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）：神经科学中一个基本但未解决的问题是神经元之间的特定连接如何成为皮层回路中信息处理的基础。大脑皮层中的局部回路由数万个神经元组成，每个神经元产生数千个连接。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它们的实际布线图。但是，如果我们有一个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：它的生理学。在这项提案中，我们计划开发和应用新的方法，大规模的电子显微镜，对映射布线图皮层电路的功能背景下的目标。我们将使用双光子钙成像来观察功能性局部回路中神经元的活动。然后，我们将使用大规模连续切片电子显微镜来追踪同一块皮层中的电路。 功能成像和连续切片电子显微镜（EM）的最新进展使我们能够研究这个难题，但在我们能够从这些方法中获益之前，还需要进行大量的技术工作。双光子显微镜功能成像是一个技术成熟的领域，但大规模连续切片EM的方法仍处于起步阶段。我们建议应用双重方法的功能成像，然后高分辨率的解剖成像，我们已经执行了一次，在一个大型的试点项目，以提高专门用于大规模EM的技术，与功能研究的目标。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，第二代透射EM相机阵列（TEMCA），这将使我们能够在一周内捕获非常大的三维数据集（300到500微米），而不是几个月。我们建议解决一类问题：是否有每个局部皮层回路处理不同的信息的子网络？但这种方法是通用的，可以应用于广泛的问题，包括临床相关的问题。阿尔茨海默病斑块附近的神经连接是否中断？当干细胞整合到一个回路中时，它们是否形成了发挥功能作用的连接？这些问题第一次应该在我们的能力范围内。通过开发大规模成像的高通量方法，我们将开始研究神经回路本身：在所有的复杂性和在许多意义上完整的数据集。