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

描述(申请人提供)：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，以及结构和功能组织在退化过程中是如何受到影响的。视觉系统中第一突触的信号发散为研究平行通路的起源提供了独特的机会，其中一个锥体为10-12种锥体双极细胞提供了输入。这种突触也表现出会聚，其中每种类型的锥体双极细胞接受来自固定数量的锥体的输入。我们最近的工作表明，三种类型的视锥双极细胞根据不同的策略和分离的时间线，建立了它们与突触前视锥感光细胞独特的结构接触模式。然而，我们对这些差异如何转化为成熟回路中的功能特性知之甚少。此外，锥体双极细胞类型如何在疾病期间对光感受器的进行性丧失做出反应尚不清楚。这项拟议工作的长期目标是了解视觉信息是如何在视网膜的视锥对视锥双极突触中被解析和处理的，并确定这种信息在疾病中是如何受到干扰的。这项拟议工作的目标是确定三种形态特征的双极细胞的功能特性，我们已经知道它们的结构连接模式，并确定这些双极细胞在退化的视网膜中的结构和功能变化。在目标1中，我们将确定锥体收敛和发散如何塑造三种类型的锥体双极细胞的功能特性。我们将对双极电池的空间、时间和增益特性进行功能测量。在目标2中，我们将确定锥体退化对双极细胞结构、连通性和功能的影响。许多导致失明的视网膜疾病起源于光感受器的死亡。疾病是如何发展到影响突触后神经元的，目前在很大程度上仍不清楚。我们将使用激光消融和转基因方法来控制锥体死亡的程度和时间。成像和电生理学将使我们能够确定受控视锥细胞死亡后双极细胞的结构连接模式、谷氨酸受体分布和对光刺激的反应。这种方法是创新的，因为我们正在单独确定特定类型的双极细胞对光感受器退化的功能和反应。拟议的工作意义重大，因为它将揭示双极细胞的功能属性是如何由其与视锥的解剖联系决定的，并将提供对双极细胞如何响应光感受器退化的理解，作为视网膜疾病潜在电路重排的模型。

DESCRIPTION (provided by applicant): 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 effect 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.