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Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior
Sean C Piantadosi1,2,3, Elizabeth E Manning2,4, Brittany L Chamberlain1,2
1Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Nature Communications
|May 24, 2024
Summary
Compulsive behaviors in obsessive-compulsive disorder (OCD) are linked to striatal indirect pathway hyperactivity. Suppressing this pathway reduced compulsive grooming in a mouse model, suggesting it as a novel treatment target.
Area of Science:
- Neuroscience
- Behavioral Science
Background:
- Compulsive behaviors are a core symptom of obsessive-compulsive disorder (OCD).
- Striatal hyperactivity is implicated in compulsive behavior, but the roles of its direct and indirect pathways are unclear.
Purpose of the Study:
- To investigate the contribution of direct and indirect striatal pathways to compulsive behavior generation and treatment.
Main Methods:
- Utilized the Sapap3-knockout mouse model, exhibiting OCD-relevant compulsive grooming.
- Employed optogenetics to suppress indirect pathway activity.
- Administered fluoxetine, a first-line OCD pharmacotherapy.
Main Results:
- Found indirect pathway hyperactivity correlated with compulsive grooming in Sapap3-knockout mice.
- Demonstrated that suppressing indirect pathway activity reduced grooming.
- Observed that fluoxetine treatment also decreased grooming behavior.
Conclusions:
- Challenges the traditional hypothesis regarding direct and indirect pathway roles in compulsive behavior.
- Highlights the striatal indirect pathway as a potential therapeutic target for OCD-related compulsive behaviors.
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