The hippocampus and neocortical inhibitory engrams protect against memory interference

Abstract Our experiences often overlap with each other, sharing features, stimuli or higher-order information. But despite this overlap, we are able to selectively recall individual memories to guide our decisions and future actions. The neural mechanisms that support such precise memory recall, however, remain unclear. Here, using ultra-high field 7T MRI we reveal two distinct mechanisms that protect memories from interference. The first mechanism involves the hippocampus, where the BOLD signal predicts behavioural measures of memory interference, and contextual representations that aid separation of overlapping memories are organised using a relational code. The second mechanism involves neocortical inhibition: when we reduce the concentration of neocortical GABA using trans-cranial direct current stimulation (tDCS) neocortical memory interference increases in proportion to the reduction in GABA, which in turn predicts behavioural performance. Together these findings suggest that memory interference is mediated by both the hippocampus and neocortex, where the hippocampus aids separation of memories by coding context-dependent relational information, while neocortical inhibition prevents unwanted co-activation between overlapping memories.