Subspace communication in the hippocampal-retrosplenial axis

Nature. 2026 May 13. doi: 10.1038/s41586-026-10481-z. Online ahead of print.

ABSTRACT

The capacity of hippocampal circuits to transform inputs into downstream outputs is fundamental to navigation and memory, yet the circuit-level mechanisms that enable this flexibility in adapting to experience remain unclear. Here we approach this problem by performing large-scale (up to 1,024 channel) recordings across the hippocampal-retrosplenial cortex (RSC) circuit in behaving mice, enabling simultaneous access to spiking activity in dentate gyrus (DG), CA3, CA2, CA1 and RSC. On the basis of a linear dimensionality-reduction technique known as partial canonical correlation analysis, we identify low-dimensional communication subspaces¹ between two regions while accounting for influences from a third area. These subspaces captured distinct input-output transformations in the CA1 region, linking upstream hippocampal activity (DG, CA3 and CA2) to downstream cortical targets (RSC). Intrinsic firing properties and anatomical location constrained subspace memberships-members were mapped to deep sublayers of the CA3-CA1-RSC axis during both spatial and non-spatial tasks. These subspaces could recombine overlapping neuronal pools to support distinct interareal interactions across changing experiences and brain states. Reactivation patterns of CA1-CA3 subspaces, but not those of CA1-RSC, during post-experience sleep correlated with replay, reflecting a plasticity-stability balance in the input-output transformation along the hippocampal-retrosplenial axis. Our findings suggest a model in which hippocampal-neocortical communication reconfigures predetermined circuit motifs to flexibly encode experiences.

PMID:42129569 | DOI:10.1038/s41586-026-10481-z