Cocaine-context memories are transcriptionally encoded in nucleus accumbens Arc ensembles
- Marine Salery
- Arthur Godino
- Yu Qing Xu
- John F. Fullard
- Romain Durand-de Cuttoli
- Alexa R. LaBanca
- Leanne M. Holt
- Scott J. Russo
- Panos Roussos
- Eric J. Nestler
2025-07-02
Learned associations between the rewarding effects of drugs and the context in which they are experienced are critical for context-induced relapse. While context re-exposure triggers the recall of such drug-related associative memories it is unclear whether this relies on the reactivation of and plasticity in neuronal populations previously engaged in their acquisition. Here, using the immediate early gene Arc , we captured a discrete population of nucleus accumbens (NAc) cells activated during the encoding of cocaine-context memory in mice and showed that this neuronal ensemble is later reactivated upon context-induced recall. Furthermore, we show that ensembles recruited at early vs. late stages of memory encoding are largely distinct and contribute differentially to memory retrieval. Single nuclei RNA-sequencing of these ensembles identified plasticity-related transcriptional programs that segregate cocaine-recruited NAc engram-like cells beyond cell-type composition and revealed molecular features unique to distinct stages of memory processing. These findings suggest that activity-dependent transcription upon initial engram allocation further stamps cells for persistent plasticity programs and thereby supports memory traces at the single-cell level. This study also provides insights into the mechanisms supporting pathological memory formation associated with cocaine exposure.