Imaging studies suggest that obsessive-compulsive disorder (OCD) may be due to overactivity within the lateral orbitofrontal cortex (LO);an area known to be important in stimulus valuation. Secondly, the vmPFC has been suggested to play a role based on its function in extinction. We propose that OCD is due to a dysfunction of hyperactivity within the LO, causing the patient to over-value a stimulus that is no longer behaviorally salient, and hypoactivity within the vmPFC, interfering with normal extinction of nonsalient stimuli. High-frequency stimulation (HFS) of the brain, is proposed to act therapeutically by restoring normal function to these circuits. This project uses in vivo recordings of LO and vmPFC activity and how these circuits respond to HFS of the NAc, which is the rodent analog of the stimulation site found to be effective in treating OCD in humans. Stimuli will be presented acutely, subchronically (90 min-8 hours), and chronically using implanted custom-designed stimulators (2 weeks) to evaluate the changes that occur during the course of stimulation. These changes will be evaluated in terms of rhythmic activity, neuronal firing, and synaptic plasticity changes that occur over these time intervals. A unique component to this proposal is that stimulation and most measurements will be performed in the awake animal to circumvent anesthesia issues. This study will be done along three specific aims: 1) Examine the effects of subchronic HFS stimulation of the NAc site on mPFC, LO and NAc spontaneous and evoked fields, along with c-fos to evaluate which neuron types are affected. 2) Examine chronic HFS effects on vmPFC, LO and NAc activity states and the time course of the changes. During the last day of stimulation, animals will be anesthetized and recordings of neurons identified by juxtacellular labeling and immunocytochemistry to assess the cellular nature of the changes observed. 3) Examine the effects of chronic HFS on mPFC-LO interactions to evaluate whether the changes observed in vmPFC are dependent on the LO, and vice-versa. We propose that HFS will decrease LO activity to decrease the emotional salience of the stimulus, while activating the mPFC to facilitate extinction;both of which may be required for a therapeutic response. Such information will provide essential data with respect to HFS effects at a systems level, as well as how network interactions can modulate regionally-selective alterations at the cellular level. Furthermore, this project will provide essential information to evaluate the imaging and clinical findings, the alterations in activity that will be tested in behavioral experiments, and the neuronal types activated for comparison with the in vitro cellular analyses.
This study will provide information regarding the modulation and interaction of cortical circuits proposed to have a role in OCD, as well as mechanisms by which rhythmic activity is modulated within these circuits. In addition, it will provide a cellular basis for the therapeutic effects of HFS used in the treatment of OCD, and help to refine the stimulation sites and parameters to most effectively induce the desired changes.
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| Martínez-Rivera, Freddyson J; Rodriguez-Romaguera, Jose; Lloret-Torres, Mario E et al. (2016) Bidirectional Modulation of Extinction of Drug Seeking by Deep Brain Stimulation of the Ventral Striatum. Biol Psychiatry 80:682-690 |
| Do-Monte, Fabricio H; Manzano-Nieves, Gabriela; Quiñones-Laracuente, Kelvin et al. (2015) Revisiting the role of infralimbic cortex in fear extinction with optogenetics. J Neurosci 35:3607-15 |
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