Sparse memory ensembles set brain-wide network states to sustain learned associations

The ability to recall spatial memories and adapt behavior to changing conditions underlies efficient navigation. These processes are thought to rely on sparse populations of neurons, embedded within distributed brain networks. Here, we sought to address how these neurons impact large-scale network connectivity to sustain behavior. We tagged neurons that were active during an appetitive spatial memory task in TetTag-hM3Dq mice and chemogenetically reactivated these ensembles during fMRI. The reactivation of these ensembles triggered widespread network reorganization, optimizing modular specialization while maintaining integration via key hubs and gateways. We identified distinct clusters dominated by the ventral and dorsal hippocampus that exhibit unique connectivity with cortical and subcortical areas. While control mice showed effective extinction learning (EL), reactivating the tagged memory ensembles prevented EL. These findings reveal brain-wide hubs that support spatial memory and indicate that decay of this network connectivity is likely an essential facet of effective EL of spatial experience.