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。关于大脑皮层如何工作，目前还没有一个统一的理论，这是因为我们对大脑皮层的微电路（即任何皮层区域的详细连接模式）一无所知，也因为大脑皮层的功能很可能是基于一个涌现的水平，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更大的神经元群体的活动，同时保持单细胞分辨率。使用这种技术，我们发现了一种高度分布的、基本上随机的皮层微回路的迹象。基于这些结果，我们提出了这样的想法，即皮层是一个随机电路，这意味着每个突触连接都是随机选择的，独立于其他连接。这些电路在数学上类似于完全连接的电路，将最大限度地分配信息，并使紧急功能状态的出现成为可能。这种模型与传统的皮层观点相反，传统的皮层观点是从单个神经元的采样中产生的，它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，我想测试大脑皮层是一个随机网络的假设，将新颖的双光子方法应用于对小鼠大脑皮层微电路的大规模和系统性研究。 我提出了一个三管齐下的方法：1-图像的整个皮层模块在小鼠的活动，以检测所有细胞的所有尖峰。 2-执行“Circuit Cracker”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。 实验将在感觉刺激和休息下，在清醒、头部受限的小鼠体内皮质中进行。转基因菌株将B

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