Functional connectomics of the neocortical microcircuit

描述(由申请人提供)：新皮质微电路的功能连接 大脑皮层是高级认知功能和精神疾病的主要部位。没有统一的 皮质如何工作的理论仍然存在，这是因为我们对其微电路(即 任何皮质区域的详细连接模式)，还因为它的功能很可能基于 在紧急水平上，由大型神经元群的活动状态决定。 双光子钙成像和光激活技术使我们能够同时记录和 光学操控较大神经元群体的活动，同时保持单细胞分辨率。 使用这样的技术，我们已经遇到了一些迹象，这些迹象可能是高度分散的，基本上 随机皮质微电路。基于这些结果，我们提出了大脑皮层是一个随机的概念。 回路，意味着每个突触连接都是随机选择的，独立于其他突触连接。这些 电路，在数学上类似于完全连接的电路，将最大化分布 信息，并允许出现紧急功能状态。此模型与 大脑皮层的传统观点，即通过对单个神经元进行采样而产生的观点，认为这是一种非常特殊的 精确确定每个神经元的连接性和功能的机器。 利用这个奖项，我想检验大脑皮层是一个随机网络的假设，应用小说 双光子方法在大规模和系统地研究小鼠皮质微电路中的作用。 我提出一个三管齐下的方法： 1-想象老鼠整个皮质模块的活动，以检测所有细胞的所有棘波。 2-执行“电路破解”分析，以获得模块连接的蓝图。 3-光学操作布居活动，以测试其行为是否为随机电路。 实验将在体内的小鼠皮质中进行，使用清醒的、头部约束的准备，在 感觉刺激和休息。转基因菌株将被用来选择性地标记已识别的亚群 将检查几个大脑皮层区域，以探索共同的模块特征。 这项拟议的工作将第一次对任何神经的活动提供完整的描述 电路和大脑皮层电路的蓝图，并将开创“功能连接”，即， 从电路的功能关联中破译电路的连通性。如果数据确认 微电路确实是随机的，我们的结果也可能带来一种新的皮质功能模型，一 基于浮现功能状态的存在。这种模式可以取代目前的模式， 并有助于更有效地了解癫痫等皮质疾病的病理生理学。 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.