Optogenetic inhibition of indirect pathway neurons in the dorsomedial striatum reduces excessive grooming in Sapap3-knockout mice

Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activi...

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Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2022-01, Vol.47 (2), p.477-487
Main Authors: Ramírez-Armenta, Kathia I, Alatriste-León, Hector, Verma-Rodríguez, Anil K, Llanos-Moreno, Argelia, Ramírez-Jarquín, Josué O, Tecuapetla, Fatuel
Format: Article
Language:English
Subjects:
Activity patterns
Animals
Calcium imaging
Corpus Striatum - metabolism
Grooming
Grooming - physiology
Humans
Mice
Mice, Knockout
Neostriatum
Nerve Tissue Proteins - metabolism
Neurons
Neurons - metabolism
Obsessive compulsive disorder
Optogenetics
Phenotypes
Rodents
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Summary:Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activity patterns of striatal circuitry underlies the excessive grooming observed in Sapap3-KO mice. To test this hypothesis, we used in-vivo calcium imaging of individual cells to record striatal activity in these animals and optogenetic inhibition to manipulate this activity. We identified striatal neurons that are modulated during grooming behavior and found that their proportion is significantly larger in Sapap3-KO mice compared to wild-type littermates. Inhibition of striatal cells in Sapap3-KO mice increased the number of grooming episodes observed. Remarkably, the specific inhibition of indirect pathway neurons decreased the occurrence of grooming events. Our results indicate that there is striatal neural activity related to excessive grooming engagement in Sapap3-KO mice. We also demonstrate, for the first time, that specific inhibition of striatal indirect pathway neurons reduces this compulsive phenotype, suggesting that treatments that alleviate compulsive symptoms in OCD patients may exert their effects through this specific striatal population.
ISSN:0893-133X
1740-634X
DOI:10.1038/s41386-021-01161-9