Activation of medial orbitofrontal cortex abolishes fear extinction and interferes with fear expression in rats

Pavlovian fear conditioning and extinction procedures have long been used to study the regulation of learned fear. The amygdala is vital for the association of cues and fear expression, whereas the medial prefrontal cortex (mPFC) is critical for fear regulation after extinction. The medial orbitofrontal cortex (mOFC) has an extensive connection with the fear circuit. In human studies, emotional regulation disorders, such as obsessive-compulsive disorder and post-traumatic stress disorder, are often linked to an abnormality in the orbitofrontal cortex (OFC). Therefore, in a series of experiments, we examined whether abnormal mOFC activities interfere with the regulation of learned fear. The mOFC of rats was pharmacologically activated with N-methyl-D-aspartate (NMDA) during the acquisition, early consolidation, or retrieval phase of fear extinction. Under mOFC activation, there was a general initial suppression of the fear response followed by the development of nonspecific fear expression. Moreover, pre-extinction activation of the mOFC abolished extinction acquisition, causing an up-shift in the fear response during the retrieval test. Nonetheless, immediate post-extinction activation of the mOFC did not interfere with extinction consolidation. Overall, our results suggested that mOFC activation abolished fear extinction acquisition and interfered with fear expression.