Quantitiative model for the development of neural topographic maps

描述(申请人提供)：我们的目标是了解大脑中神经网络在发育过程中形成的量化原理。研究这些原理的理想对象是从视网膜到视顶盖或哺乳动物上丘的地形图投影。邻近视网膜细胞的轴突终止于上丘的近端，从而形成一种被称为地形图或视网膜定位图的视觉世界的精确地形图。在视网膜和靶组织中，通过分级表达分子标记，如Eph受体酪氨酸激酶及其配体，ephins，对坐标轴进行编码。相关的神经活动促进了投射的额外锐化。在这项提案中，我们将把不同的发展机制结合在一个单一的量化模型中，并展示它们的相互作用如何提供所需的地形图绘制精度。这一建议的具体目标包括：i)如何在同一模型中结合活动依赖和活动非依赖因素？Ii)为什么轴突和树突在发育过程中的动态不同？3)突触成熟在轴突和树突分支动力学中的作用是什么？我们的项目将有助于理解分子标记形式的遗传程序和相关神经活动传达的环境信息如何塑造发育中的神经元连接的机制。因此，我们的研究将为以感觉功能异常发展为特征的神经疾病提供见解，包括Eph/ePhin通路中断对人类视觉加工障碍的可能影响。我们的模型将有助于解决与电路缺陷有关的发育障碍和神经退行性疾病。所有研究都将与实验小组密切合作进行。我们会就计划的所有阶段征询专家意见。

DESCRIPTION (provided by applicant): Our goal is to understand the quantitative principles whereby neural networks in the brain are formed during development. An ideal candidate to study these principles is the topographic projection from retina to optic tectum or mammalian superior colliculus. Axons of neighboring retinal cells terminate proximally in the superior colliculus thus forming a topographically precise representation of the visual world called topographic or retinotopic map. Coordinate axes are encoded in retina and in the target through graded expression of molecular labels, such as Eph receptor tyrosine kinases and their ligands, ephrins. Additional sharpening of projections is facilitated by correlated neural activity. In this proposal we will combine various developmental mechanisms in a single quantitative model and show how their interactions provide required precision of topographic mapping. The specific aims of this proposal include: i) How can one combine activity-dependent and activity-independent factors in the same model? ii) Why is the dynamics of axons and dendrites different during development? iii) What is the role of synaptic maturation in the axon and dendrite branch dynamics? Our project will help to understand the mechanisms whereby genetic program in the form of molecular labels and environmental information conveyed by correlated neural activity shape the developing neuronal connectivity. Our study will therefore provide insights on neurological conditions characterized by abnormal development of sensory function, including a possible effect of disruption of Eph/ ephrin pathways on impairment of visual processing in humans. Our model will aid in addressing developmental disabilities and neuro-degenerative diseases linked to defects in circuitry. All studies will be carried out in close collaboration with experimental groups. Expert advice will be solicited on all stages of the project.