Prefrontal pathways provide top down control of memory for sequences of events

Summary We remember our lives as sequences of events, but it is unclear how these memories are controlled during retrieval. In rats, prelimbic cortex (PL) is positioned to influence sequence memory through extensive top down inputs to the nucleus reuniens of the thalamus (RE) and perirhinal cortex (PER), regions heavily interconnected with the hippocampus. Here, we tested the hypothesis that specific PL➔RE and PL➔PER projections regulate sequence memory retrieval using an hM4Di synaptic-silencing approach. First, we show that the suppression of PL activity impairs sequence memory. Second, we show that inhibiting PL➔RE and PL➔PER pathways effectively eliminated sequence memory. Last, we performed a sequential lag analysis showing that the PL➔RE pathway contributes to a working memory retrieval strategy, and the PL➔PER pathway contributes to a temporal context memory retrieval strategy. These results demonstrate that the PL➔RE and PL➔PER pathways serve as top down mechanisms that control sequence memory retrieval strategies.