The medial prefrontal cortex is critical for memory retrieval and resolving interference.

The prefrontal cortex (PFC) is known to be critically involved in strategy switching, attentional set shifting, and inhibition of prepotent responses. A central feature of this kind of behavioral flexibility is the ability to resolve conflicting response tendencies, suggesting a general role of the PFC in resolving interference. If so, the PFC should also be involved in memory retrieval, which involves competition between potential retrieval targets. Moreover, the PFC should be needed whenever interference is high, regardless of the strategic or attentional requirements of the task. To test this hypothesis, we temporarily inactivated the mPFC with muscimol and tested rats on several olfactory learning tasks. Rats given muscimol were able to learn a few discrimination problems when they were learned one at a time. However, they were severely impaired when they had to learn and remember many odors concurrently. Rats given muscimol also suffered greater interference when learning two lists of conflicting odor discrimination problems. Additionally, temporary mPFC inactivation during the acquisition of one set of odor memories actually improved the ability to learn a new set of conflicting odor memories. This paradoxical release from interference suggests that the mPFC plays an important role in acquiring and promoting the long term retrieval of memories. These results suggest that the mPFC plays a general role in resolving interference and that this is a key aspect of behavioral flexibility.