Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

Alcohol-associated memories play an important role in relapse in alcohol use disorder. Disrupting these memories, which become labile upon retrieval, through interference with their reconsolidation process, could reduce relapse. Memories are thought to be encoded within specific patterns of sparsely distributed neurons, called neuronal ensembles. Here, we explored the role of neuronal ensembles in alcohol-memory reconsolidation and relapse and characterized their transcriptional signature. Upon retrieving alcohol-related memories, we observed increased neuronal activation in the nucleus accumbens (NAc). We established the causal role of these NAc ensembles in alcohol-memory reconsolidation using the Daun02 method with the Fos-LacZ transgenic rat, which expresses {beta}-galactosidase ({beta}-gal) under the Fos promoter, allowing the selective ablation of activated neurons. Selective inactivation of the active NAc neuronal ensemble produced a long-lasting attenuation of relapse. Through fluorescence-activated cell sorting (FACS) and RNA sequencing, we found a unique transcriptional fingerprint in activated Fos-positive neuronal ensembles in NAc following alcohol memory retrieval (vs. no retrieval controls) that was not present in the Fos-negative neurons. Our findings underscore the critical role of NAc neuronal ensembles in alcohol-associated memory reconsolidation. These neurons have a unique transcriptional profile that can provide novel targets for reducing alcohol relapse.