的视锥-视锥双极突触处被解析和处理，以及 来确定这些信息在疾病中是如何被扰乱的。拟议工作的目标是 确定三种形态特征的双极细胞类型的功能特性，其中 我们已经知道结构连接模式，并确定这些双极的结构和 退化的视网膜中的功能性变化。在目标1中，我们将确定锥收敛和 趋异塑造了三种类型的锥双极细胞的功能特性。我们将使功能 双极细胞的空间、时间和增益特性的测量。在目标2中，我们将确定 视锥细胞变性对双极细胞结构、连通性和功能的影响。许多视网膜疾病导致 失明的原因是光感受器的死亡。疾病如何影响突触后 神经元在很大程度上仍是未知的。我们将使用激光消融和转基因方法来控制 视锥死亡的程度和时间。影像学和电生理学可以帮助我们确定 双极细胞的连接模式、谷氨酸受体分布和对光刺激的反应 在控制性的球果死亡之后这种方法是创新的，因为我们是单独确定 特定双极细胞类型对光感受器变性的功能和反应。拟议工作 是重要的，因为它将揭示双极细胞的功能特性是如何由其 解剖学上与视锥细胞的联系，并将提供双极细胞如何响应 作为视网膜疾病中潜在电路重排模型的光感受器变性。

PROJECT SUMMARY/ABSTRACT To restore vision, we must understand how information is processed in the mature retina and how structural and functional organization are affected during degeneration. The divergence of signals at the first synapse in the visual system, where a single cone provides input to 10-12 types of cone bipolar cells, provides a unique opportunity to study the origin of parallel pathways. This synapse also exhibits convergence, where each type of cone bipolar cell receives inputs from a stereotyped number of cones. Our recent work demonstrates that three types of cone bipolar cells establish their unique patterns of structural contact with presynaptic cone photoreceptors according to different strategies and segregated timelines. However, we know little about how these differences translate into functional properties in the mature circuit. Moreover, how cone bipolar cell types respond to progressive loss of photoreceptors during disease is unclear. The long-term goal of the proposed work is to understand how visual information is parsed and processed in the retina at the cone-to-cone bipolar synapse, and to determine how this information is perturbed in disease. The objectives of the proposed work are to determine the functional properties of three morphologically characterized bipolar cells types, for which we already know structural connectivity patterns, and to determine these bipolars' structural and functional changes in a degenerating retina. In Aim 1, we will determine how cone convergence and divergence shapes the functional properties of three types of cone bipolar cells. We will make functional measures of the bipolar cells' spatial, temporal, and gain properties. In Aim 2, we will identify the effects of cone degeneration on bipolar cell structure, connectivity, and function. Many retinal diseases leading to blindness originate with death of photoreceptors. How disease progresses to affect postsynaptic neurons remains largely unknown. We will use laser ablation and transgenic approaches to control the extent and timing of cone death. Imaging and electrophysiology will allow us to determine the structural connectivity patterns, glutamate receptor distributions, and responses to light stimuli of bipolar cells following controlled cone death. The approach is innovative because we are separately determining the function and response of specific bipolar cell types to photoreceptor degeneration. The proposed work is significant because it will reveal how a bipolar cell's functional properties are determined by its anatomical connections with cones and will provide an understanding of how bipolar cells respond to photoreceptor degeneration as a model of potential circuit rearrangements in retinal disease.