Abstract
Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca2+ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity toward the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson's disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson's disease.
Highlights
32 33 The neuromodulator dopamine (DA) is an essential component of basal ganglia circuits that control goal-directed behaviors
We subsequently performed two-photon microscopy through an imaging window chronically implanted in cortex over dorsal striatum (Howe & Dombeck 2016; Bloem et al, 2017) in head-fixed mice locomoting on a freely rotating circular treadmill (Figure 1B; Figure 1 – 108 figure supplement 1A,B; Video 1). This approach allows Ca2+ signals arising in dSPNs to be clearly distinguished from those occurring in tdTomato-negative neurons (Figure 1C, D), which are overwhelmingly iSPNs, and which together with dSPNs account for approximately 95% of all striatal neurons in mice (Gerfen & Surmeier 2011)
Population Ca2+ signals in tdTomato-positive dSPNs were similar to data obtained using photometry in mice expressing
Summary
20 21 Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. We use two-photon Ca2+ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity towards the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson’s disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson’s disease
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