biostudies-literatureLee JHNIMH NIH HHSU.S. Department of Health & Human Services | National Institutes of Health (NIH)U.S. Department of Health & Human Services | National Institutes of Health259-273https://www.ebi.ac.uk/biostudies/studies/S-EPMC9905017biostudies-literatureUnknown26(2)While initial encoding of contextual memories involves the strengthening of hippocampal circuits, these memories progressively mature to stabilized forms in neocortex and become less hippocampus dependent. Although it has been proposed that long-term storage of contextual memories may involve enduring synaptic changes in neocortical circuits, synaptic substrates of remote contextual memories have been elusive. Here we demonstrate that the consolidation of remote contextual fear memories in mice correlated with progressive strengthening of excitatory connections between prefrontal cortical (PFC) engram neurons active during learning and reactivated during remote memory recall, whereas the extinction of remote memories weakened those synapses. This synapse-specific plasticity was CREB-dependNature neuroscienceNeocortical synaptic engrams for remote contextual memories.PMC9905017R01 MH118339R56MH113894R56 MH113894R01MH118339Cho JHKim WBPark EHLee JHfalseNeocortical synaptic engrams for remote contextual memories.While initial encoding of contextual memories involves the strengthening of hippocampal circuits, these memories progressively mature to stabilized forms in neocortex and become less hippocampus dependent. Although it has been proposed that long-term storage of contextual memories may involve enduring synaptic changes in neocortical circuits, synaptic substrates of remote contextual memories have been elusive. Here we demonstrate that the consolidation of remote contextual fear memories in mice correlated with progressive strengthening of excitatory connections between prefrontal cortical (PFC) engram neurons active during learning and reactivated during remote memory recall, whereas the extinction of remote memories weakened those synapses. This synapse-specific plasticity was CREB-depend2023-01-01T00:00:00Z2023 Feb2025-04-19T13:32:04.55Z2025-04-19T13:32:04.55ZS-EPMC99050173656454610.1038/s41593-022-01223-1