Generative replay across hippocampal-neocortical circuits

To make flexible decisions, the brain needs to make inferences between events that were not directly experienced together. In sharp-wave ripple (SWR) events, during periods of rest and sleep, spiking activity in the hippocampus appears to support this process, by co-activating mnemonic representations of discrete cues and events that have not been experienced together. However, it remains unclear whether this 'generative replay' also occurs in other brain regions to update beliefs across the brain. To address this question, here we use multi-unit electrophysiology and calcium imaging in freely moving mice during a multi-day inference task. We show evidence for a putative anatomical pathway from the dorsal CA1 (dCA1) region of the hippocampus to primary visual cortex (V1), via the granular Retrosplenial Cortex (RSCg). We then characterise the neuronal activity across this pathway during an inference task and in subsequent periods of sleep. We show that during inference, mnemonic activity in V1 mirrors that observed in dCA1 to represent learned associations. In sleep, we show evidence for generative replay in V1, where co-activity can be observed between cells representing inferred relationships between cues that have not been directly experienced together. This activity in V1 is predicted by activity in dCA1, suggesting that the hippocampus coordinates generative replay across neocortical circuits. This coordinated generative replay may underpin the formation of a hierarchical generative model capable of predicting future scenarios that extend beyond direct experience.