Molecular Specification of Direction Selectivity in the Visual System

描述（由申请人提供）：有序的神经回路是神经系统信息处理的基础：我们的感知，决策和行为。神经生物学的一个主要目标是了解电路是如何形成的。我们使用视网膜来解决这个问题。不同类型的视网膜神经节细胞响应不同的视觉特征，基于它们从视网膜中间神经元接收的输入。有几种类型是方向选择性的，对在特定方向上移动的对象响应最好。哺乳动物视网膜至少含有3种方向选择性神经节细胞（DSGCs）。然而，缺乏分子标记物来选择性地识别DSGCs，阻碍了对它们的发育、视网膜中的突触输入和大脑中的靶点的分析。我们现在已经发现了3种类型的DSGCs的标记物，并开发了转基因方法来标记体内的每种类型。这种方法使我们能够阐明调节这些神经元分化的分子机制，并追踪启动对移动物体反应的神经元回路。在具体目标1-3中，我们将表征其中每种DSGC类型被特异性标记的小鼠。我们将分析每种DSGC类型的形态和功能发育，并寻求亚型特异性基因（粘附分子JAM-B和两种分泌分子FSTL 4和SPIG 1/FSTL 5）在这些过程中的作用。在具体目标4中，我们将使用跨突触示踪剂来定义每种DSGC类型的连接。最后（具体目标5），我们将寻找调节DSGC发育各个方面的新分子。总之，这些研究将为视觉处理的细胞基础提供新的见解。在哈佛大学脑科学中心的指导期结束后，我将在一家学术机构作为独立调查员建立自己的实验室。我的长期目标是研究神经回路是如何通过经验形成和修改的。我希望我的工作能为研究精神疾病中神经回路如何失效提供见解。

DESCRIPTION (provided by applicant): Orderly neural circuits underlie processing of information in the nervous system: our perceptions, decisions and behaviors. A main goal of neurobiology is to understand how the circuits form. We use the retina to address this issue. Distinct types of retinal ganglion cells respond to different visual features, based on which inputs they receive from retinal interneurons. Several types are direction selective, responding best to objects moving in a particular direction. The mammalian retina contains at least 3 types of direction selective ganglion cells (DSGCs). However, the lack of molecular markers to selectively identify DSGCs has impeded analysis of their development, synaptic inputs in the retina, and targets in the brain. We have now found markers for 3 types of DSGCs and developed transgenic approaches to label each type in vivo. This method allows us to elucidate molecular mechanisms that regulate differentiation of these neurons, and to trace the neuronal circuits that initiate responses to moving objects. In specific aims 1-3, we will characterize mice in which each DSGC type is specifically labeled. We will analyze the morphological and functional development of each DSGC type, and seek roles of the subtype specific genes (an adhesion molecule, JAM-B and two secreted molecules, FSTL4 and SPIG1/FSTL5) in these processes. In specific aim 4, we will use transsynaptic tracers to define the connections of each DSGC type. Finally (specific aim 5), we will seek new molecules that regulate diverse aspects of DSGC development. Together, these studies will provide novel insights into the cellular basis of visual processing. Following the mentored period in the Center for Brain Science at Harvard University, I will start my own lab as an independent investigator at an academic institution. My long-term goal is to study how neural circuits are formed and modified by experience. I hope that my work will provide insights in studying how neural circuit fails in psychiatric diseases.