Topographic mapping labels in visual development

描述（由申请人提供）：我们提出的实验旨在解决发育神经科学中的两个重要问题。第一个是长期存在的争论，映射分子（“自然”）和活动依赖性过程（“培育”）对CNS连接的发展的相对重要性。我们已经开始回答这个问题的地形图在鼠标视觉系统的发展。在目的1中，我们将确定视网膜丘地图上的发展后果时，ephrin-As，图案化的神经活动，ephrin-As和神经活动在体内被破坏。我们将确定这些机制中的每一个如何具体地起作用，以帮助形成地图，在何种程度上，他们可以相互补偿，以及如果地形需要发展正常的感受野反应的目标神经元。我们还将这些结果与皮层视觉区的结果进行比较，以确定不同的大脑区域是否不同地使用这些机制。目标1的第二个目标是确定地形图对齐的机制。SC接收来自大脑多个区域的输入，这些区域被排列成与视觉世界相关联。我们已经设计了实验，将测试的假设，肝配蛋白-作为和神经活动的组合也将被用来映射和调整的corticollicular投影与retinocollicular投影，但具有较大的相对重要性的活动依赖性机制。这些实验将利用我们的发现，即EphA 3-ki小鼠和ephrin-A2/A3/A5 tko小鼠具有结构不同的SC和V1图谱。对这些小鼠的分析将使我们能够确定当皮层和丘地图具有不同的地形结构时，大脑在结构或功能上能够适应创造一个有凝聚力的视觉世界的程度。目标2中提出的实验将从机械上解决地形图是如何形成的。已经提出了多个模型的地形图，每一个是一致的，在体内和体外实验数据。我们计划通过两种方式来确定这些模型中的哪一个（如果有的话）是正确的。首先，我们将通过使用条件敲除技术从视网膜或SC特异性地去除肝配蛋白-A5来确定肝配蛋白-A5在映射中的视网膜相对于丘的贡献。第二，我们要确定轴突轴突竞争的作用，在地形图的形成，通过分析小鼠视网膜丘地图，减少了RGCs的数量，因此，减少了竞争的目标空间在SC。公共卫生相关性精确的神经元连接的形成是严格要求的神经元之间的生产性通信。了解视觉系统中指定正确连接的基本过程将直接与治疗涉及异常神经元连接和处理的神经系统疾病相关，例如全身性癫痫发作，睡眠障碍和智力迟钝。此外，很可能在发育过程中用于建立神经元连接的相同机制可以被操纵，以便在因损伤或疾病而受损后重新连接大脑。

Description (provided by applicant): The experiments we propose aim to resolve two important issues in developmental neuroscience. The first is the long-standing debate as to the relative importance of mapping molecules ("nature") and activity-dependent processes ("nurture") toward the development of CNS connectivity. We have started to answer this question with respect to the development of topographic maps in the mouse visual system. In Aim 1, we will determine the developmental consequences on the retinocollicular map when ephrin-As, patterned neural activity, and both ephrin-As and neural activity are disrupted in vivo. We will determine how each of these mechanisms specifically acts to help form maps, the extent to which they can compensate for each other, and if topography is required to develop normal receptive field responses of target neurons. We will also compare these results with those obtained in cortical visual areas, to determine if different brain areas use these mechanisms differentially. A secondary goal of Aim 1 is to determine the mechanisms by which topographic maps align. The SC receives inputs from multiple regions of the brain, which are arranged such that they are in register with the visual world. We have designed experiments that will test the hypothesis that a combination of ephrin-As and neural activity will also be used to map and align the corticocollicular projection with that of the retinocollicular projection, but with a larger relative importance of activity-dependent mechanisms. These experiments will take advantage of our findings that EphA3-ki mice and ephrin-A2/A3/A5 tko mice have SC and V1 maps that differ in structure. Analysis of these mice will allow us to determine the extent to which the brain can adapt in structure or function to create a cohesive visual world when cortical and collicular maps have different topographic structures. Experiments proposed in Aim 2 will resolve mechanistically how topographic maps form. Multiple models for topographic mapping have been proposed and each is consistent with much of the published experimental in vivo and in vitro data. We plan to determine which, if any, of these models is true in two ways. First, we will determine the retinal vs. collicular contributions of ephrin-A5 in mapping, by removing ephrin-A5 specifically from the retina or SC, using conditional knock out technology. Second, we to determine the role of axon-axon competition in topographic map formation by analyzing the retinocollicular maps in mice that have reduced numbers of RGCs and, therefore, reduced competition for target space in the SC. PUBLIC HEALTH RELEVANCE The formation of precise neuronal connections is strictly required for productive communication between neurons. Understanding the basic processes that specify proper connectivity in the visual system will be directly relevant to treating neurological disorders involving aberrant neuronal connections and processing, such as generalized seizures, sleep disorders, and mental retardation. In addition, it is likely that the same mechanisms used to make neuronal connections during development can be manipulated in order to rewire the brain after damage due to injury or disease.