THE CORTICAL CAUDAL ACC-TO-PL PROJECTION SUPPRESSES REMOTE FEAR MEMORY EXPRESSION

Remote memories require reactivation of sparsely distributed cortical neurons defined during learning, so-called engram neurons. During systems consolidation, intercortical connectivity is thought to strengthen over time to support memory persistence. Engram neurons in both the caudal anterior cingulate cortex (cACC) and prelimbic cortex (PL) play a pivotal role in remote memory retrieval. However, little is known about how the connection between the cACC and PL contributes to systems consolidation and remote memory retrieval.
Using neuronal activity-dependent retrograde tracing, we observed preferential reactivation of cACC engram neurons that project to the PL during remote memory retrieval, suggesting a functional role for this projection. Next, we performed several tracing strategies, including anterograde transsynaptic tracing, to characterize the cACC-to-PL projection. We found that the cACC projects to a substantial proportion (~35%) of PL engram neurons. However, the reactivation rate of PL engram populations that received or not received cACC input was similar, suggesting it was not influenced by this projection. In contrast, a non-engram PL population receiving cACC input was activated to a greater extent than other non-engram neurons that were not innervated by the cACC. Interestingly, chemogenetic inhibition of the cACC-to-PL projection enhanced freezing during a remote memory test, whereas activation reduced freezing.
Together, these findings indicate that the cACC-to-PL projection modulates remote fear memory through suppression of freezing behavior, potentially via recruitment of a new (non-engram) ensemble in the PL. Further elucidating the mechanisms by which this projection dampens freezing responses may inform strategies for regulating remote fear memory retrieval.