Impaired instrumental reversal learning is associated with increased medial prefrontal cortex activity in Sapap3 knockout mouse model of compulsive behavior
Open accessAbstract
Convergent functional neuroimaging findings implicate hyperactivity across the prefrontal cortex (PFC) and striatum in the neuropathology of obsessive compulsive disorder (OCD). The impact of cortico-striatal circuit hyperactivity on executive functions subserved by these circuits is unclear, because impaired recruitment of PFC has also been observed in OCD patients during paradigms assessing cognitive flexibility. To investigate the relationship between cortico-striatal circuit disturbances and cognitive functioning relevant to OCD, Sapap3 knockout mice (KOs) and littermate controls were tested in an instrumental reversal-learning paradigm to assess cognitive flexibility. Cortical and striatal activation associated with reversal learning was assessed via quantitative analysis of expression of the immediate early gene cFos and generalized linear mixed-effects models. Sapap3-KOs displayed heterogeneous reversal-learning performance, with almost half (n = 13/28) failing to acquire the reversed contingency, while the other 15/28 had similar acquisition as controls. Notably, reversal impairments were not correlated with compulsive grooming severity. cFos analysis revealed that reversal performance declined as medial PFC (mPFC) activity increased in Sapap3-KOs. No such relationship was observed in controls. Our studies are among the first to describe cognitive impairments in a transgenic OCD-relevant model, and demonstrate pronounced heterogeneity among Sapap3-KOs. These findings suggest that increased neural activity in mPFC is associated with impaired reversal learning in Sapap3-KOs, providing a likely neural basis for this observed heterogeneity. The Sapap3-KO model is thus a useful tool for future mechanistic studies to determine how mPFC hyperactivity contributes to OCD-relevant cognitive dysfunction.
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Skin lesions arising from excessive grooming typically appear in Sapap3-KO mice at advanced age.
“Skin lesions arising from excessive grooming typically appear in Sapap3-KO mice at advanced age, therefore, OCD-like behavioral phenotypes have mostly been studied in mice of about 6 months or older, shortly before the onset of lesions [9,10,13,14,17].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [13]
Sapap3-KO mice exhibit behavioral inflexibility.
“Such phenotypes are excessive grooming [9][10][11], anxiety-like behavior [9,12], behavioral inflexibility [13,14], and deficits in the balance of habitual and goal-directed behavior [15,16].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [13]
OCD-like behavioral phenotypes in Sapap3-KO mice have mostly been studied in mice of about 6 months or older, shortly before the onset of lesions.
“Skin lesions arising from excessive grooming typically appear in Sapap3-KO mice at advanced age, therefore, OCD-like behavioral phenotypes have mostly been studied in mice of about 6 months or older, shortly before the onset of lesions [9,10,13,14,17].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [13]
Excessive grooming in Sapap3-KO mice has been consistently observed across experimental conditions, including testing during light cycle and during the dark period.
“In contrast, excessive grooming in Sapap3-KO mice has been consistently observed across experimental conditions, including testing during light cycle [9,12,13] and during the dark period [9,10,17,33], which shows the robustness of the phenotype.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [13]
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- Authors
- Manning, E. E., Dombrovski, A. Y., Torregrossa, M. M., & Ahmari, S. E.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Ahmari, Susanne E.
- Venue
- Neuropsychopharmacology
- Published
- 2018-12-26
- Volume
- 44
- Issue
- 8
- Pages
- 1494-1504
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC6785097
- OpenAlex
- W2906276550
- Cited by
- 79
- References
- 55
- Citations by year
- 2026: 10 · 2025: 6 · 2024: 14 · 2023: 6 · 2022: 6 · 2021: 17 · 2020: 10 · 2019: 9
- FWCI
- 10.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Australian Association (Sir Keith Murdoch Fellowship)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01 MH104255)
- McKnight Endowment Fund for Neuroscience (Neuroscience Scholar Award)
- Burroughs Wellcome Fund (CAMS Award)
- Esther A. and Joseph Klingenstein Fund (Klingenstein-Simons Fellowship in the Neurosciences)
- MQ Fellows Award
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- obsessive-compulsive disorder, compulsive behavior, cognitive flexibility, corticostriatal circuits, compulsive grooming, Fos expression, individual heterogeneity, cognitive impairment
- MeSH terms
- Animals, Compulsive Behavior, Conditioning, Operant, Corpus Striatum, Female, Male, Nerve Tissue Proteins, Reversal Learning, Proto-Oncogene Proteins c-fos, Prefrontal Cortex, Mice, Knockout, Mice
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