Abstract
Adaptive decision-making depends on the formation of novel memories. In Drosophila, the mushroom body (MB) is the site of associative olfactory long-term memory (LTM) storage. However, due to the sparse and stochastic representation of olfactory information in Kenyon cells (KCs), genetic access to individual LTMs remains elusive. Here, we develop a cAMP response element (CRE)-activity-dependent memory engram label (CAMEL) tool that genetically tags KCs responding to the conditioned stimulus (CS). CAMEL activity depends on protein-synthesis-dependent aversive LTM conditioning and reflects the time course of CRE binding protein 2 (CREB2) activity during natural memory formation. We demonstrate that inhibition of LTM-induced CAMEL neurons reduces memory expression and that artificial optogenetic reactivation is sufficient to evoke aversive behavior phenocopying memory recall. Together, our data are consistent with CAMEL neurons marking a subset of engram KCs encoding individual memories. This study provides new insights into memory circuitry organization and an entry point towards cellular and molecular understanding of LTM storage.