Abstract
To adapt behavior in changing environments, animals must continuously re-evaluate previously learned associations. This flexibility of memory systems has been identified as a promising strategy to target maladaptive memories. Here, we show that re-exposure to an unconditioned stimulus (US) alone, a sugar reward, can re-evaluate appetitive memories in Drosophila melanogaster. Using olfactory conditioning, we demonstrate that unpaired US exposure after memory formation reduces conditioned responses to multiple odor-reward associations. This reduction is specific to the re-exposure of the trained US and does not result from an altered motivational state or generalized behavioral suppression. Importantly, this US-induced memory devaluation engages mechanisms distinct from dopamine-driven modulation of memory accessibility, indicating a separate process of memory re-evaluation. Moreover, we find that sugar re-exposure diminishes both short- and long-term memory phases and can act on consolidated memories, suggesting broad temporal applicability. Notably, this devaluation does not change the reward-memory trace in specific mushroom body output neurons, implying that the underlying memory trace remains intact despite behavioral suppression. Our findings reveal a mechanism by which reward re-experience pervasively devalues associated memories, offering a potential approach to target multiple memories without requiring re-exposure to individual cues. This work provides insight into how experience can broadly reshape memory networks and may inform future approaches for persistent memory modification.
