Microconnectomics of neocortex: a multiscale computer model

描述(由申请人提供)：我们将根据正在进行的研究中获得的丰富的实验数据集，开发一个初级运动皮质(M1区)的多尺度模型。该模型的范围从树突中离子通道的水平，到来自皮质其他区域的输入和输出的水平，范围从微米到厘米，时间范围从毫秒到10秒。我们将评估跨尺度的动态相互作用，这一结构变得更加复杂，其特点是第五层锥体细胞的长尖树突跨越皮质各层，从而跨越尺度。这一特征产生了复杂的结构-功能关系：心尖树突直接处理来自不同皮质层的输入，以便从局部微电路输出(直接输入/输出)。它们还在规模层次结构中发挥作用，形成本地网络的一个组件，该组件提供输入的并行处理，以通过整个第5层金字塔细胞系产生输出。第5层锥体形成两组不同的细胞：皮质纹状体细胞投射到纹状体和其他皮质区域，皮质脊髓细胞向下投射到脑干和脊髓。我们的双输出假说将它们概念化为由两种大规模细胞类型锚定的部分可分离的子电路。我们认为，这些亚回路之间的单向投射(皮质纹状体到皮质脊髓)影响了主要的编码转换：主导皮质时间编码(皮质纹状体亚回路)到主导速率编码(皮质脊髓亚回路)。对于这一假说来说，重要的是，皮质脊髓锥体细胞表现出线性激活特性，几乎没有适应性。我们的目标是通过一系列紧密联系的实验和模拟从低到高进行的，通过预测导致实验导致修改模拟：1.模拟突触信号在树突中的整合，基于不同树突位置(亚细胞尺度：1-10�m)的细胞激活测量的iH和IA密度；2.基于细胞放电的模型 基于电流钳位实验(单元尺寸：30-800�m)；3.基于投影强度测量建立电路级模型(微电路尺寸：2-5 mm)；4.通过输入/输出分析(投影尺度：10-100 mm)，使用信息论和动力学方法对SPI-STR码转换假设进行评估。我们预测，根据基于输入的位置、频率、相位和幅度的标签，新皮质电路可以合并或多路传输信号。

DESCRIPTION (provided by applicant): We will develop a multi-scale model of primary motor cortex (area M1) based on a rich experimental dataset obtained in ongoing studies. The model will range from the level of ion channels in dendrites, up to the level of the inputs from and outputs to other areas of cortex, a range of microns to centimeters, with a temporal range of milliseconds to 10 sec. We will evaluate dynamical interactions across scale, made more complicated by a structure that features long apical dendrites of Layer 5 pyramidal cells that reach across layers of cortex and thereby across scales. This feature produces complex structure-function relations: apical dendrites directly process inputs from different cortical layes for export from the local microcircuit (direct input/output). They also act within the scale hierarchy, forming a component of the local network which provides a parallel processing of inputs to produce outputs via the entire Layer 5 pyramidal cell ensemble. Layer 5 pyramids form two distinct groups: corticostriatal cells that project to striatum and to other cortical area, and corticospinal cells that project downwards to brainstem and spinal cord. Our dual-output hypothesis conceptualizes these as partially separable subcircuits anchored by the two massive cell types. We suggest that the one-way projection (corticostriatal to corticospinal) between these subcircuits effects a major code transformation: dominant corticocortical temporal coding (corticostriatal subcircuit) to dominant rate coding (corticospinal subcircuit). Importantly for ths hypothesis, the corticospinal pyramidal cells show linear activation properties with little adaptation. Our Aims proceed from low to high through sets of tightly-linked experiment and simulation, with predictions leading to experiments leading to modified simulations: 1. Simulate integration of synaptic signals in dendrites, based on densities of Ih and IA measured with cell activation at different dendritic locations (subcellular scale: 1-10�m); 2. Model cell firing based on current clamp experiments (cell scale: 30-800�m); 3. Create circuit-level models based on projection strength measurements (microcircuit scale: 2-5mm); 4. Use information theoretic and dynamical measures to evaluate SPI-STR code transformation hypothesis through input/output analysis (projection scale: 10-100mm). We predict that the neocortical circuit can either combine or multiplex signals, depending on tags based on location, frequency, phase, and amplitude of inputs.