Investigating the role of striatal spiny projection neurons in compulsive behaviors

[摘要] Obsessive compulsive disorder (OCD) is a chronic, severe mental illness that affects 2-3% of the world’s population. In recent years, neuroimaging studies have consistently shown abnormal patterns of activity within corticostriatal thalamocortical (CSTC) circuits in patients with OCD and reported that effective treatment with selective serotonin reuptake inhibitors (SSRIs) normalizes aberrant CSTC activity. However, the mechanism of this effect is unknown.Because it is difficult, if not impossible, to investigate cellular and circuit mechanisms in human subjects, our lab turns to translational mouse models. Using Sapap3-knockout (KO) mice, which display a compulsive grooming phenotype and corticostriatal abnormalities, we sought to determine the role of spiny projection neurons (SPNs) in mediating compulsive behavior and to uncover potential neural correlates of effective SSRI administration. Using novel in vivo calcium imaging technology, we observed overall striatal hyperactivity in Sapap3-KO mice at grooming- onset relative to wild-type (WT) littermates, an effect that is driven by increased recruitment of groom onset-activated SPNs. SSRI treatment reduced the compulsive grooming behavior of Sapap3-KOs and decreased the neural correlate of this behavior, the percent of groom onset- activated SPNs observed in Sapap3-KOs.To investigate the contributions of individual striatal subpopulations to the overall striatal hyperactivity observed in Sapap3-KOs, we used a double-transgenic strategy to generate D1-cre x Sapap3-KO and D1-cre x Sapap3-WT mice. Contrary to our predictions, we observed a significant reduction in activity of D1-SPNs in Sapap3-KOs relative to WT mice. Following 7 days SSRI treatment, the compulsive grooming phenotype of D1-cre x Sapap3-KO mice was significantly reduced, but only minor changes in D1-SPN activity were observed. These findings suggest that D2-SPNs may be responsible for driving grooming-associated striatal hyperactivity in Sapap3-KO mice. While additional research is necessary to attain a more comprehensive understanding of the corticostriatal abnormalities in this translational model, the present findings provide clinically-relevant insights into the circuit level mechanisms underlying compulsive behaviors and the mechanisms by which SSRI treatment effectively reduces them.

[发布机构] the University of Pittsburgh