Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior

Sean C. Piantadosi, Elizabeth E. Manning, Brittany L. Chamberlain, James Hyde, Zoe LaPalombara, Nicholas M. Bannon, Jamie L. Pierson, Vijay M. K Namboodiri and Susanne E. Ahmari ()
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Sean C. Piantadosi: University of Pittsburgh
Elizabeth E. Manning: University of Pittsburgh
Brittany L. Chamberlain: University of Pittsburgh
James Hyde: University of Pittsburgh
Zoe LaPalombara: University of Pittsburgh
Nicholas M. Bannon: University of Pittsburgh
Jamie L. Pierson: University of Pittsburgh
Vijay M. K Namboodiri: University of San Francisco
Susanne E. Ahmari: University of Pittsburgh

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior.

Date: 2024
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DOI: 10.1038/s41467-024-48331-z

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