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

The role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds, which involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited opposing dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model. This model predicted that disrupting either D2-MSN or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also increased response times, shifted MSN dynamics, and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs make complementary contributions to interval timing despite opposing dynamics, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for a broad range of human striatal diseases and for therapies targeting striatal pathways.

Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson's disease.

Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson's disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.