Dissociable neuronal substrates for positive and negative valence stimuli in the nucleus accumbens

The nucleus accumbens (NAc) responds to both natural and artificial rewards and to aversive stimuli; however, it remains unclear whether these opposing valence signals engage distinct neuronal ensembles. Here we used Fos-CreERT2-based activity-dependent tagging to label NAc neuronal ensembles activated by cocaine or foot shock. We found that cocaine ensemble consisted predominantly of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs), whereas foot shock ensemble similarly recruited D1- and D2-MSNs. One-photon calcium imaging in freely moving mice revealed that acute cocaine primarily excited D1-MSNs while inhibiting the majority of D2-MSNs, whereas foot shock induced excitatory responses in both types of MSNs. Optogenetic reactivation of the cocaine-ensemble elicited a strong behavioural preference, whereas reactivation of the shock-ensemble produced no significant behavioural effect. Together, these findings demonstrate that cocaine recruits a functionally specific NAc ensemble distinct from that recruited by shock, providing mechanistic insight into the valence-specific neuronal substrates underlying reward and aversion processing.