Molecular Specification of Direction Selectivity in the Visual System

描述(由申请人提供)：神经系统信息处理的基础是有序的神经回路：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这些回路是如何形成的。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对不同的视觉特征做出反应，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，对沿特定方向移动的对象反应最好。哺乳动物的视网膜至少含有3种方向选择性神经节细胞(DSGCs)。然而，缺乏选择性地识别DSGCs的分子标记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。我们现在已经找到了三种类型的DSGCs的标记，并开发了转基因方法来标记每种类型的体内。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的反应的神经元回路。在特定的目标1-3中，我们将描述每种类型的特定标记的小鼠的特征。我们将分析每种类型的DSGC的形态和功能发育，并寻找亚型特异性基因(黏附分子JAM-B和两个分泌分子FSTL4和SPIG1/FSTL5)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类型的DSGC的连接。最后(具体目标5)，我们将寻找新的分子来调节DSGC发育的不同方面。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接受了一段时间的指导后，我将在一家学术机构担任独立研究员，开始自己的实验室。我的长期目标是研究神经回路是如何通过经验形成和改变的。我希望我的工作将为研究神经回路如何在精神疾病中失效提供见解。

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.