Distributed neuronal ensembles support episodic-like memory retrieval

Memory is proposed to depend on neuronal ensembles distributed across multiple brain regions, yet how episodic-like memories are organized across the brain remains unclear. Here we investigated the brain-wide organization of object-place-context (OPC) memory in mice. By mapping c-Fos activation across the brain during memory recall and comparing it to multiple control conditions, we identified a set of brain regions selectively engaged during episodic-like memory retrieval, consistent with the recruitment of a fronto-posterior medial network. Chemogenetic manipulation of learning-activated neuronal ensembles revealed that the selected brain regions are necessary for memory retrieval. Within this network, the retrosplenial cortex emerged as a key region required for successful memory recall, with neuronal ensembles exhibiting properties of engram cells. Electrophysiological recordings during recall revealed distinct novelty-related dynamics across regions. In mPFC, theta power increased during novel exploration, while firing rate increased both immediately before and during interaction with the novel object configuration. In RSP, novelty was associated with a sharp increase in firing rate during exploration. Together, our findings suggest a distributed organization supporting episodic-like memory retrieval in mice, in which a posterior-medial network is activated and necessary for a successful behavioral expression.