Probabilistic maps of spiking and connectivity in human and mouse cortex

动物实验虽然提供了指导原则，但永远只是人类大脑的一个模型。我们提出了新的体外和体内电生理实验和计算技术来表征人类皮层神经元，描述皮层层内和皮层层之间的信息流动，以及这种信息流如何被人脑中最普遍的振荡- θ振荡调制。我们从我们的关键观察开始，在人类皮层组织中，θ振荡协调皮层表层和深层之间的活动。为了确定产生这些同步θ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。我们将重点关注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节的——乙酰胆碱是一种与注意力有关的神经递质，也是人类皮层切片中θ波振荡所必需的。为了进行大规模的细胞和电路表征，我们将使用高通量电生理记录，使用微电极阵列（MEA）将细胞尖峰特征分类为不同的尖峰表型。通过汇集患者的数据，我们将开发人类大脑尖峰表型的第一层特定概率图。为了估计不同表型之间的连通性，峰值时间序列将用于计算信息传递（传递熵）。为了确定这种连接图如何被调节，神经递质激动剂将被应用。为了验证这一技术，将在小鼠皮层中进行平行实验，其中存在一些连接数据。为了描述θ波振荡在连接图谱重组中的因果作用，将利用光遗传学技术利用转基因小鼠来驱动皮层振荡。一个长期的目标是使用这些计算技术来创建连接图，从人类体内实验中使用急性层（跨皮质层）记录。这里开发的工具将推动记录和解释人类大脑皮层间和皮层内交流的领域。以这种方式理解人类皮层回路将对治疗脑部疾病的神经调节策略有意义，特别是那些由θ波振荡介导的疾病。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富有成效的合作将通过资助该研究项目得到进一步加强，并将提供一个丰富的环境来培养高素质的人才，他们将在探索人类大脑的过程中看到协作神经科学的力量。

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.