The European Neuroscience Institute in Paris, Pasteur
Understanding the complexities of information processing within the brain requires more than just knowing the precise neuronal wiring diagram, it also requires a detailed description of the temporal and spatial dynamics of signal flow between and within single neurons connected in a complex network. This daunting task is simplified by studying small groups of connected neurons, or microcircuits (1). A particularly attractive model microcircuit is that of the cerebellar cortex, because of its ordered, well-defined connectivity and small numbers of neuron types. Nevertheless, surprisingly little is known about how this microcircuit builds upon its well-known synaptic and cellular properties to dynamically integrate and process sensory information, largely because of the difficulty of measuring dynamic activity of many individual synapses or the ensuing postsynaptic signals in fine dendrites. To overcome these challenges, my laboratory has combined optical and electrical recordings to tackle the challenges of studying dynamic neuronal computations within a canonical microcircuit, the cerebellar cortex. In order to control, monitor, and analyze information flow, we will employ state-of-the-art optical (ChR2-based photoactivation, rapid 3D two-photon (2P) imaging of dendritic Ca2+ and voltage, and neurotransmitter uncaging) and electrophysiological (in vivo whole-cell patch-clamp recording of neuronal responses to sensory stimuli) techniques. Several projects in the lab are focused on the development of advanced in vivo and super-resolution imaging strategies. Through collaborations we are also taking advantage of cutting-edge mathematical approaches to analysis of how biophysical properties of neurons lead to computations (Boolean functional analysis, reconstructed single-neuron and network modeling). Specifically, biological projects in the laboratory are focused on: a) sensory-specific synaptic properties and integration at the input stage of cerebellar cortex, b) cellular mechanisms underlying dendritic computations by molecular layer interneurons, and c) general theoretical and experimental approaches to examine how dendritic computations participate in the processing of specific sensory features along the mossy fiber (MF) - granule cell (GC) – molecular layer interneuron (MLI) – Purkinje cell (PC) – axis of the cerebellar circuit. We hope to provide new and comprehensive insights into the neuronal computations, their underlying molecular and cellular mechanisms, and impact on microcircuit information processing.
Abrahamsson T., Cathala L., Matsui K., Shigemoto R., and DiGregorio DA. (2012) Thin dendrites of cerebellar interneurons confer sublinear synaptic integration and a gradient of short-term plasticity. Neuron. , 73 (6) : 1159-72.
Fink AE., Bender KJ., Trussell LO., Otis TS., and DiGregorio DA. (2012) Two-photon compatibility and single-voxel, single-trial detection of subthreshold neuronal activity by a two-component optical voltage sensor. PLoS One , 7 (8): e41434.
Nakamura Y, Harada H, Kamasawa N, Matsui K, Rothman JS, Shigemoto R, Silver RA, DiGregorio DA, Takahashi T. Nanoscale Distribution of Presynaptic Ca(2+) Channels and Its Impact on Vesicular Release during Development (2015) Neuron 85(1):145-58. doi: 10.1016/j.neuron.2014.11.019. Epub 2014 Dec 18.