Probabilistic maps of spiking and connectivity in human and mouse cortex

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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.