Journal
SCIENCE
Volume 340, Issue 6137, Pages 1243-1246Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1232380
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Funding
- Simons Initiative on Autism
- Brain at MIT
- National Institute of Child Health and Development, NIH [R37 HD028341]
- Defense Advanced Research Projects Agency [W911NF1010059]
- National Institute on Mental Health, NIH [R01 MH081201]
- Simons Foundation Autism Research Initiative
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Dysfunctions in frontostriatal brain circuits have been implicated in neuropsychiatric disorders, including those characterized by the presence of repetitive behaviors. We developed an optogenetic approach to block repetitive, compulsive behavior in a mouse model in which deletion of the synaptic scaffolding gene, Sapap3, results in excessive grooming. With a delay-conditioning task, we identified in the mutants a selective deficit in behavioral response inhibition and found this to be associated with defective down-regulation of striatal projection neuron activity. Focused optogenetic stimulation of the lateral orbitofrontal cortex and its terminals in the striatum restored the behavioral response inhibition, restored the defective down-regulation, and compensated for impaired fast-spiking neuron striatal microcircuits. These findings raise promising potential for the design of targeted therapy for disorders involving excessive repetitive behavior.
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