The impact of dopamine signaling on cell type-specific striatal neuron activity in vivo

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Dopamine signaling in the striatum has profound effects on behaviour, as it influences movement, motivation, cognition, and affect. The importance of this neurotransmitter is well appreciated, as drugs that affect dopamine signaling are widely used to clinically treat a host of psychiatry disorders. The problem is that we still do not understand some of the most basic interactions in this circuitry. Principally, it is unclear how dopamine signaling in vivo modifies the activity of the two principal striatal output pathways. The aim of the research proposed here is to identify the influence of dopamine signaling on striatal network activity in order to gain insight into the circuit dynamics that underlie and differentiate healthy and pathological brain function. Researchers have long struggled to identify the influence of dopamine signaling on specific striatal circuit components. The challenge is that the affected cells are intermingled within cell populations that express different types of dopamine receptors, which in turn have differential effects on neuronal physiology. Fortunately, with the lab infrastructure I built with funds from the Canada Foundation for Innovation, my group is well-positioned to capitalize on the recent methodological advances that make it possible to optogenetically control midbrain dopamine neuron activity in behaving animals while simultaneously monitoring distinct fluorescent indicators of neural activity (GCaMP & RCaMP) differentially expressed in striatal direct and indirect pathway neurons. The proposed experiments will reveal the extent to which dopamine signalling differentially affects the two striatal output pathways, and vice versa, across different behavioural states. This research will provide key insights into striatal physiology that are critical for ongoing efforts to understand and model basal ganglia circuit function. Moreover, rational drug development efforts have been hampered by our inadequate understanding of basal ganglia physiology. The proposed research will foster these treatment development efforts by improving our understanding of healthy brain function. I have hired two outstanding new trainees (a graduate student and postdoc) to help spearhead this research. My publication record demonstrates my extensive expertise using these optogenetic and calcium imaging techniques in vivo. Research from my lab funded with my first Discovery Grant (2014-2019) is published in Neuron, Biological Psychiatry, and Cell Reports, and I have additional articles under review at Cell Reports and Frontiers in Neural Circuits. My NSERC funding also permitted me to write a review article and successfully collaborate on projects that have been published in Nature Neuroscience, Journal of Neuroscience, and Cell Reports. McGill University is also strongly supportive of my research program, as they have named me a William Dawson Scholar and recently nominated me for a Canada Research Chair.