MODULATION OF BRAIN-WIDE NETWORKS BY MEMORY ENSEMBLES TO SUPPORT RECALL

Learning to navigate environments and adapt behavior to changing contingencies relies on the activity of distributed neuronal ensembles. Although it is known that reactivation of memory-linked ensembles can promote recall, how ensemble activity shapes brain-wide network organization remains poorly understood.
Here, we used TetTag-hM3Dq transgenic mice to label neuronal ensembles active during recall of a well-consolidated spatial appetitive memory acquired in a T-maze task, to test whether their reactivation alters large-scale brain networks and behavioral flexibility. These ensembles were chemogenetically reactivated via intraperitoneal (i.p.) injections of deschloroclozapine during extinction learning and subsequently during resting-state 7-Tesla fMRI under isoflurane anesthesia. Immunohistochemistry was additionally used to quantify tagged cells across brain regions.
We found that recall of spatial appetitive memory recruits sparse neuronal populations whose reactivation sustains learned behavior, thereby impairing extinction learning. At the network level, ensemble reactivation induced marked reorganization, characterized by increased modular specialization while preserving global integration. Notably, the dorsal and ventral hippocampus showed enhanced network influence following memory ensemble reactivation, which correlated with task performance and resistance to extinction. Together, these findings demonstrate how sparse memory-linked neuronal ensembles can exert widespread effects on brain-wide network architecture and behavior.
Supported by the Deutsche Forschungsgemeinschaft (SFB 1280/A04, project number: 316803389).