Nucleus accumbens medial shell D1 and D2 medium spiny neurons signal the valence of conditioned stimuli in a sex-dependent manner.

Assigning valence to stimuli supports survival by promoting approach of stimuli associated with beneficial outcomes and avoidance of those associated with noxious outcomes, a process dysregulated in many psychiatric disorders. The nucleus accumbens (NAc) uses valence information to guide appropriate behavioral responses. NAc medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors have long been thought to play opponent roles in valence processing, although this has been challenged by recent work. To test this, we used fiber photometry Ca2+ imaging to record from D1 and D2 MSNs in the NAc medial shell during a mixed-valence conditioning procedure in which distinct cues were paired with either foot-shock (CSS), food reward (CSR), or no outcome (CS-). We find that the reinforced cues elicit bidirectional responses in both D1 and D2 MSNs, with CSS increasing activity and CSR decreasing activity, although only in female mice, suggesting that both cell types may encode the valence of conditioned stimuli in a sex-biased manner. By contrast, unconditioned stimuli (i.e. foot-shock, chocolate milk) increase activity in both D1 and D2 MSNs, with responses scaling to stimulus magnitude regardless of valence or sex, suggesting salience encoding. Additionally, unsignaled outcomes elicit greater responses than signaled outcomes in D2, but not D1 MSNs, suggesting that D2 MSN activity is sensitive to prediction error. Overall, our findings confirm limited functional opposition between NAc D1 and D2 MSNs in valence processing, and highlight the importance of considering sex and examining appetitive and aversive processing together.