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。第一个是长期以来关于绘制分子（“自然”）和活动依赖过程（“培育”）对中枢神经系统连接发展的相对重要性的争论。我们已经开始用鼠标视觉系统中地形图的发展来回答这个问题。在Aim 1中，我们将确定当ephrin- a、模式神经活动以及ephrin- a和神经活动在体内被破坏时对视网膜视丘图的发育后果。我们将确定这些机制如何具体地帮助形成地图，它们可以相互补偿的程度，以及是否需要地形来发展目标神经元的正常感受野反应。我们还将把这些结果与皮质视觉区获得的结果进行比较，以确定不同的大脑区域是否使用不同的机制。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一致。我们设计了一些实验来验证这样一个假设，即肾上腺素- a和神经活动的结合也将用于绘制和对齐皮质丘投影和视网膜丘投影，但与活动依赖机制的相对重要性更大。这些实验将利用我们的发现，EphA3-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大脑在结构或功能上适应的程度，以创造一个有凝聚力的视觉世界，当皮层和collcolla地图具有不同的地形结构时。在目标2中提出的实验将机械地解决地形图是如何形成的。已经提出了多种地形测绘模型，每种模型都与许多已发表的体内和体外实验数据一致。我们计划以两种方式确定这些模型中哪个是正确的。首先，我们将通过使用条件敲除技术从视网膜或SC中特异性去除ephrin-A5，来确定ephrin-A5在视网膜和睫状体定位中的作用。其次，我们试图通过分析RGCs数量减少的小鼠的视丘图来确定轴突-轴突竞争在地形图形成中的作用，从而减少了SC中靶空间的竞争。公共卫生相关性神经元之间有效通信严格要求形成精确的神经元连接。了解指定视觉系统中适当连接的基本过程将直接关系到治疗涉及异常神经元连接和处理的神经系统疾病，如全局性癫痫、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也可以被操纵，以便在因受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.