Using microstimulation to map prefrontal fear modules in the rat

University Of Rochester, Rochester NY

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Abstract

Obsessive compulsive disorder (OCD) is characterized by persistent intrusive thoughts (obsessions) and repetitive intentional behaviors (compulsions). The overall hypothesis of this center is that these symptoms are due, in part, to impaired extinction of fear, which disrupts the normal balance between fear avoidance and reward- seeking. These behaviors depend on medial prefrontal (mPFC)-orbitofrontal (OFC)-basal ganglia circuits, which are known to be dysfunctional in OCD. Deep brain stimulation (DBS) of sites in the ventral capsule/ventral striatum (VS/VS) region reduces OCD symptoms, but the mechanisms are unknown. The VS/VC contains fibers emanating from widespread areas of OFC and mPFC. Therefore, a thorough behavioral mapping of stimulation effects in mPFC, OFC, and VC/VS is needed to optimize electrode placement and understand the mechanisms of therapeutic action of DBS. Project 4 will carry out this mapping. In Aim 1, we will use acute microstimulation to map mPFC and OFC subregions in the expression and extinction of conditioned fear. In Aim 2, we will assess the effects of subchronic microstimulation of OFC and mPFC, and their output axons in the accumbens, in the transfer of fear extinction to instrumental avoidance, using a newly developed behavioral task in rats. By administering the stimulation at various times during training, we will be able to separately evaluate its effects on: 1) extinction learning and retention, 2) the transfer of Pavlovian extinction to instrumental avoidance, and 3) the persistence of avoidance behaviors despite extensive extinction (can microstimulation "cure" the rats by reducing preservative avoidance?) In Aim 3, we will correlate this behavioral mapping with a neural mapping, use immunocytochemical techniques to assess the activation patterns in OFC and mPFC induced by subchronic microstimulation of sites shown to be effective in our task. Mapping the behavioral and neural effects of DBS-like microstimulation in a rodent model will facilitate the translation of rodent circuit models to primates and humans, and could suggest new targets for DBS in OCD. In addition, it will increase our basic understanding of mPFC- OFC interactions, and the role of this network in regulating fear learning and expression. RELEVANCE (See instructions): While deep brain stimulation (DBS) has been shown to be effective in the treatment of OCD, little is known about its mechanisms. Mapping the effects of DBS-like microstimulation in a rodent model could suggest new targets for DBS in OCD. In addition, it will increase our basic understanding of mPFC-OFC interactions, and the role of this network in regulating fear learning and expression.