Novelty Influences Dopamine Responses to Conditioned and Unconditioned Aversive Stimuli over Extended Temporal Windows

Dopamine release in the nucleus accumbens is classically linked to associative learning, signaling relationships between predictive cues and outcomes. Yet, dopamine is also strongly modulated by novelty, a nonassociative factor that has received comparatively little attention. Here, we used optical dopamine sensors in awake, behaving male and female mice to define how novelty alters the temporal dynamics of dopamine release during aversive learning. We manipulated novelty in three ways: (1) omitting expected footshocks, (2) introducing novel neutral cues concurrently with shock-predictive stimuli, and (3) presenting novel stimuli in an unpaired fashion within a context. Across all conditions, manipulations robustly increased dopamine release and in some cases altered the directionality of cue-evoked dopamine responses. Notably, these effects extended beyond the immediate stimulus window, altering subsequent responses to both conditioned cues and footshocks. Together, these findings demonstrate that changes in the environment that extend beyond prediction-based learning can exert a powerful and sustained influence on dopamine signaling, reshaping how aversive cues and outcomes are represented in the brain.