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Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in humans and 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 have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of the direct relative to indirect pathway promotes compulsive behavior.

To improve our understanding of how activity of these specific striatal neuronal populations and their associated pathways through the basal ganglia contribute to the generation of compulsive behaviors, investigators including Sean Piantadosi, PhD (now University of Washington, Seattle); Elizabeth Manning, PhD (now University of Newcastle, Australia); Brittany Chamberlain, BA (University of Pittsburgh MD/PhD student); and Susanne Ahmari, MD, PhD (Associate Professor of Psychiatry), directly examined activity of spiny projection neuron subtypes in freely moving Sapap3-knockout mice, a strain that exhibits serotonin reuptake inhibitor-sensitive, OCD-relevant behavioral phenotypes including compulsive grooming behavior, along with well-established structural and physiological striatal abnormalities.

The team recently published results from the study in Nature Communications. Contrary to their hypothesis, they demonstrated that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. In addition, they found that suppression of indirect pathway activity using optogenetics or treatment with the first-line obsessive compulsive disorder pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. 

“We are very excited to share this work with the community, because the results were so surprising to us. Our data suggest that indirect pathway neurons in the striatum may play an important role in compulsive behavior disorders. Though substantial effort is still needed to translate these results into an understanding of OCD in humans, this work may ultimately lead to new treatment approaches for this disorder,” said Dr. Ahmari, the study’s senior and corresponding author.

Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior
Piantadosi SC, Manning EE, Chamberlain BL, Hyde J, LaPalombara Z, Bannon NM, Pierson JL, Namboodiri VMK, Ahmari SE
Nature Communications volume 15, Article number: 4434 (2024)