Functional connectomics of the neocortical microcircuit

描述（由申请人提供）：皮层构成高级认知功能和精神疾病的主要部位。由于我们对其微电路（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突发水平，由大型神经元群的活动状态决定的，目前还没有关于皮层如何工作的统一理论。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更大神经元群的活动，同时保持单细胞分辨率。使用这些技术，我们已经发现了可能是高度分布的、本质上是随机的皮层微回路的迹象。基于这些结果，我们提出皮层是一个随机回路的想法，这意味着每个突触连接都是偶然选择的，独立于其他连接。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相反，传统的观点认为，大脑皮层是一个非常特殊的机器，每个神经元的连接和功能都是精确确定的。利用这个奖项，我想测试皮层是一个随机网络的假设，应用新的双光子方法对小鼠皮层微电路进行大规模和系统的研究。我提出了一个三管齐下的方法：1-对小鼠整个皮质模块的活动进行成像，以检测来自所有细胞的所有尖峰。2-进行“电路破解”分析，得到模块的连通性蓝图。光学操纵人口活动，以测试其是否表现为随机电路。实验将在小鼠皮层中进行，在清醒、头部约束、感觉刺激和休息下进行。转基因菌株将

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