Deep brain stimulation (DBS) of the ventral capsule/ventral striatum in humans reduces symptoms of intractable obsessive-compulsive disorder (OCD);however the mechanisms of action are unknown. In most OCD patients, obsessive behaviors include repetitive avoidance behaviors to perceived threats, suggesting a deficit in circuits that regulate fear extinction. Models of fear extinction can shed light on the mechanisms of DBS. Using a model of fear extinction, we recently reported that DBS of a specific zone in the ventral striatum facilitated fear extinction and induced plasticity in cortico-amygdalar circuits. Using anatomical tract-tracing techniques, we found that descending cortical fibers from the medial portion of the orbitofrontal cortex (mOFC) may play a key role in the DBS mediated enhancement of extinction. Furthermore, our previous findings showed that DBS at this specific striatal site induced plasticity (pERK) in the lateral portion of the orbitofrontal cortex (lOFC). This grant will study the role of both mOFC and lOFC in fear extinction and in mediating the deep brain stimulation (DBS) effects of extinction memory.
In Aim 1, we will investigate the role of OFC subregions in fear extinction using pharmacological inactivation tools.
In Aim 2, we will use optogenetic techniques to selectively activate mOFC fibers in the ventral striatum with DBS frequencies and assess fear extinction and plasticity in cortico-amygdalar circuits.
This research will explore the role of orbitofrontal cortex (OFC) in fear extinction and its role in mediating the deep brain stimulation (DBS) enhancement of extinction memory. Understanding the mechanisms of DBS will provide insight into the pathological circuitry driving psychiatric diseases and open avenues for future therapeutic approaches leading to treatments for mental disorders characterized by excessive fear.
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