Single cell resolution multiscope recording and manipulation of striatal circuitry during decision making

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This proposal aims to implement simultaneous multi-region, single-cell resolution neural recording and manipulation in behaving mice at McGill University. This exciting new technology enables imaging two fluorescent indicators of neural activity in up to four brain regions, in combination with targeted optogenetic manipulations, all at single-cell resolution. It will be used in the labs of Drs. Jonathan Britt and Rosemary Bagot - two CRC professors in the Department of Psychology - to investigate how ensemble activity of genetically-defined striatal neurons is coordinated within cortico-meso-limbic circuits across varying behavioural states. Single-cell multiscope imaging will dramatically accelerate the NSERC-funded research of both applicants in two key ways. First, this technology is unique in providing simultaneous single-cell measurement of neural activity across multiple brain regions in freely moving mice, thus permitting high-resolution computational analysis of network activity within and across cell types in behaviourally-relevant circuits. Second, it allows for fully integrated optogenetic manipulations that can be targeted to subsets of cells. The technology ideally complements the expertise of both labs in population-level recording techniques such as fiber photometry. While powerful, population-level techniques cannot resolve certain phenomena. For example, an increase in signal could be driven by an increase in the number of active cells or by increased synchrony of a stable population of cells. The necessity to resolve single-cell activity in projection- and genetically-defined populations was recently underscored by demonstrations that dopamine does not alter the firing rate of active neurons but rather determines how many striatal neurons get recruited during behaviour (i.e., the size of the active ensemble; Maltese et al., eLife 2021). Thus, to identify how striatal circuits respond to precise perturbations of dopamine signaling (Britt lab) and ultimately integrate information about reward and loss (Bagot lab), single-cell resolution is critical for tracking the ensemble size, identity, coherence, and balance of activity across striatal afferent and efferent cell populations. Implementation of this technology will promote collaborations with computational neuroscientists within and beyond McGill, as the uniquely rich physiological and behavioural data offer interesting opportunities to test computational theories about neuronal networks as well as development of dimensionality reduction techniques and dynamic pattern analyses. This equipment will support HQP recruitment, as it provides cutting-edge training opportunities for HQP and increases the overall impact of the research.