Medial prefrontal cortex reduces proactive interference by modifying active hippocampal representations

Memory can improve or impair learning. Memory speeds learning when relevant information generalizes across situations, and slows learning when established memories conflict with learning of new information. The interference of memories of prior experience with current learning is referred to as proactive interference. Work in humans has demonstrated that the ability to resolve proactive interference is critically dependent on the prefrontal cortex (PFC), however, the mechanisms via which the PFC resolves interference are unknown. In this thesis I describe a series of experiments in which I examine a potential mechanism for resolution of proactive interference in which the PFC modifies memory representations during learning to drive the establishment of distinct, non-overlapping memories. Specifically, the proposed mechanism states that internal context, e.g., the set of rules represented by the PFC that one uses to guide behavior, allow for the differentiation of otherwise overlapping memories, thus mitigating interference. In a series of behavioral experiments I demonstrate that the rodent medial PFC (mPFC), which bears some functional homology to the primate lateral PFC, mitigates proactive interference in a spatial reversal task that requires animals to rapidly switch amongst conflicting rules to guide behavior. Rather than the mPFC minimizing interference from previous experience with current learning, however, it appears to modify representations as they're learned in order to minimize the likelihood of interference with subsequent learning. In a series of recording experiments I demonstrate that task rule information is prominently represented in both the mPFC and the hippocampus and that mPFC activity predicts changes in hippocampal activity during learning in a manner that in turn predicts interference during subsequent learning. In a final experiment I show that inactivation of the mPFC results in a reduction of the distinction amongst rule states decoded from the hippocampus. Taken together, the results provide converging evidence that the mPFC promotes the incorporation of rule information with active hippocampal representations in order to drive the establishment of distinct memories that are less prone to overlap, thus less likely to interfere with subsequent learning.