Circuit Assembly in the Vertebrate Retina-Supplement

脊椎动物视网膜补充中的电路组装

• 批准号: 8792319
• 负责人: Rachel O Wong
• 金额: $ 2.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792319
• 关键词: Adult; Affect; Cell Death; Cell Survival; Cell Therapy; Cells; Cessation of life; Characteristics; Complex; Cone; DNA; Development; Disease; Electron Microscopy; Goals; Image; Immunohistochemistry; Investigation; Knowledge; Label; Learning; Light; Location; Maintenance; Modeling; Molecular; Molecular Genetics; Motion; Mus; Neighborhoods; Neurons; Output; Pattern; Photoreceptors; Population; Process; Property; Proteins; RBM5 gene; Relative (related person); Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Role; Shapes; Signal Transduction; Site; Structure; Synapses; Techniques; Testing; Time; Transfection; Transgenic Mice; Vertebrates; Vision; base; cell type; design; gene gun; imaging modality; insight; light microscopy; neurotransmission; novel; postsynaptic; presynaptic; reconstruction; relating to nervous system; repaired; response; restoration; retinal neuron; tool; transmission process

DESCRIPTION (provided by applicant): Vision requires proper information transfer from photoreceptors to retinal ganglion cells (RGCs), the output neurons of the retina. This information is distributed by retinal bipolar cells (BCs) along many anatomically and functionally distinct channels. Because BC channels carry different chromatic and temporal information, the light response of a RGC is shaped by the unique combination of BC input it receives. To date, the circuitry of only a few functionally defined RGC types is known, largely because reconstructions by serial electron microscopy are technically challenging and time consuming. Using state-of-the art imaging approaches and molecular tools to visualize synapses and connectivity, we are able to readily reconstruct these circuits by light microcopy. We will establish, and compare, the connectivity patterns of three functionally distinct BC-RGC circuits in the mouse retina, in order to learn new principles or uncover distinct strategies by which BC input can shape RGC output (Aim 1). We will investigate how loss of neurotransmission (Aim 2), or death of retinal neurons (Aim 3) alters circuitry in the inner retina. Because the effects of activity blockade can vary according to how neurotransmission is perturbed in development or in disease, we will determine how disruption of input and/or output of BCs influence their connectivity with RGCs. We will use novel transgenic mice in which transmission is perturbed in distinct ways, and also mice in which activity is altered in either a few or entire populations of BCs. In Aim 3, we will determine the potential of mature BCs and RGCs to re-connect when cells from one or the other population are ablated. We will do this by using transgenic mice in which the magnitude and timing of cell death can be controlled. These findings will be particularly significant for designing cell-based therapies to restore vision. Together, the discoveries of this project will significantly increase our understanding of the cellular mechanisms that regulate the function, assembly and repair of retinal channels necessary for conveying information from photoreceptors to RGCs.

描述（由申请人提供）：视觉需要从感光细胞（RGC）（视网膜的输出神经元）的视网膜神经节细胞（RGC）的适当信息传递。该信息由视网膜双极细胞（BC）分布，沿许多解剖学和功能上不同的通道分布。由于BC通道带有不同的色彩和时间信息，因此RGC的光响应是由它接收到的BC输入的独特组合所影响的。迄今为止，仅少数功能定义的RGC类型的电路才知道，这主要是因为串行电子显微镜的重建在技术上具有挑战性且耗时。使用最先进的成像方法和分子工具来可视化突触和连通性，我们能够轻松地通过光微副本重建这些电路。我们将建立并比较鼠标视网膜中三个在功能上不同的BC-RGC电路的连接模式，以了解新的原理或发现BC输入可以塑造RGC输出的不同策略（AIM 1）。我们将研究神经传递的丧失（AIM 2）或视网膜神经元死亡（AIM 3）如何改变内部视网膜中的电路。由于活动封锁的影响会根据神经传递在发育或疾病中的干扰方式而有所不同，因此我们将确定BCS的输入和/或输出的破坏如何影响其与RGC的连通性。我们将使用新型的转基因小鼠，其中以不同的方式扰动传播，并且在几个或整个BC的种群中都会改变活性的小鼠。在AIM 3中，我们将确定成熟的BC和RGC的潜力，即当来自一个或另一个人群的细胞消融时重新连接。我们将通过使用可以控制细胞死亡的大小和时机的转基因小鼠来做到这一点。这些发现对于设计基于细胞的疗法以恢复视力特别重要。总之，该项目的发现将大大增加我们对调节视网膜通道功能，组装和修复视网膜通道所必需的信息从光感受器到RGC所需的视网膜通道的理解。