Differential Effects of Deep Brain Stimulation of the Internal Capsule and the Striatum on Excessive Grooming in Sapap3 Mutant Mice
Abstract
Background Deep brain stimulation (DBS) is an effective treatment for patients with obsessive-compulsive disorder (OCD) that do not respond to conventional therapies. Although the precise mechanism of action of DBS remains unknown, modulation of activity in corticofugal fibers originating in the prefrontal cortex is thought to underlie its beneficial effects in OCD.Methods To gain more mechanistic insight into DBS in OCD, we used Sapap3 mutant mice. These mice display excessive self-grooming and increased anxiety, both of which are responsive to therapeutic drugs used in OCD patients. We selected two clinically relevant DBS targets through which activity in prefronto-corticofugal fibers may be modulated: the internal capsule (IC) and the dorsal part of the ventral striatum (dVS).Results IC-DBS robustly decreased excessive grooming, whereas dVS-DBS was on average less effective. Grooming was reduced rapidly after IC-DBS onset and reinstated upon DBS offset. Only IC-DBS was associated with increased locomotion. DBS in both targets induced c-Fos expression around the electrode tip and in different regions of the prefrontal cortex. This prefronto-cortical activation was more extensive after IC-DBS, but not associated with behavioral effects. Furthermore, we found that the decline in grooming cannot be attributed to altered locomotor activity and that anxiety, measured on the elevated plus maze, was not affected by DBS.Conclusions DBS in both the IC and dVS reduces compulsive grooming in Sapap3 mutant mice. However, IC stimulation was more effective, but also produced motor activation, even though both DBS targets modulated activity in a similar set of prefrontal cortical fibers.
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Studies that have used Sapap3-KO mice to test treatment approaches for OCD remain limited.
“Despite construct, face and predictive validity of the Sapap3-KO mouse model, studies that have used Sapap3-KO mice to test treatment approaches for OCD remain limited [17,18].”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [17]
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 [17]
Excessive grooming in Sapap3-KO mice can be alleviated with clinically effective treatments (fluoxetine and deep brain stimulation), which supports predictive validity of the mouse model.
“Excessive grooming can be alleviated with clinically effective treatments (i.e., the pharmacological compound fluoxetine [9] and deep brain stimulation [17]), which supports predictive validity of the mouse model.”
From Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice (2020) · cites this paper as [17]
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 [17]
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 [17]
SAPAP3−/− mice display compulsive-like grooming.
“Similar to subtypes of OCD patients, SAPAP3−/− display compulsive‐like grooming that can be decreased by deep‐brain stimulation.15”
From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [15]
A compromised PFC-striatal network present in SAPAP3−/− is possibly responsible for the lack of adaptation to changing situational requirements.
“Thus, a compromised PFC‐striatal network present in SAPAP3−/−, which was shown to be involved in their excessive grooming,7, 8, 15, 16 is possibly responsible for the lack of adaptation to changing situational requirements.”
From Behavioral flexibility in a mouse model for obsessive‐compulsive disorder: Impaired Pavlovian reversal learning in SAPAP3 mutants (2019) · cites this paper as [15]
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References 45 · Cited by 54
- Authors
- Pinhal, C. M., van den Boom, B. J. G., Santana-Kragelund, F., Fellinger, L., Bech, P., Hamelink, R., Feng, G., Willuhn, I., Feenstra, M. G. P., & Denys, D.
- Affiliations
- Netherlands Institute for Neuroscience (NL)
- McGovern Institute for Brain Research (US)
- Corresponding author
- Willuhn, Ingo
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 84
- Issue
- 12
- Pages
- 917-925
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2804683430
- Cited by
- 54
- References
- 45
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 10 · 2023: 5 · 2022: 6 · 2021: 10 · 2020: 6 · 2019: 10
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Keywords
- deep brain stimulation, obsessive-compulsive disorder, excessive grooming, internal capsule, corticofugal fibers, prefrontal cortex, Fos expression, locomotor activity, anxiety, compulsive behavior
- MeSH terms
- Animals, Disease Models, Animal, Female, Grooming, Male, Mutation, Nerve Tissue Proteins, Obsessive-Compulsive Disorder, Internal Capsule, Deep Brain Stimulation, Mice, Ventral Striatum
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