Quantitiative model for the development of neural topographic maps

描述（由申请人提供）：我们的目标是了解大脑中神经网络在发育过程中形成的定量原理。研究这些原理的理想候选者是从视网膜到视顶盖或哺乳动物上丘的地形投影。邻近视网膜细胞的轴突在上丘的近端终止，从而形成视觉世界的精确地形图，称为地形图或视网膜定位图。坐标轴在视网膜和靶标中通过分子标记的分级表达进行编码，如Eph受体酪氨酸激酶及其配体ephrin。相关的神经活动促进了投影的进一步锐化。在这个建议中，我们将在一个单一的定量模型中结合各种发展机制，并展示它们的相互作用如何提供所需的地形测绘精度。本提案的具体目标包括：i)如何在同一模型中结合活动依赖因素和活动独立因素？ii)为什么在发育过程中轴突和树突的动态是不同的？iii)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遗传程序以分子标记和相关神经活动传递的环境信息的形式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育为特征的神经系统疾病提供见解，包括Eph/ ephrin通路中断对人类视觉处理损伤的可能影响。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。所有研究都将在实验组的密切合作下进行。将在项目的各个阶段征求专家意见。

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.