Circuit Assembly in the Vertebrate Retina

脊椎动物视网膜中的电路组装

• 批准号: 7878621
• 负责人: Rachel O Wong
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878621
• 关键词: Address; Aminobutyric Acids; Animals; Arts; Axon; Behavior; Biological Assay; Brain Part; Cell physiology; Cells; Cellular Structures; Cues; DNA Sequence Rearrangement; Defect; Dendrites; Development; Diphtheria Toxin; Disease; Event; Feedback; Future; Genetic; Goals; In Vitro; Interneurons; Investigation; Knowledge; Label; Lead; Life; Light; Location; Mediating; Methods; Microscopy; Modeling; Molecular; Mus; Mutant Strains Mice; Nervous System Part; Nervous system structure; Neuraxis; Neurites; Neurons; Neuropil; Output; Pathway interactions; Photoreceptors; Process; Proteins; Retina; Retinal; Retinal Cone; Retinal Ganglion Cells; Rodent; Role; Sensory; Signal Transduction; Stratification; Structure; Synapses; Technology; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Trauma; Vision; Visual; Visual system structure; cell type; design; developmental disease; gamma-Aminobutyric Acid; horizontal cell; imaging modality; in vivo; insight; interdisciplinary approach; optical imaging; outer plexiform layer; promoter; receptor; recombinase; relating to nervous system; research study; retinal neuron; synaptic function; visual process; visual processing

DESCRIPTION (provided by applicant): The proper functioning of the central nervous system (CNS) requires that its many cellular components are connected appropriately, in order to process and encode information specific to each part of the brain. Thus, determining how the CNS is wired up precisely during development is fundamentally important. Although we have gained a significant understanding of the cellular and molecular mechanisms that are critical for circuit development, much has yet to be unraveled. Discovering these mechanisms requires approaches that will elucidate how cells interact with each other to form and maintain connections. Our long term goal is to understand how highly specific synaptic connections are established between the many cell types of the vertebrate retina, largely for 2 reasons: The retina is (1) essential for vision; and (2) its strongly correlated structure and function makes it an excellent model for investigating how neural cricuits are organized during development. In this proposal, we will focus on the first synaptic layer of the retina, the outer plexiform layer (OPL), within which visual signals are first processed in the visual system. In the OPL, photoreceptors contact bipolar cells that then relay signals along distinct pathways to retinal output cells. Horizontal cells modulate information conveyed from photoreceptors. Despite the importance of visual processing by the OPL, little is understood concerning its assembly during development. We propose to use and generate transgenic mice to examine how the various outer retinal cell types interact with each other to establish circuitry in the OPL. We will label photoreceptors, bipolar and horizontal cells in live animals, by causing them to express fluorescent proteins using cell-specific promoters. State-of-the-art optical imaging methods will be applied to visualize and follow how processes of these cells come to form appropriate contact with each other. We will also use and generate mutant mice to address the importance of horizontal cells, which develop earliest, in regulating the structural and functional development of the OPL. Our results should provide a deeper understanding of how interactions between cells lead to the establishment of their circuits, and thus provide further insight into developmental disorders in the nervous system. Our findings could potentially help focus future investigations aimed at designing strategies to re-establish retinal function in trauma or disease.

描述（由申请人提供）：中枢神经系统（CNS）的正确功能要求其许多细胞成分已适当连接，以便处理和编码针对大脑每个部分的信息。因此，在开发过程中确定中枢神经系统的确切结束是从根本上重要的。尽管我们已经对对电路发育至关重要的细胞和分子机制有了重大的了解，但尚未阐明很多。发现这些机制需要方法，以阐明细胞如何相互相互作用以形成和保持连接。我们的长期目标是了解如何在脊椎动物视网膜的许多细胞类型之间建立高度特异性的突触连接，这主要是有两个原因：视网膜（1）对于视觉至关重要； （2）它的结构和功能密切相关，使其成为研究在发育过程中如何组织神经山皮的绝佳模型。在此提案中，我们将重点关注视网膜外丛状层（OPL）的第一个突触层，其中首先在视觉系统中处理视觉信号。在OPL中，光感受器接触双极细胞，然后沿着不同的途径传递到视网膜输出细胞。水平细胞调节从光感受器传达的信息。尽管OPL的视觉处理很重要，但在开发过程中的组装方面几乎没有理解。我们建议使用并生成转基因小鼠来检查各种视网膜外细胞类型如何相互作用以在OPL中建立电路。我们将使用细胞特异性启动子表达荧光蛋白来标记活动物中的光感受器，双极细胞和水平细胞。最先进的光学成像方法将应用于可视化和遵循这些单元的过程如何相互形成适当的接触。我们还将使用并生成突变小鼠来解决最早发展的水平细胞的重要性，以调节OPL的结构和功能发展。我们的结果应更深入地了解细胞之间的相互作用如何导致其电路的建立，从而进一步深入了解神经系统中的发育障碍。我们的发现可能有可能有助于将未来的调查集中在设计策略中，以重新建立创伤或疾病中的视网膜功能。