Aberrant dopaminergic activity during consolidation causes age-related memory generalization in Drosophila

Overactivation of memory networks and pathways can induce post-traumatic stress disorders and memory generalization, where memories are recalled in inappropriate situations. Here, we demonstrate that age-related defects in long-term memories in Drosophila are also caused by memory generalization. Aversive memory engram cells are formed in both young and old flies trained in an odor avoidance task. However, while engrams in young flies are activated specifically by odors previously paired with electrical shocks, engrams in old flies are activated by shock-paired, unpaired, and novel odors. This enhancement of engram cell activation occurs because of increased activity of dopaminergic neurons during memory consolidation in old flies. Increased dopamine signaling results from an inability of old flies to inhibit glutamatergic activation and leads to increased activation of dopamine D2 receptors on engram cells. Our data suggest that increased dopaminergic activity after training generalizes the responsiveness of engram cells to disrupt appropriate memory recall.