Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction

Anxiety disorders are thought to reflect deficits in the regulation of fear expression. Evidence from rodent studies implicates the ventromedial prefrontal cortex (vmPFC) in the regulation of conditioned fear. Lesions of the vmPFC have had differing effects on the acquisition and expression of conditioned fear, as well as on recall of extinction. The use of permanent lesions, however, makes it difficult to assess the phase of training in which the vmPFC is acting and can trigger recruitment of other structures, thereby masking lesion deficits. To overcome these problems, we temporarily inactivated the vmPFC of rats with tetrodotoxin (10 ng in a 0.5-mu l midline infusion) at one of four time points: prior to conditioning, prior to extinction, immediately after extinction or prior to recall of extinction. Consistent with lesion findings, inactivation of the vmPFC prior to acquisition had no effect but inactivation prior to extinction led to impaired recall of extinction the following day. In contrast to lesion findings, inactivation of the vmPFC decreased freezing at all time points, suggesting that some component of the vmPFC facilitates the expression of conditioned fear. These findings suggest that inactivation of the vmPFC can have opposite effects depending on the phase of training. The vmPFC appears to be involved both in stimulating the expression of conditioned fear and in serving as a site of extinction-related plasticity that inhibits fear during recall of extinction.