Distinct cocaine- and shock-responsive ensembles in the nucleus accumbens

The nucleus accumbens (NAc) responds to both natural and non-natural rewards as well as aversive stimuli; however, it remains unclear how motivationally relevant rewarding and aversive experiences are represented within NAc neuronal ensembles. Here we used Fos-CreER T2 -based activity-dependent tagging to label NAc neuronal ensembles activated by a potent non-natural reward, cocaine, or by foot shock. We found that the cocaine ensemble consists predominantly of dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs), whereas the foot shock ensemble contains both D1- and D2-MSNs. One-photon calcium imaging in freely moving mice revealed that acute cocaine primarily excites D1-MSNs while inhibiting most D2-MSNs, whereas foot shock induced excitatory responses in both types of MSNs. Optogenetic reactivation of the cocaine-ensemble elicited a strong behavioral preference, whereas reactivation of the shock-ensemble produced only modest behavioral effect. Together, these findings indicate that rewarding and aversive experiences recruit partially overlapping NAc ensembles with distinct cellular composition, activity dynamics, and behavioral outcomes. While both stimuli engage shared neuronal populations, only reactivation of cocaine-responsive ensembles change behavioral preference and reinforcement, highlighting functional differences in how motivationally relevant experiences are represented within the NAc.