Physiological state gates acquisition and expression of mesolimbic reward prediction signals

Significance Associating environmental cues with their outcomes occurs through multiple strategies relying on different neural substrates. Unpredicted reward evokes dopamine release, which also develops to predictive cues, suggesting that predictive dopamine signals arise only after extensive pairings of cues with appetitive outcomes. However, recent work suggests that dopamine may also contribute to model-based learning, which does not require that cues and their appetitive outcomes be experienced in tandem. Taking advantage of the appetitive value of a hypertonic sodium solution, which radically and reversibly changes with physiological state, we show that dopamine differentially encodes hypertonic NaCl depending on sodium balance independent of prior experience. Conversely, dopamine only encoded a NaCl cue after extensive, state-dependent experience, firmly supporting dopamine’s role in experience-dependent learning. Phasic dopamine signaling participates in associative learning by reinforcing associations between outcomes (unconditioned stimulus; US) and their predictors (conditioned stimulus; CS). However, prior work has always engendered these associations with innately rewarding stimuli. Thus, whether dopamine neurons can acquire prediction signals in the absence of appetitive experience and update them when the value of the outcome changes remains unknown. Here, we used sodium depletion to reversibly manipulate the appetitive value of a hypertonic sodium solution while measuring phasic dopamine signaling in rat nucleus accumbens. Dopamine responses to the NaCl US following sodium depletion updated independent of prior experience. In contrast, prediction signals were only acquired through extensive experience with a US that had positive affective value. Once learned, dopamine prediction signals were flexibly expressed in a state-dependent manner. Our results reveal striking differences with respect to how physiological state shapes dopamine signals evoked by outcomes and their predictors.