Complementary cognitive roles for D2-MSNs and D1-MSNs in interval timing.

Striatal pathways control motivation and movement; however, their role in cognition is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds. Interval timing involves working memory for temporal rules and attention to the passage of time. We discovered that both pharmacological and optogenetic disruptions of D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) or D1-dopamine receptor-expressing MSNs (D1-MSNs) delayed timing. Disrupting D2-MSNs or D1-MSNs did not affect task-specific movements. Furthermore, pharmacological blockade of D2-dopamine receptors or D1-dopamine receptors degraded dorsomedial MSN temporal encoding. We compared the timing-related firing of optogenetically-tagged D2-MSNs and D1-MSNs. Strikingly, we found that D2-MSNs and D1-MSNs exhibited opposite dynamics over temporal intervals despite similar effects of D2-MSN and D1-MSN disruptions. MSN dynamics helped construct and constrain a four-parameter drift-diffusion computational model that captured interval timing behavior and D2-MSN and D1-MSN perturbations. Despite opposing dynamics, disrupting either D2-MSNs or D1-MSNs slowed timing, implying that D2-MSNs and D1-MSNs make complementary contributions to interval timing. These data provide novel insight into basal ganglia cognitive operations beyond movement. Our findings carry implications for a broad range of human striatal diseases and for therapies targeting striatal pathways.