Functional connectomics of the neocortical microcircuit

描述(申请人提供)：大脑皮层是高级认知功能和精神疾病的主要部位。关于大脑皮层是如何工作的，目前还没有统一的理论，这是因为我们对它的微电路(即任何皮质区域的详细连接模式)的基本无知，也因为它的功能很可能是基于一个紧急水平，由大型神经元集合的活动状态决定的。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。使用这样的技术，我们已经遇到了可能是高度分布和本质上随机的皮质微电路的迹象。基于这些结果，我们提出了大脑皮层是一个随机回路的观点，这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，将使信息的分布最大化，并使紧急功能状态的出现成为可能。这个模型与传统的大脑皮层观点背道而驰，大脑皮层是通过对单个神经元进行采样而产生的，它是一台非常特定的机器，可以精确地确定每个神经元的连接性和功能。利用这个奖项，我想通过应用新的双光子方法对小鼠皮质微电路进行大规模和系统的研究，来检验大脑皮质是一个随机网络的假设。我提出了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-进行电路破解分析，获得模块连通性蓝图。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，在清醒、头枕、感觉刺激和休息的情况下进行准备。转基因菌株将成为

DESCRIPTION (provided by applicant): 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 "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 b