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Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior
Open accessAbstract
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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“Accumulating evidence from animal and clinical research has shown that hyperactivity in the OFC-striatum pathway plays a pivotal role in the pathology of compulsivity64–66.”
From Dissociable roles of prefrontal plasticity in decision-making strategy and execution of habitual behavior (2026) · cites this paper as [64]
In the citing paper
“While acute stimulation did not generate repetitive behaviors, repeated hyperactivation for multiple days in a row led to a progressive and persistent increase in grooming that correlated with an increased evoked-firing rate at OFC-VMS synapses.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [105]
In the citing paper
“Increased grooming and evoked firing were both reversed by chronic fluoxetine treatment.”
From DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS: Review: Dissecting OCD Circuits: Animals to Treatments (2015) · cites this paper as [105]
In the citing paper
“Brief, repeated, optogenetic stimulation of mOFC terminals in VS progressively led to the development of repetitive grooming behavior that may be relevant to OCD (Ahmari et al., 2013).”
From A framework for understanding the emerging role of corticolimbic-ventral striatal networks in OCD-associated repetitive behaviors (2015) · cites this paper as Ahmari et al., 2013
In the citing paper
“While these findings demonstrate that a circuit-level manipulation of OFC-VS projections produces OCD-like behaviors in mice (Ahmari et al., 2013)”
From A framework for understanding the emerging role of corticolimbic-ventral striatal networks in OCD-associated repetitive behaviors (2015) · cites this paper as Ahmari et al., 2013
In the citing paper
“Together, these data suggest that abnormal functional connectivity in this interregional connection could underlie pathological repetitive behaviors (Ahmari et al., 2013).”
From A framework for understanding the emerging role of corticolimbic-ventral striatal networks in OCD-associated repetitive behaviors (2015) · cites this paper as Ahmari et al., 2013
In the citing paper
“Moreover, they found that both grooming behaviour and the hyperactivity induced through chronic optogenetic stimulation were remediated using a common treatment for OCD, the selective-serotonin reuptake inhibitor fluoxetine (Ahmari et al., 2013).”
From The role of habit in compulsivity (2016) · cites this paper as Ahmari et al., 2013
In the citing paper
“They found that a causal relationship between this hyperactivity and the onset of compulsive grooming behaviour in otherwise healthy mice.”
From The role of habit in compulsivity (2016) · cites this paper as Ahmari et al., 2013
In the citing paper
“Compulsive grooming can be induced by optogenetically increasing medial/ventral OFC-to-DS pathway activity [49].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [49]
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InfluentialEndocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation
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Self-citationFrom compulsivity to compulsion: the neural basis of compulsive disorders
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“Conversely, chronic photostimulation of mOFC inputs into the ventral striatum induced excessive grooming in wild-type mice 156 .”
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“The limited role of the ATR in the efficacy of DBS for OCD could be considered surprising, as the ATR connects different brain structures within the CSTC network that are at the core of the pathophysiological model of OCD [25].”
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Corticostriatal circuit defects in Hoxb8 mutant mice
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Illuminating circuitry relevant to psychiatric disorders with optogenetics
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Self-citationInvestigating habits: strategies, technologies and models
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“…to use in isolating pathways and cell types necessary or sufficient for goal-directed behaviors (Gremel and Costa, 2013), ritualistic behaviors (Ahmari et al., 2013; Burguiere et al., 2013), behavioral initiation or cessation (Kravitz et al., 2010), and linking rewards or drugs with behavioral…”
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“Second, clinical research and experimental manipulations in rodents suggest a role for abnormal function of corticostriatal-thalamo-cortical circuits in repetitive motor behaviors (Saxena et al. 1998; Marsh et al. 2009; Ahmari et al. 2013; Burguiere et al. 2013).”
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“Notably, repeated optogenetic stimulation of OFC as well as its downstream striatal projection terminals can generate compulsive-like repetitive behavior in transgenic mice (45).”
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“Brief, repeated, optogenetic stimulation of mOFC terminals in VS progressively led to the development of repetitive grooming behavior that may be relevant to OCD (Ahmari et al., 2013).”
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“Ahmari et al. (2013) found that stimulating OFC corticostriatal neurons resulted in excessive selfgrooming in mice, which was reversed by administration of fluoxetine, a treatment for OCD.”
