Learning critically drives parkinsonian motor deficits through imbalanced striatal pathway recruitment

Significance Dopamine (DA) is critical for movements, and its loss causes debilitating motor deficits in Parkinson’s disease (PD). However, dopamine is also strongly implicated in reward learning. Here, we used two distinct motor tasks to show that, in mice, dopamine-dependent learning also contributes to PD symptoms: dopamine depletion caused motor impairments that worsened with performance, and repeated dopamine replacement induced long-term rescue that persisted despite treatment withdrawal. We propose that dopamine-dependent motor learning is an important contributor to the critical—but poorly understood—long-duration response (LDR) from dopaminergic therapies. Further understanding of LDR may improve both “motor fluctuation” treatments and our ability to accurately assess the effectiveness of disease-modifying PD therapies.