Spontaneous recovery of reward memory through active forgetting of extinction memory

Learned behavior can be suppressed by the extinction procedure. Such extinguished memory often returns spontaneously over time, making it difficult to treat diseases such as addiction. However, the biological mechanisms underlying such spontaneous recovery remain unclear. Here, we report that the extinguished reward memory in Drosophila recovers spontaneously because extinction training forms an aversive memory that can be actively forgotten via the Rac1/Dia pathway. Manipulating Rac1 activity does not affect sugar-reward memory and its immediate extinction effect but bidirectionally regulates spontaneous recovery-the decay process of extinction. Experiments using thermogenetic inhibition and functional imaging support that such extinction appears to be coded as an aversive experience. Genetic and pharmacological inhibition of formin Dia, a downstream effector of Rac1, specifically prevents spontaneous recovery after extinction in both behavioral performance and corresponding physiological traces. Together, our data suggest that spontaneous recovery is caused by active forgetting of the opposing extinction memory.