Dissecting the Fabric of the Cerebral Cortex

解剖大脑皮层的结构

• 批准号: 8523898
• 负责人: Andreas Tolias
• 金额: $ 75.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523898
• 关键词: Animal Disease Models; Architecture; Area; Brain; Cells; Cerebral cortex; Cerebrum; Cognition; Collaborations; Databases; Faculty; Goals; Housing; Image; Individual; Label; Measures; Methods; Microscope; Microscopic; Microscopy; Molecular; Monitor; Neurologic; Neurons; Neurosciences; Optics; Perception; Pharmaceutical Preparations; Process; Property; Psyche structure; Research; Scanning; Schizophrenia; Series; Sister; Stem cells; Stroke; Structure; Surface; System; Textiles; Work; autism spectrum disorder; base; gene discovery; gene therapy; in vivo; information processing; insight; multi-photon; novel; quantum; relating to nervous system; two-photon; virus genetics

The cerebral cortex houses our mental functions like perception, cognition and action. Despite major advances in discovering the properties of single cells and molecular-level processes, we still do not know how the cortex works at the circuit level. The essence of the problem lies in understanding how the billions of neurons communicating through trillions of connections orchestrate their activities to give rise to our mental faculties. We are far from being able to simultaneously measure the activity of all the myriads of cortical cells and assemble their physical wiring diagram (connectome). However, if there are underlying principles and rules that govern this complexity, discovering these principles provides an obvious strategy for understanding how the cortex functions. Indeed, it has been hypothesized that the cortex is composed of elementary information processing modules. For almost a century anatomists have observed remarkable regularity in the cortical microarchitecture: strings of cells derived from a common progenitor cell and having a propensity of being synaptically connected are arranged to form small columns orthogonal to the cortical surface. These microcolumns are hypothesized to be the elementary functional units of cortical circuitry. If one were able to understand their organizing principles, the task of understanding how the cortex works would be simplified immensely. Discovering the function of these elementary modules would be analogous to the discovery of the gene, which ultimately led to the molecular revolution of the 20th century. So far, these structures could not be studied in detail due to technical limitations. To understand the function of a microcolumn, it is imperative to simultaneously monitor the activity of all its constituting neurons in vivo. It is our goal to overcome these technical challenges and develop in-vivo methods to study an entire microlumn. We propose to develop in vivo microscopy based on 3D random-access multi-photon (3D-RAMP) excitation. This tour de force microscope will employ a series of acousto-optical deflectors operating at long wavelengths that will generate any desired 3D scanning path at frame rates two orders of magnitude faster than current state-of-the-art two-photon imaging systems. This will allow simultaneous in-vivo recordings of the activity of an entire column of sister cells across all six cortical layers. The microscope will employ two 3D-RAMP scanners that will enable simultaneous recording and photostimulation of neural activity to assemble the functional connectivity diagram of the microcolumn. Viral and genetic methods will be used to identify and label ontogenetic microcolumns in vivo. Through collaboration their connectome will be assembled. We plan to create a database of the Microcolumn Architecture of the Cortex that will include functional, anatomical and ontogenetic information about the organization of microcolumns across cortical areas, species and animal models of diseases. Our proposal promises to unravel the elementary principles of how cortical circuits are organized to give rise to mental function. If we succeed our results will constitute a quantum leap in our quest to understand the brain.

大脑皮层负责我们的心理功能，如感知、认知和行动。尽管在发现单细胞和分子水平过程的特性方面取得了重大进展，但我们仍然不知道皮层在电路水平上是如何工作的。问题的本质在于理解数十亿个神经元如何通过数万亿个连接来协调它们的活动以产生我们的心智能力。 我们还远远无法同时测量无数皮质细胞的活动并组装它们的物理接线图（连接组）。然而，如果存在控制这种复杂性的基本原则和规则，那么发现这些原则为理解皮层如何运作提供了一个明显的策略。事实上，有人假设皮层是由基本信息组成的 处理模块。近一个世纪以来，解剖学家观察到皮质微结构具有显着的规律性：源自共同祖细胞并具有突触连接倾向的细胞串排列成与皮质表面正交的小柱。这些微柱被假设为皮质电路的基本功能单元。如果一个人能够 了解它们的组织原理后，了解皮层如何工作的任务就会大大简化。发现这些基本模块的功能类似于发现基因，最终导致了 20 世纪的分子革命。到目前为止，由于技术限制，这些结构还无法进行详细研究。要了解微柱的功能，必须 同时监测体内所有组成神经元的活动。我们的目标是克服这些技术挑战并开发体内方法来研究整个微管。我们建议开发基于 3D 随机访问多光子 (3D-RAMP) 激发的体内显微镜。这款杰作显微镜将采用一系列在长波长下工作的声光偏转器，可产生任何所需的光 3D 扫描路径的帧速率比当前最先进的双光子成像系统快两个数量级。这将允许同时体内记录所有六个皮质层上的整列姐妹细胞的活动。该显微镜将采用两个 3D-RAMP 扫描仪，能够同时记录和光刺激神经活动，以组装功能连接图 的微柱。病毒和遗传学方法将用于识别和标记体内个体发生微柱。通过合作，他们的连接组将被组装起来。我们计划创建一个皮质微柱结构数据库，其中包括有关跨皮质区域、物种和疾病动物模型的微柱组织的功能、解剖和个体发育信息。我们的提议有望揭示皮层回路如何组织以产生的基本原理 心理功能。如果我们成功了，我们的结果将构成我们对大脑的探索的巨大飞跃。