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

项目摘要/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，以及如何 结构和功能组织在退化过程中受到影响。交通信号的发散 视觉系统中的第一个突触，其中一个锥体向10-12种类型的锥体双极提供输入 细胞，为研究平行通路的起源提供了一个独特的机会。这个突触还展示了 汇聚，其中每种类型的锥体双极细胞从固定数量的锥体接收输入。 我们最近的工作表明，三种类型的锥体双极细胞建立了它们独特的模式 根据不同的策略与突触前锥体光感受器进行结构性接触 分开的时间线。然而，我们对这些差异如何转化为功能性的知之甚少 成熟赛道中的物业。此外，锥体双极细胞类型如何对进行性丢失做出反应 疾病期间的光感受器尚不清楚。拟议工作的长期目标是了解 视觉信息是如何在视锥-视锥双极突触的视网膜中被解析和处理的，以及 以确定这种信息在疾病中是如何受到干扰的。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 我们已经知道结构连接模式，并确定这些两极的结构和 退化视网膜的功能变化。在目标1中，我们将确定锥体收敛和 发散决定了三种类型的锥体双极细胞的功能特性。我们将使其具有功能性 测量双极单元的空间、时间和增益特性。在目标2中，我们将确定影响 锥体退化对双极细胞结构、连接和功能的影响。许多视网膜疾病导致 失明源于光感受器的死亡。疾病进展如何影响突触后 神经元在很大程度上仍不为人所知。我们将使用激光消融和转基因方法来控制 锥体死亡的范围和时间。成像和电生理学将使我们能够确定结构 双极细胞的连接模式、谷氨酸受体分布和对光刺激的反应 在控制性锥体死亡之后。这种方法是创新的，因为我们正在单独确定 特定双极细胞类型对光感受器退化的功能和反应。拟议中的工作 具有重要意义，因为它将揭示双极电池的功能属性是如何由其 并将提供对双极细胞如何响应的理解 光感受器变性作为视网膜疾病潜在回路重排的模型。

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.