Mechanisms of retinotectal map development

描述(申请人提供)：视觉地图对视觉功能至关重要。因此，了解视觉地图发展和再生的机制对于了解视觉是如何发展的，以及受伤后视觉如何恢复至关重要。也许视觉地图开发最重要的模型系统是从视网膜到顶盖/上丘的地形图投影。虽然在这个系统中地图形成的机制已经被实验研究了几十年，但没有统一的理论框架来解释这些数据中的一小部分。如果没有这样的框架，就不可能严格地说明视网膜顶盖系统中地图形成的真正机制，也很难从当前的数据之外推断出系统的新扰动将如何影响地图的发展。虽然之前已经提出了几种视网膜顶盖地图形成的理论模型，但它们都有两个严重的局限性。首先，它们通常只解决通过依赖活动的Hebbian学习规则来绘制地形的精化，而不解决初始地形是如何通过活动无关的过程形成的。其次，他们通常没有考虑到自1995年以来出现的关于ePhin/Eph梯度在视网膜顶盖地图形成中的关键作用的任何数据。为了克服这些问题，我们建议开发一个全面的新模型，该模型(1)基于分子梯度的轴突指导，而不是Hebbian学习规则，以及(2)将最近关于ePhin/Eph梯度的数据与关于对系统的手术操作的旧数据进行合成。PI处于能够做到这一点的独特位置，因为他结合了这一领域广泛的实验数据的详细知识，以及在视觉系统中轴突引导和地图形成的理论建模方面的广泛经验。该项目的成果将是一个计算框架，它严格识别趋化和竞争等机制对视网膜顶盖地图形成的相对贡献，做出可测试的预测，并可以指导未来的实验工作。

DESCRIPTION (provided by applicant): Visual maps are crucial for visual function. Understanding the mechanisms by which visual maps develop and regenerate is therefore crucial for understanding how vision develops, and how vision could be restored after injury. Perhaps the most important model system for visual map development is the topographic projection from the retina to the tectum/superior colliculus. Although the mechanisms of map formation in this system have been studied experimentally for many decades, there is no unifying theoretical framework that can explain more than a small subset of this data. Without such a framework it is impossible to rigorously state what the mechanisms underlying map formation in the retinotectal system really are, and it is difficult to extrapolate beyond current data to predict how novel perturbations to the system will affect map development. Although several theoretical models of retinotectal map formation have been proposed previously, they have two serious limitations. Firstly, they generally address only refinements to map topography by activity-dependent Hebbian learning rules, and do not address how initial topography forms by activity independent processes. Secondly, they generally take no account of any of the data that has emerged since 1995 on the crucial role of ephrin/Eph gradients in retinotectal map formation. To overcome these problems, we propose to develop a comprehensive new model which (1) is based on axon guidance by molecular gradients rather than Hebbian learning rules, and (2) synthesizes recent data on ephrin/Eph gradients with older data regarding surgical manipulations to the system. The PI is in a unique position to be able to do this, since he combines a detailed knowledge of the extensive experimental data in this area with wide-ranging experience in the theoretical modeling of axon guidance and map formation in the visual system. The outcome of this project will be a computational framework that rigorously identifies the relative contributions of mechanisms such as chemotaxis and competition to the formation of retinotectal maps, makes testable predictions, and can guide future experimental work.