Synergy of Distinct Dopamine Projection Populations in Behavioral Reinforcement

Dopamine neurons of the ventral tegmental area (VTA) regulate reward association and motivation. It remains unclear whether there are distinct dopamine populations to mediate these functions. Using mouse genetics, we isolated two populations of dopamine-producing VTA neurons with divergent projections to the nucleus accumbens (NAc) core and shell. Inhibition of VTA-core-projecting neurons disrupted Pavlovian reward learning, and activation of these cells promoted the acquisition of an instrumental response. VTA-shell-projecting neurons did not regulate Pavlovian reward learning and could not facilitate acquisition of an instrumental response, but their activation could drive robust responding in a previously learned instrumental task. Both populations are activated simultaneously by cues, actions, and rewards, and this co-activation is required for robust reinforcement of behavior. Thus, there are functionally distinct dopamine populations in the VTA for promoting motivation and reward association, which operate on the same timescale to optimize behavioral reinforcement. •Genetic isolation of projection-specific VTA neurons•Differential role of VTA neurons in reward association and motivation•Synergistic action of specialized VTA dopamine neurons for behavioral reinforcement Heymann et al. genetically isolate dopamine-producing neurons of the ventral tegmental area with differential projections to the nucleus accumbens core and shell. They demonstrate that these projection-specific populations contribute distinctly to reward association and motivation and work cooperatively to optimize behavioral reinforcement.