A Road Map to the Neocortex

新皮质路线图

• 批准号: 8896866
• 负责人: Sharad Ramanathan
• 金额: $ 84.5万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896866
• 关键词: Adult; Bayesian Analysis; Brain; Brain Part; Calcium; Cells; Complex; Computer Analysis; Congenital Abnormality; Conscious; Coupled; Data; Data Analyses; Development; Disease; Epilepsy; Event; Gene Expression; Genes; Genetic; Imaging technology; In Vitro; Language; Maps; Measures; Midbrain structure; Mitotic; Mus; Neocortex; Organ; Pattern; Pregnancy; Reporter; Research; Series; Space Perception; Stem cells; System; Testing; Time; abstracting; cell type; hippocampal pyramidal neuron; human disease; mouse development; new technology; novel; research study; tool

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： 新皮质是大脑中极为复杂的部分，被认为赋予我们产生有意识的思维、发展语言以及执行复杂的感知和空间推理任务的能力。了解新皮质是如何构建的是了解我们的大脑如何运作的关键。在这里，我们建议开发新颖的计算和实验工具，以帮助我们了解电活动和遗传电路如何耦合以在这个复杂的器官中产生不同的细胞类型。虽然人们可能会想象一个异常复杂的基因网络产生了大脑，但一些重编程实验表明，只有少数对发育重要的关键因素控制着特定的命运选择。我们的目标是发现这些因素集，以构建通往新皮质的关键基因表达事件的粗略路线图，并将所有其他基因的表达模式叠加在该图上。我们将使用具有小鼠大脑从妊娠中期到成年的发育过程中每个小鼠基因的空间和时间表达模式的数据来做到这一点。我们将开发一种新颖的计算范式来分析这些数据并提取控制新皮质构建的规则。我们将直接在体外定向分化系统中测试这些规则，重点关注锥体神经元。为了实现此类测试，我们正在开发突破性的成像技术，以测量和干扰数千个单细胞的基因表达和电活动，因为它们在体外从干细胞分化为有丝分裂后锥体神经元。我们将通过使用多个荧光报告器来测量通过计算分析预测的候选因子的动态以及单细胞中的钙和电活动。通过使用贝叶斯统计分析来分析这些单细胞时间序列表达和活性数据，并直接扰乱特定基因和 e 的表达动态。

项目成果

Discovering sparse transcription factor codes for cell states and state transitions during development.

发现发育过程中细胞状态和状态转换的稀疏转录因子代码。

• 发表时间: 2017-03-15
• 影响因子: 7.7
• 作者: Furchtgott, Leon A;Melton, Samuel;Menon, Vilas;Ramanathan, Sharad
• 通讯作者: Ramanathan, Sharad

Controlling interneuron activity in Caenorhabditis elegans to evoke chemotactic behaviour.

控制秀丽隐杆线虫的中间神经元活性以引起趋化行为。

• 发表时间: 2012-10-11
• 影响因子: 64.8
• 作者: Kocabas, Askin;Shen, Ching;Guo, Zengcai V;Ramanathan, Sharad
• 通讯作者: Ramanathan, Sharad

Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states.

从单细胞转录组学推断的胚胎干细胞分化动力学显示了离散细胞状态的一系列转变。

• 发表时间: 2017
• 影响因子: 7.7
• 作者: Jang, Sumin;Choubey, Sandeep;Furchtgott, Leon;Zou, Ling;Doyle, Adele;Menon, Vilas;Loew, Ethan B;Krostag, Anne;Martinez, Refugio A;Madisen, Linda;Levi, Boaz P;Ramanathan, Sharad
• 通讯作者: Ramanathan, Sharad