1164 Stable Ensembles in the Nucleus Accumbens Differentially Encode Cocaine Reward Versus Natural Rewards

INTRODUCTION: The nucleus accumbens (NAc) plays an integral role in natural and drug reward seeking, and represents a potential target for intervention in treatment-resistant substance use disorder (SUD). It remains unclear if similar neurobiological mechanisms in the NAc underlie drug and natural rewards. METHODS: We recorded single-cell activity of D1-MSNs of NAc using miniscope imaging in freely-behaving mice, trained to self-administer cocaine or sucrose in an operant box for 12 days. Mice were placed into forced abstinence for 7 days, before testing for unrewarded seeking behavior, as a model for relapse. Single-cell neuronal activity was temporally time-locked to seeking activity. Spatial maps of recorded neurons were used to track the same neuron across mutliple days to monitor stability. Support Vector Machine models were used to decode seeking behavior. RESULTS: D1-MSNs showed heterogenous activity associated with seeking of either reward. Activity was clustered into: excited, inhibited, and neutral ensembles. Ensemble sizes were similar between both groups. The stability of cocaine/sucrose ensembles was asssessed within/across sessions. Sucrose encoding within excited D1-MSNs was dynamic, as different sessions/trials involved the activation of a different subset of neurons, while cocaine encoding within was stable, where 25-50% of neurons remain stable across the session. Excited D1-MSNs accurately decoded cocaine and sucrose seeking activity during rewarded self-administration sessions. However, excited D1-MSNs uniquely decoded cocaine seeking activity during unrewarded relapse sessions. Cocaine-associated ensembles retained the same encoding information between self-administration and relapse session, as tracked neurons were sufficient to decode seeking activity after 7 days of abstinence. CONCLUSIONS: A stable excitory D1-MSN ensemble uniquely encodes cocaine seeking and may contribute to why drug seeking is prepotent over natural reward seeking in SUD.