Abstract
Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces anxiety, fear, and compulsive symptoms in patients suffering from refractory obsessive-compulsive disorder. In a rodent model, DBS-like high-frequency stimulation of VS can either enhance or impair extinction of conditioned fear, depending on the location of electrodes within VS (dorsal vs ventral). As striatal DBS activates fibers descending from the cortex, we reasoned that the differing effects on extinction may reflect differences in cortical sources of fibers passing through dorsal–VS and ventral–VS. In agreement with prior anatomical studies, we found that infralimbic (IL) and anterior insular (AI) cortices project densely through ventral–VS, the site where DBS impaired extinction. Contrary to IL and AI, we found that medial orbitofrontal cortex (mOFC) projects densely through dorsal–VS, the site where DBS enhanced extinction. Furthermore, pharmacological inactivation of mOFC reduced conditioned fear and DBS of dorsal-VS-induced plasticity (pERK) in mOFC neurons. Our results support the idea that VS DBS modulates fear extinction by stimulating specific fibers descending from mOFC and prefrontal cortices.
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Acknowledgements
We thank the members of the Silvio O. Conte Center for Research in OCD: Barry W Connors, Darin Dougherty, Emad N. Eskandar, Anthony A Grace, Benjamin D Greenberg, Mohammed R Milad, and Steven A Rasmussen for useful discussions. We also thank Julia F Lehman, Anna E. Borkowska-Belanger, Carlos Rodriguez, and Zarkalys Quintero for technical assistance. This work was supported by NIH grants P50 MH086400 (to SNH and GJQ), R37 MH058883 and R01 MH081975 (to GJQ), R36 MH105039 (to JRR), and the University of Puerto Rico President’s Office.
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Rodriguez-Romaguera, J., Do-Monte, F., Tanimura, Y. et al. Enhancement of Fear Extinction with Deep Brain Stimulation: Evidence for Medial Orbitofrontal Involvement. Neuropsychopharmacol 40, 1726–1733 (2015). https://doi.org/10.1038/npp.2015.20
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DOI: https://doi.org/10.1038/npp.2015.20
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