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 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.

12 13 14 15 SUMMARY 16 17Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our 18 understanding of its influence on the activity of target neurons in vivo remains limited. Here, we 19 use two-photon Ca 2+ imaging to simultaneously monitor the activity of direct and indirect-20 pathway spiny projection neurons (SPNs) in the striatum of behaving mice during acute and 21 prolonged manipulations of DA signaling. We find that, contrary to prevailing models, DA does 22 not modulate activity rates in either pathway strongly or differentially. Instead, DA exerts a 23 prominent influence on the overall number of direct and indirect pathway SPNs recruited during 24behavior. Chronic loss of midbrain DA neurons in a model of Parkinson's disease selectively 25 impacts direct pathway ensembles and profoundly alters how they respond to DA elevation. Our 26 results indicate that DA regulates striatal output by dynamically reconfiguring its sparse 27 ensemble code and provide novel insights into the pathophysiology of Parkinson's disease.

No abstract