Differentiation of Human Medial Prefrontal Cortex Activity Underlies Long-Term Resistance to Forgetting in Memory

It is well known that distributing study events over time leads to better memory over long time scales, compared with massing study events together. One explanation for such long-term resistance to forgetting is that distributed study leads to neural differentiation in memory, which supports retrieval of past experiences by disambiguating highly similar memory representations. Neuroanatomical models of episodic memory retrieval propose that the hippocampus and medial prefrontal cortex (MPFC) work together to enable retrieval of behaviorally appropriate memories. However, it is not known how representations in these regions jointly support resistance to forgetting long after initial learning. Using fMRI, we measured differentiation in retrieved memory representations following an extended delay in male and female human participants. After 1 week, word-object associations were better remembered if studied across 2 d (overnight), allowing associations to be learned in distinct temporal contexts, compared with learning within a single day (same day). MPFC retrieval patterns showed differentiation for overnight relative to same day memories, whereas hippocampal patterns reflected associative retrieval success. Overnight memory differentiation in MPFC was higher for associative than item memories and higher than differentiation assessed over a brain-wide set of retrieval-active voxels. The memory-related difference in MPFC pattern differentiation correlated with memory success for overnight learning and with hippocampal-MPFC functional connectivity. These results show that learning information across days leads to differentiated MPFC memory representations, reducing forgetting after 1 week, and suggest this arises from persistent interactions between MPFC and hippocampus.SIGNIFICANCE STATEMENT Neural activity in both the hippocampus and medial prefrontal cortex (MPFC) has been linked to memory-related representations, but prior work has not examined how these representations support episodic memory retrieval over extended time scales that are characteristic of everyday retrieval. We show that differentiation in MPFC activity 1 week after encoding is higher for retrieved information learned across 2 d compared with within a single day. In hippocampus, differentiation was greater for detailed memory retrieval but was not influenced by whether information had been learned over 1 or 2 d. Differentiation in MPFC predicted behavioral robustness to forgetting and was correlated with hippocampal-MPFC connectivity. The results suggest that context-based differentiation supports robust long-term memory via persistent MPFC-hippocampal interactions.