Functional connectomics of the neocortical microcircuit

描述（由申请人提供）：新皮质微回路的功能性连接组学 大脑皮层是高级认知功能和精神疾病的主要部位。没有统一 关于大脑皮层如何工作的理论还存在，这是由于我们对它的微电路（即大脑皮层）的基本无知。 任何皮层区域的详细连接模式），也因为它的功能很可能是基于 在紧急水平上，由大型神经元集合的活动状态决定。 双光子钙成像和光激活技术使我们能够同时记录和 光学操纵较大神经元群体的活动，同时保持单细胞分辨率。 使用这种技术，我们已经遇到了一个高度分布的，本质上是 随机皮层微电路基于这些结果，我们提出了大脑皮层是一个随机的 这意味着每个突触连接都是随机选择的，独立于其他连接。这些 电路，数学上类似于完全连接的电路，将最大限度地分布 信息，并使紧急功能状态的出现。这种模式与 传统的观点认为，大脑皮层是一个非常具体的神经元， 机器，其中每个神经元的连接和功能被精确地确定。 利用这个奖项，我想测试大脑皮层是一个随机网络的假设， 双光子方法在小鼠皮层微电路的大规模和系统的研究。 我建议采取三管齐下的办法： 1-对小鼠整个皮层模块的活动进行成像，以检测所有细胞的所有尖峰。 2-执行“电路破解器”分析以获得模块连接的蓝图。 3-光学操纵人口活动，以测试它是否表现为随机电路。 实验将在小鼠皮质中进行，在清醒的情况下，头部受限的制备， 感官刺激和休息。转基因菌株将用于选择性标记已鉴定的亚群 的细胞，和几个皮质区将被检查，以探索共同的模块化功能。 这项拟议中的工作将首次提供对任何神经元活动的完整描述。 电路和皮质电路的蓝图，并将开创“功能性连接组学”，即， 从其功能相关性中破译电路的连通性。如果数据证实， 微电路确实是随机的，我们的研究结果也可能为皮层功能带来一种新的模型， 基于紧急功能状态的存在。这种模式可以取代目前的范式， 并且能够更有效地理解皮质疾病的病理生理学，例如癫痫 和精神分裂症

DESCRIPTION (provided by applicant): Functional Connectomics of the Neocortical Microcircuit The cortex constitutes the primary site of higher cognitive functions and mental disease. No unified theory of how the cortex works exists yet, due to our basic ignorance about its microcircuits (i.e. the detailed connectivity patterns of any cortical area), and also because it is likely that its function is based on an emergent level, determined by the states of activity of large neuronal ensembles. Two-photon calcium imaging and photo-activation techniques enable us to simultaneous record and optically manipulate the activity of larger neuronal populations, while maintaining single cell resolution. Using such techniques we have encountered signs of what could be a highly distributed and essentially random cortical microcircuit. Based on these results, we propose the idea that the cortex is a random circuit, meaning that each synaptic connection is chosen by chance, independently from others. These circuits, mathematically analogous to completely connected ones, would maximize the distribution of information and enable the appearance of emergent functional states. This model runs contrary to the traditional view of the cortex, one that arose from sampling individual neurons, as a very specific machine where the connectivity and function of each neuron is precisely determined. Using this award, I want to test the hypothesis that the cortex is a random network, applying novel two-photon methods in a large-scale and systematic study of the mouse cortical microcircuit. I propose a three-pronged approach: 1- Image the activity of an entire cortical module in a mouse, to detect all spikes from all cells. 2- Perform a “Circuit Cracker” analysis to obtain the blueprint of connectivity of the module. 3- Optically manipulate the population activity to test whether it behaves as a random circuit. Experiments will be done in mouse cortex in vivo, with awake, head-restrained preparations, under sensory stimulation and rest. Transgenic strains will be used to selectively label identified subpopulations of cells, and several cortical areas will be examined to explore common modular features. The proposed work will provide, for the first time, a complete description of the activity of any neural circuit and the blueprint of the cortical circuit and will pioneer “Functional Connectomics”, i.e., deciphering the connectivity of the circuit from its functional correlations. If the data confirm that the microcircuit is indeed random, our results could also usher in a novel model for cortical function, one based on the existence of emergent functional states. This model could replace the current paradigm, and enable a more efficient understanding of the pathophysiology of cortical diseases, such as epilepsy and schizophrenia.