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

描述（由申请人提供）：为了恢复视力，我们必须了解信息是如何在成熟的视网膜中处理的，以及在退化过程中结构和功能组织是如何受到影响的。在视觉系统的第一个突触中，单个锥体向10-12种锥体双极细胞提供输入，信号的发散为研究平行通路的起源提供了独特的机会。这种突触也表现出收敛性，其中每种类型的锥体双极细胞接收来自固定数量的锥体的输入。我们最近的工作表明，三种类型的锥体双极细胞根据不同的策略和分离的时间线建立了与突触前锥体光感受器的独特结构接触模式。然而，我们对这些差异如何转化为成熟电路的功能特性知之甚少。此外，视锥双极细胞类型如何对疾病期间光感受器的逐渐丧失作出反应尚不清楚。这项工作的长期目标是了解视觉信息是如何在视网膜的锥对锥双极突触上被解析和处理的，并确定这些信息在疾病中是如何受到干扰的。本研究的目的是确定三种形态特征的双相细胞类型的功能特性，我们已经知道了它们的结构连接模式，并确定这些双相细胞在退化视网膜中的结构和功能变化。在目标1中，我们将确定锥体汇聚和发散如何塑造三种类型的锥体双极细胞的功能特性。我们将对双极细胞的空间、时间和增益特性进行功能测量。在目标2中，我们将确定锥体变性对双极细胞结构、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。疾病如何发展到影响突触后神经元仍然很大程度上是未知的。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结构连接模式、谷氨酸受体分布以及双极细胞在受控锥体死亡后对光刺激的反应。该方法具有创新性，因为我们分别确定了特定双极细胞类型对光感受器变性的功能和反应。这项工作意义重大，因为它将揭示双极细胞的功能特性是如何由其与锥体的解剖连接决定的，并将提供双极细胞如何响应光感受器变性的理解，作为视网膜疾病中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.