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“Increased striatal activity has been associated with OCD behaviors in both clinical populations (5–7) and animal models (3,4).”
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“For example, an optogenetic mouse model was constructed via chronic stimulation of cortical inputs to the striatum (Ahmari et al., 2013).”
BackgroundMethodInfluentialA Unified Functional Network Target for Deep Brain Stimulation in Obsessive-Compulsive Disorder
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“Specifically, neuronal hyperactivity within the orbitofrontal cortex and ventromedial striatum has been associated with OCD behaviour [4-7].”
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Nucleus Accumbens Cell Type- and Input-Specific Suppression of Unproductive Reward Seeking
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Genome-wide analyses identify 30 loci associated with obsessive–compulsive disorder
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“These findings are in line with traditional neural circuitry models of OCD, which focus on frontal cortical–striatal pathways 68,69 .”
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Obsessive-compulsive disorder: Insights from animal models
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“First, Ahmari et al. (2013) demonstrated for the first time that hyperactivation of circuits linked to OCD in humans can lead, over time, to the development of abnormal repetitive grooming behavior in wild-type, healthy mice.”
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Self-citationAstrocyte regulation of synaptic signaling in psychiatric disorders
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Learning From Animal Models of Obsessive-Compulsive Disorder
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“Using this strategy, a recent study directly tested the CSTC hyperactivity hypothesis of OCD [52].”
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Nakayama, H., Ibáñez-Tallon, I., & Heintz, N. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.3537-17.2018 · Cited by 80
“Furthermore, the frequency of innate habitual motor programs, such as grooming in rodents, increases with repeated hyperstimulation of the ventromedial orbitofrontal cortex (Ahmari et al., 2013).”
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“Unlike transgenic strains (30–32) and optogenetic manipulations billed as animal models of OCD characterized by excessively self-destructive grooming behavior (7, 8, 33), our mouse model is beneficial Fig.”
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Using mice to model Obsessive Compulsive Disorder: From genes to circuits
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“…below, which indicate it is possible that hyperactivity in medial OFC regions connected to limbic structures may lead to OCD-relevant symptoms (Ahmari et al., 2013), while hyperactivity in lateral OFC regions important for inhibitory control may lead to symptom reduction (Burguiere et al.,…”
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Cortical-subcortical interactions in goal-directed behavior
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Abnormal Striatal Development Underlies the Early Onset of Behavioral Deficits in Shank3B Mice
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“Repeated corticostriatal stimulation in ventromedial striatum generates persistent overgrooming in mice (Ahmari et al., 2013), whereas reduction of corticostriatal connectivity in individuals with obsessive-compulsive disorder (OCD) significantly improves compulsive behaviors (Dunlop et al.”
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Metadata
- Authors
- Ahmari, S. E., Spellman, T., Douglass, N. L., Kheirbek, M. A., Simpson, H. B., Deisseroth, K., Gordon, J. A., & Hen, R.
- Affiliations
- New York State Psychiatric Institute (US)
- Columbia University Irving Medical Center (US)
- Stanford Medicine (US)
- Corresponding author
- Ahmari, Susanne E.
- ORCID
- Venue
- Science
- Published
- 2013-06-07
- Volume
- 340
- Issue
- 6137
- Pages
- 1234-1239
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3954809
- OpenAlex
- W2003956812
- Cited by
- 502
- References
- 43
- Citations by year
- 2026: 27 · 2025: 34 · 2024: 26 · 2023: 26 · 2022: 38 · 2021: 43 · 2020: 47 · 2019: 47 · 2018: 30 · 2017: 44 · 2016: 41 · 2015: 53 · 2014: 33 · 2013: 11
- FWCI
- 51.12
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01mh096274-06)
- National Institute of Mental Health (K24MH091555, R01-MH096274, K01MH099371, K08MH087718)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- obsessive-compulsive disorder, cortico-striato-thalamo-cortical circuit, orbitofrontal cortex, ventromedial striatum, grooming, fluoxetine, optogenetics, mouse model
- MeSH terms
- Channelrhodopsins, Adenoviridae, Animals, Bacterial Proteins, Behavior, Animal, Corpus Striatum, Electric Stimulation, Fluoxetine, Frontal Lobe, Luminescent Proteins, Male, Obsessive-Compulsive Disorder, Thalamus, Selective Serotonin Reuptake Inhibitors, Artificial Gene Fusion, Mice, Optogenetics
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