Biol Psychiatry. 2024 Jun 18:S0006-3223(24)01388-X. doi: 10.1016/j.biopsych.2024.06.008. Online ahead of print.

ABSTRACT

BACKGROUND: Substance use disorder (SUD) is characterized by long-lasting changes in reward-related brain regions, such as the nucleus accumbens (NAc). Previous work has shown that cocaine exposure induces plasticity in broad, genetically-defined cell types in the NAc; however, in response to a stimulus, only a small percent of neurons are transcriptionally active – termed an ensemble. Here, we identify an Arc-expressing neuronal ensemble that has a unique trajectory of recruitment and causally controls drug self-administration after repeated, but not acute, cocaine exposure.

METHOD: Using Arc-CreER^T2 transgenic mice, we expressed transgenes in Arc+ ensembles activated by cocaine exposure [either acute (1 x 10mg/kg IP), or repeated (10 x 10mg/kg IP)]. Using genetic, optical, and physiological recording and manipulation strategies, we assessed the contribution of these ensembles to behaviors associated with SUD.

RESULTS: Repeated cocaine exposure reduced the size of the ensemble, while simultaneously increasing its control over behavior. Neurons within the repeated cocaine ensemble were hyperexcitable and their optogenetic excitation was sufficient for reinforcement. Finally, lesioning the repeated cocaine, but not acute cocaine, ensemble blunted cocaine self-administration. Thus, repeated cocaine exposure reduced the size of the ensemble while simultaneously increasing its contributions to drug reinforcement.

CONCLUSIONS: We show that repeated, but not acute, cocaine exposure induces a physiologically distinct ensemble characterized by the expression of the immediate early gene Arc, that is uniquely capable of modulating reinforcement behavior.

PMID:38901723 | DOI:10.1016/j.biopsych.2024.06.008