Search

Maternal stress during pregnancy, or prenatal stress, is a risk factor for neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD). In ASD, dorsal striatum displays abnormalities correlating with symptom severity, but there is a gap in knowledge about dorsal striatal cellular and molecular mechanisms that may contribute. Using a mouse model, we investigated how prenatal stress impacted striatal-dependent behavior in adult offspring. We observed enhanced motor learning and earlier response times on an interval timing task, with accompanying changes in time-related medium spiny neuron (MSN) activity. We performed adult dorsal striatal single-cell RNA sequencing following prenatal stress which revealed differentially expressed genes (DEGs) in multiple cell types; downregulated DEGs were enriched for ribosome and translational pathways consistently in MSN subtypes, microglia, and somatostatin neurons. DEGs in MSN subtypes over-represented ASD risk genes and were enriched for synapse-related processes. These results provide insights into striatal alterations relevant to neurodevelopmental disorders., Competing Interests: Declaration of interests Hanna E. Stevens is the chair of the advisory committee of the Klingenstein Third Generation Foundation.

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 and 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 distinct 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-MSNs 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 interval timing response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also changed 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 human striatal diseases and therapies targeting striatal pathways.