Circuit-specific reorganization of hippocampal-entorhinal-prefrontal subnetworks supports memory recall across the lifespan

Abstract

How memories reorganize across brain circuits as they age remains a central question in systems neuroscience. Systems consolidation is thought to progressively shift memory reliance from the hippocampus to distributed cortical networks, yet the contribution of cortical regions beyond the prefrontal cortex and the nature of this shift remains unclear. Here we define the circuit-level organization of remote memory recall across entorhinal, prefrontal, and hippocampal subregions. Using high-resolution activity mapping combined with causal manipulations that leverage natural memory decay, we adapted a murine object-location paradigm to examine memory recall across the lifespan. We find that recall of early remote memories (1 month) selectively depends on a LEC-hippocampal (CA1/CA3) circuit, whereas recall of older memories (6-12 months) recruits a distinct and broader network involving both LEC and MEC together with ACC and CA1. These findings reveal a temporally ordered, circuit-specific reconfiguration of hippocampo-cortical networks and identify the EC as a dynamic hub in remote memory retrieval. Our results refine prevailing systems consolidation theories by showing that memory consolidation is a circuit-specific and temporally ordered process, rather than a passive gradual phenomenon, and position the EC as a central and dynamic component of remote memory retrieval alongside the PFC. Graphical abstract