Probabilistic maps of spiking and connectivity in human and mouse cortex

动物实验虽然提供了指导原则，但永远只是人脑的一个模型。我们提出了新颖的体外和体内电生理实验和计算技术来表征人类皮质神经元，描述信息如何在皮质层内和皮质层之间流动，以及这种信息流是如何被theta振荡调制的--theta振荡是人类大脑中最普遍的振荡。我们首先从我们的关键观察开始，在人类皮质组织中，theta振荡协调皮质浅层和深层之间的活动。为了确定产生这些同步theta振荡的细胞特征，将在人类兴奋性和抑制性神经元中进行全细胞记录。我们将专注于这些细胞的尖峰和尖峰特征，以及它们是如何被乙酰胆碱调制的--乙酰胆碱是一种参与注意力的神经递质，是人类大脑皮层脑片中theta振荡所必需的。为了进行大规模的细胞和电路表征，我们将使用使用微电极阵列(MEA)的高通量电生理记录来将细胞尖峰-尖峰特征分类为不同的尖峰表型。通过汇集患者的数据，我们将开发出有史以来第一个人类大脑尖峰表型的层特定概率图。为了估计不同表型之间的连通性，将使用尖峰时间序列来计算信息转移(转移熵)。为了确定如何调节这种连接图，将应用神经递质激动剂。为了验证这一技术，将在小鼠大脑皮质进行平行实验，其中存在一些连接数据。为了表征theta振荡在重新组织连接地图中所起的因果作用，将使用转基因小鼠利用光遗传学来驱动皮质振荡。一个长期的目标是使用这些计算技术，使用急性层流(跨皮质板层的MEAs)记录，从人体活体实验中创建连接图。这里开发的工具将推动记录和解释人脑皮质间和皮质内交流的领域。以这种方式了解人类大脑皮层回路将有助于神经调节策略来治疗大脑疾病，特别是那些由theta振荡介导的疾病。多伦多西部医院、多伦多西部医院研究所、生物材料和生物医学工程研究所、心理学、计算机科学和计算神经科学之间正在进行的卓有成效的合作将通过资助这一研究计划而得到进一步加强，并将提供丰富的环境来培养高素质的人才，他们将在行动中看到协作神经科学在探索人脑方面的优势。

Animal experiments although providing guiding principles, will always be but a model of the human brain. We propose novel in vitro and in vivo electrophysiological experiments and computational techniques to characterize human cortical neurons, describe how information flows within and between cortical layers, and how this flow of information is modulated by theta oscillations – the most ubiquitous oscillation in the human brain. We start with our critical observation that in human cortical tissue, theta oscillations coordinate activity between superficial and deep cortical layers. To determine the cellular characteristics that generate these synchronous theta oscillations whole-cell recordings will be performed in human excitatory and inhibitory neurons. We will focus on spike and spiking characteristics of these cells and how they are modulated by acetylcholine – a neurotransmitter involved in attention, and required for theta oscillations in human cortical slices. To perform large scale cellular and circuit characterizations we will use high throughput electrophysiological recordings using microelectrode arrays (MEA) to classify cellular spike\spiking characteristics into different spiking phenotypes. By pooling data across patients we will develop the first ever layer specific probabilistic maps of spiking phenotypes for the human brain. To estimate connectivity between the different phenotypes, spike time series will be used to compute information transfer (transfer entropy). To determine how such connectivity maps can be modulated, neurotransmitter agonists will be applied. To validate this technique, parallel experiments will be carried out in mouse cortex, for which some connectivity data exists. To characterize the causal role theta oscillations play in reorganizing connectivity maps, transgenic mice will be used to drive cortical oscillations using optogenetics. A long term goal is to use these computational techniques to create connectivity maps from human in vivo experiments using acute laminar (MEAs across cortical laminae) recordings. The tools developed here will advance the field of recording and interpreting inter-cortical and intra-cortical communication in the human brain. Understanding human cortical circuits in this way will contribute meaningfully to neuromodulatory strategies to treat diseases of the brain, particularly those mediated by theta oscillations. Ongoing fruitful collaborations between the Toronto Western Hospital, the Toronto Western Hospital Research Institute, Institute of Biomaterials and Biomedical Engineering, Psychology, Computer Science, and Computational neuroscience will be further strengthened by funding this research program, and will provide a rich environment to train high quality personnel who will see in action the strength of collaborative neuroscience in the pursuit of probing the human brain.