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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH086400-05
Application #
8477293
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$189,474
Indirect Cost
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Haber, Suzanne N; Behrens, Timothy E J (2014) The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders. Neuron 83:1019-39
Garnaat, Sarah L; Greenberg, Benjamin D; Sibrava, Nicholas J et al. (2014) Who qualifies for deep brain stimulation for OCD? Data from a naturalistic clinical sample. J Neuropsychiatry Clin Neurosci 26:81-6
Patel, Shaun R; Ghose, Kaushik; Eskandar, Emad N (2014) An open source 3-d printed modular micro-drive system for acute neurophysiology. PLoS One 9:e94262
Sesia, Thibaut; Bizup, Brandon; Grace, Anthony A (2014) Nucleus accumbens high-frequency stimulation selectively impacts nigrostriatal dopaminergic neurons. Int J Neuropsychopharmacol 17:421-7
Bravo-Rivera, Christian; Roman-Ortiz, Ciorana; Brignoni-Perez, Edith et al. (2014) Neural structures mediating expression and extinction of platform-mediated avoidance. J Neurosci 34:9736-42
Heilbronner, Sarah R; Haber, Suzanne N (2014) Frontal cortical and subcortical projections provide a basis for segmenting the cingulum bundle: implications for neuroimaging and psychiatric disorders. J Neurosci 34:10041-54
Mian, Matthew K; Sheth, Sameer A; Patel, Shaun R et al. (2014) Encoding of rules by neurons in the human dorsolateral prefrontal cortex. Cereb Cortex 24:807-16
Ewing, Samuel G; Porr, Bernd; Riddell, John et al. (2013) SaBer DBS: a fully programmable, rechargeable, bilateral, charge-balanced preclinical microstimulator for long-term neural stimulation. J Neurosci Methods 213:228-35
Ewing, Samuel G; Grace, Anthony A (2013) Deep brain stimulation of the ventral hippocampus restores deficits in processing of auditory evoked potentials in a rodent developmental disruption model of schizophrenia. Schizophr Res 143:377-83
Lipski, Witold J; Grace, Anthony A (2013) Activation and inhibition of neurons in the hippocampal ventral subiculum by norepinephrine and locus coeruleus stimulation. Neuropsychopharmacology 38:285-92

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