Topographic mapping labels in visual development

描述(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。首先是关于绘制分子图谱(“先天”)和依赖活动的过程(“后天”)对于发展中枢神经系统连接性的相对重要性的长期争论。关于在鼠标视觉系统中开发地形图的问题，我们已经开始回答这个问题。在目标1中，我们将确定在活体内ePhin-as、模式神经活动以及ePhin-as和神经活动中断时，对视网膜小脑膜电位的发育影响。我们将确定这些机制中的每一种具体是如何帮助形成映射的，它们可以在多大程度上相互补偿，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域的结果进行比较，以确定不同的大脑区域是否使用这些机制的不同。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，这些区域的排列使它们与视觉世界相一致。我们设计的实验将检验这样一种假设，即肾上腺素-AS和神经活动的组合也将被用来映射和对齐皮质小脑投射和视网膜小脑投射，但具有更大的活动依赖机制的相对重要性。这些实验将利用我们的发现，EphA3-Ki小鼠和ePhin-A2/A3/A5 TKO小鼠具有不同结构的SC和V1映射。对这些老鼠的分析将使我们能够确定当皮质和丘脑地图具有不同的地形结构时，大脑在结构或功能上的适应程度，以创建一个具有凝聚力的视觉世界。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。已经提出了多种绘制地形图的模型，每个模型都与已发表的大部分体内和体外实验数据相一致。我们计划通过两种方式确定这些模型中的哪一个(如果有的话)是正确的。首先，我们将使用条件性基因敲除技术，通过从视网膜或SC中特异性地移除ePhin-A5，来确定ePhin-A5在映射中的视网膜和丘脑的贡献。其次，我们试图通过分析小鼠视网膜睫状体的地形图来确定轴突-轴突竞争在地形图形成中的作用，这些小鼠的RGC数量减少，从而减少了对SC中靶空间的竞争。与公共健康相关形成精确的神经元连接是神经元之间富有成效的交流所严格要求的。了解视觉系统中指定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疾病，如全身性癫痫、睡眠障碍和智力低下。此外，在发育过程中用于建立神经元连接的相同机制很可能被操纵，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.