Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors
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What Causes Obsessive Compulsive Disorder?: Obsessive compulsive disorder is a severe, chronic mental illness that affects millions of individuals. However, the mechanisms underlying this disease are still largely unknown (see the Perspective by Rauch and Carlezon Jr. ). Ahmari et al. (p. 1234 ) stimulated glutamatergic pathways between the orbitofrontal cortex and the ventromedial striatum and used grooming to assess obsessive compulsive behavior in mice. Repetitive stimulation over days triggered changes in the neuronal responses of the ventromedial striatum. Over time, the behavior of the animals became independent of stimulation and could be prevented by the antidepressant fluoxetine. Burguière et al. (p. 1243 ) investigated the neural basis of obsessive compulsive symptoms in a mutant mouse that showed excessive expression of a conditioned form of grooming.
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LOFC neurons send inputs to a subregion of striatum ranging from dorsomedial to central striatum, with dense inputs in the central subregion.
“Consistently, it has repeatedly been reported that LOFC neurons send inputs to a subregion of the striatum ranging from the dorsomedial to the central striatum. Dense inputs are observed in the central subregion60–63.”
From Dissociable roles of prefrontal plasticity in decision-making strategy and execution of habitual behavior (2026) · cites this paper as [61]
The paper reports stimulating lOFC axon terminals in the striatum and recording from the centromedial striatum (main text, indexed under Abstract). This supports an lOFC input to that region, but the cited passages do not establish a projection spanning dorsomedial to central striatum or show that inputs are especially dense centrally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBurguiere et al demonstrated impaired response inhibition in a conditioned grooming task in SAPAP3 KO mice.
“Burguiere et al 104 demonstrated impaired response inhibition in a conditioned grooming task.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [104]
Selectively stimulating projections from lateral OFC to striatum restored normal response inhibition in SAPAP3 KO mice, likely by compensating for deficits in fast-spiking interneurons.
“By selectively stimulating projections from the lateral OFC to the striatum, they were able to restore normal response inhibition, likely by compensating for SAPAP3 KO deficits in fast-spiking interneurons.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [104]
In Sapap3 mutant mice, compensatory optogenetic excitation of the lateral OFC-striatal pathway restored behaviour to the normal range and down-regulated firing of striatal neurons.
“Critically, the authors found that they could restore behaviour to the normal range in these mutant mice via compensatory optogenetic excitation of the lateral OFC-striatal pathway, which down-regulated the firing of these striatal neurons.”
From The role of habit in compulsivity (2016) · cites this paper as Burguiere et al., 2013
Deletion of the Sapap3 gene in mice induces excessive grooming behaviour alongside deficits in response inhibition and increased firing of medium spiky neurons in the striatum.
“The first used a gene mutant model where deletion of a gene (Sapap3) induces excessive grooming behaviour alongside deficits in response inhibition and increased firing of medium spiky neurons in the striatum (Burguiere et al., 2013).”
From The role of habit in compulsivity (2016) · cites this paper as Burguiere et al., 2013
The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age.
“The Sapap3-knockout (KO) mouse is a mouse model to study OCD and recapitulates OCD-like compulsion through excessive grooming behavior, with skin lesions appearing at advanced age.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [11]
Mice with a constitutive knockout of Sapap3 show complex behavioral phenotypes, which manifest as compulsive, OCD-like behaviors.
“Mice with a constitutive knockout (KO) of Sapap3 show complex behavioral phenotypes, which manifest as compulsive, OCD-like behaviors.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [11]
Sapap3-KO mice exhibit excessive grooming.
“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 [11]
The trend in striatal PV+ cell counts is consistent with reduced striatal PV+ cell abundance previously reported in 3-10 months old Sapap3-KO mice.
“This trend is consistent with reduced striatal PV + cell abundance previously reported in 3-10 months old Sapap3-KO mice [11].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [11]
Lateral OFC-to-DS projections seem to be hypoactive in Sapap3-KO mice, since optogenetic stimulation of the lateral OFC reduces compulsive grooming.
“In contrast, lateral OFC-to-DS projections seem to be hypoactive in Sapap3-KO mice, since optogenetic stimulation of the lateral OFC reduces compulsive grooming [11].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [11]
SAPAP3−/− display altered OFC-striatal activity and deficits in behavioral response inhibition that can be rescued by optogenetic stimulation of the OFC-striatal network.
“SAPAP3−/− display altered OFC‐striatal activity7, 8 and deficits in behavioral response inhibition that can be rescued by optogenetic stimulation of the OFC‐striatal network.16”
From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [16]
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Endres, D., Schiele, M. A., von Zedtwitz, K., Dressle, R. J., Maier, A., Hohagen, F., Baldermann, J. C., Coenen, V. A., Jelinek, L., Domschke, K., et al. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106320 · Cited by 11 · see citing works
Asaoka, N., Pagano, D., & Hayashi, Y. (2026) · Nature Communications · doi:10.1038/s41467-026-75706-1
- Authors
- Burguière, E., Monteiro, P., Feng, G., & Graybiel, A. M.
- Affiliations
- McGovern Institute for Brain Research (US)
- Corresponding author
- Graybiel, Ann M.
- Venue
- Science
- Published
- 2013-06-07
- Volume
- 340
- Issue
- 6137
- Pages
- 1243-1246
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3876800
- OpenAlex
- W2142150505
- Cited by
- 457
- References
- 30
- Citations by year
- 2026: 26 · 2025: 35 · 2024: 29 · 2023: 19 · 2022: 34 · 2021: 38 · 2020: 36 · 2019: 53 · 2018: 31 · 2017: 35 · 2016: 25 · 2015: 46 · 2014: 34 · 2013: 14
- FWCI
- 44.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- National Institute of Mental Health (R01MH081201, R01MH097104)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD028341, R37HD028341)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Keywords
- optogenetic stimulation, lateral orbitofrontal cortex, compulsive behavior, repetitive behavior, grooming, response inhibition, striatal projection neurons, fast-spiking interneurons, striatal microcircuits, frontostriatal circuits, neuropsychiatric disorders
- MeSH terms
- Animals, Compulsive Behavior, Corpus Striatum, Disease Models, Animal, Frontal Lobe, Grooming, Male, Nerve Tissue Proteins, Neurons, Gene Deletion, Gene Targeting, Mice, Optogenetics
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