Large-scale connectivity and function in a cortical circuit

皮质回路中的大规模连接和功能

• 批准号: 8300070
• 负责人: R CLAY REID
• 金额: $ 29.66万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300070
• 关键词: Address; Alzheimer' s Disease; Anatomy; Architecture; Autistic Disorder; Axon; Brain; Brain Diseases; Calcium; Cells; Cerebral cortex; Data; Data Set; Dendrites; Development; Dimensions; Electron Microscopy; Employee Strikes; Epilepsy; Erythrocytes; Functional Imaging; Functional disorder; Generations; Goals; Image; Maps; Measures; Mental disorders; Methods; Microscopy; Mining; Modeling; Mus; Neurons; Neurosciences; Physiology; Pilot Projects; Play; Process; Property; Public Health; Research; Resolution; Role; Sensory Physiology; Side; Sodium Chloride; Sorting - Cell Movement; Specificity; Stem cells; Stereotyping; Stroke; Structure; Synapses; System; Techniques; Technology; Time; Tissues; Transmission Electron Microscopy; Visual; Visual Cortex; Work; cell type; clinically relevant; improved; in vivo; infancy; information processing; nervous system disorder; neural circuit; novel strategies; orientation selectivity; relating to nervous system; response; technique development; tool; two-photon

DESCRIPTION (provided by applicant): A fundamental but unsolved question in neuroscience is how specific connections between neurons underlie information processing in the cortical circuits. Local circuits in the cerebral cortex consist of tens of thousands of neurons, each making thousands of connections. Perhaps the biggest reason we don't understand these circuits is that we have never been able to reconstruct their actual wiring diagrams. But if we had a partial or even complete wiring diagram, we would also need to know what each neuron in a circuit is doing: its physiology. In this proposal we plan to develop and apply new approaches for large-scale electron microscopy, towards the goal of mapping wiring diagrams of cortical circuits in a functional context. We will use two-photon calcium imaging to see the activity of neurons in a functioning local circuit. We will then use large-scale serial-section electron microscopy to trace circuits in the same piece of cortex. Recent advances in functional imaging and serial-section electron microscopy (EM) allow us to study this difficult problem, but before we can reap the benefits of these approaches, considerable technical work is necessary. Functional imaging with two-photon microscopy is a technically mature field, but approaches for large-scale serial-section EM are still in their infancy. We propose to apply the dual approach of functional imaging followed by high-resolution anatomical imaging-which we have already performed once in a large pilot project-with the goal of improving the technologies specifically for large-scale EM, correlated with functional studies. Our four-year goal is to create a high-throughput system for generating correlated structure/function data sets from the cortex. In particular, we will build a new EM imaging system, a second-generation Transmission EM Camera Array (TEMCA), that will allow us to capture very large three-dimensional data sets (300 to 500 micrometers on a side) in a week, rather than months. We propose to address one class of question: are there subnetworks within each local cortical circuit that process distinct information? But the approach is general and can be applied to a wide range of questions, including clinically relevant ones. Are neural connections disrupted near plaques in Alzheimer's disease? When stem cells incorporate into a circuit, do they form connections that play a functional role? For the first time, these questions should be within our reach. By developing high-throughput methods for large-scale imaging, we will begin to study neural circuits on their own terms: in all of their complexity and with data sets that are in many senses complete.

描述（由申请人提供）：神经科学中的一个基本但未解决的问题是神经元之间的特定联系是皮质回路中信息处理的基础。大脑皮层中的局部电路由成千上万的神经元组成，每个神经元都建立了数千个连接。也许我们不了解这些电路的最大原因是我们从来没有能够重建其实际的接线图。但是，如果我们有部分甚至完整的接线图，我们还需要知道电路中的每个神经元在做什么：其生理。在此提案中，我们计划开发和采用新的大规模电子显微镜的方法，以在功能环境中绘制皮质电路的接线图。我们将使用两光子钙成像来查看在功能的局部电路中神经元的活性。然后，我们将使用大型串行截面电子显微镜在同一块皮层中追踪电路。 功能成像和串行部​​分电子显微镜（EM）的最新进展使我们能够研究这个困难的问题，但是在我们获得这些方法的好处之前，必须进行大量技术工作。具有两光子显微镜的功能成像是一个技术上成熟的领域，但是大规模串行部分EM的方法仍处于起步阶段。我们建议采用功能成像的双重方法，然后采用高分辨率解剖成像 - 我们已经在一个大型试点项目中执行了一次，其目标是改善专门针对大型EM的技术，与功能研究相关。我们的四年目标是创建一个高通量系统，用于从皮层生成相关的结构/功能数据集。特别是，我们将建立一个新的EM成像系统，即第二代EM摄像机阵列（TEMCA），它将在一周内而不是几个月内捕获非常大的三维数据集（一侧300至500微米）。我们建议解决一类问题：在每个本地皮质电路中是否会处理不同信息的子网？但是这种方法是一般的，可以应用于包括临床相关的各种问题。在阿尔茨海默氏病斑块附近的神经联系是否中断？当干细胞集成到电路中时，它们是否形成起作用作用的连接？这些问题首次应在我们的范围内。通过开发用于大规模成像的高通量方法，我们将开始按照自己的术语来研究神经回路：以其所有的复杂性以及许多感觉完整的数据集。