title: Enhancement of fear extinction with deep brain stimulation: evidence for medial orbitofrontal involvement.
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.
authors.affiliation: 1] Department of Psychiatry, University of Puerto Rico-School of Medicine, San Juan, PR, Puerto Rico [2] Department of Anatomy and Neurobiology, University of Puerto Rico-School of Medicine, San Juan, PR, Puerto Rico.
authors.forename: Jose
authors.initials: J
authors.lastname: Rodriguez-Romaguera
authors.affiliation: 1] Department of Psychiatry, University of Puerto Rico-School of Medicine, San Juan, PR, Puerto Rico [2] Department of Anatomy and Neurobiology, University of Puerto Rico-School of Medicine, San Juan, PR, Puerto Rico.
authors.forename: Fabricio H
authors.initials: FH
authors.lastname: Do-Monte
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanimura
authors.affiliation: 1] Department of Psychiatry, University of Puerto Rico-School of Medicine, San Juan, PR, Puerto Rico [2] Department of Anatomy and Neurobiology, University of Puerto Rico-School of Medicine, San Juan, PR, Puerto Rico.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Quirk
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine, Rochester, NY, USA.
authors.forename: Suzanne N
authors.initials: SN
authors.lastname: Haber
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D046690:Deep Brain Stimulation; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005239:Fear / Q000502:physiology*; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014909:Wheat Germ Agglutinins / Q000378:metabolism
chemical_list: D058785:GABA-A Receptor Agonists; D014909:Wheat Germ Agglutinins; D009118:Muscimol; D048049:Extracellular Signal-Regulated MAP Kinases