A Road Map to the Neocortex

新皮质路线图

基本信息

批准号：
8541057
负责人：
Sharad Ramanathan
金额：
$ 81.97万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-07-31
项目状态：
已结题

项目摘要

DESCRIPTION Abstract: An enormously complex part of the brain, the neocortex, is thought to give us the ability to generate conscious thought, develop language and perform complicated perception and spatial reasoning tasks. Understanding how the neocortex is built is key to understanding how our brain functions. Here, we propose to develop novel computational and experimental tools to help us understand how electrical activity and genetic circuits are coupled to generate the different cell types in this complex organ. While one might imagine an exceptionally elaborate network of genes giving rise to the brain, several reprogramming experiments suggest that just a handful developmentally important key factors control specific fate choices. We aim to discover these sets of factors to build a coarse road map of the key gene expression events leading to the neocortex, and over lay on this map the expression patterns of all the other genes. We will do so using the data that has the spatial and temporal expression pattern of every mouse gene during the course of the development of the mouse brain from mid gestation to adult. We will develop a novel computational paradigm to analyze this data and extract the rules governing the construction of the neocortex. We will test these rules directly in an in vitro directed differentiation system, focusing on the pyramidal neurons. To enable such tests, we are developing ground-breaking imaging technologies to both measure and perturb gene expression and electrical activity in thousands of single cells as they differentiate in vitro from stem cells to post-mitotic pyramidal neurons. We will measure dynamics of candidate factors predicted by our computational analysis as well as calcium and electrical activity in single cells by using multiple fluorescent reporters. By analyzing these single cell time-series expression and activity data using a Bayesian statistical analysis and directly perturbing the dynamics of expression of specific genes and e

描述抽象的：人们认为，大脑的一个非常复杂的部分，即新皮层，使我们能够产生有意识的思想，发展语言并执行复杂的感知和空间推理任务。了解新皮层的构建方式是了解我们的大脑功能的关键。在这里，我们建议开发新颖的计算和实验工具，以帮助我们了解如何将电活动和遗传回路耦合以在该复杂器官中产生不同的细胞类型。虽然人们可能会想象一个非常复杂的基因网络引起了大脑，但几个重编程实验表明，仅仅是少数重要的开发重要因素控制特定的命运选择。我们的目的是发现这些因素集，以建立导致新皮层的关键基因表达事件的粗线图，并在此图上铺设所有其他基因的表达模式。我们将使用在小鼠大脑从妊娠到成年的小鼠脑发育过程中具有每个小鼠基因的空间和时间表达模式的数据。我们将开发一个新颖的计算范式来分析这些数据并提取有关新皮层构建的规则。我们将直接在体外定向分化系统中测试这些规则，重点是金字塔神经元。为了实现此类测试，我们正在开发开创性的成像技术，以测量和扰动基因表达和数千个单个细胞中的电活性，因为它们将体外从干细胞从干细胞区分为有丝分裂后锥体神经元。我们将通过使用多个荧光记者来衡量通过计算分析以及单个细胞中钙和电活动预测的候选因素的动力学。通过使用贝叶斯统计分析分析这些单细胞时间序列的表达和活性数据，并直接扰动特定基因和E的表达动力学