Nigrostriatal Dopamine Encodes Action–Outcome Prediction Errors

Hollon NG, Williams EW, Howard CD, Li H, Traut TI, Jin X. Nigrostriatal dopamine signals sequence-specific action-outcome prediction errors. Curr Biol 2021;31(23):5350-5363.e5. doi: 10.1016/j.cub.2021.09.040.

Background: Dopamine neurons are thought to encode prediction errors during Pavlovian learning by signaling mismatches between expected and received rewards. However, whether dopamine similarly signals discrepancies in action-outcome associations during self-initiated, goal-directed behavior has been unclear. Understanding how dopamine encodes action-outcome prediction errors is essential for linking reinforcement learning theories to the neural mechanisms of instrumental behavior.

Hypothesis: This study tested the hypothesis that nigrostriatal dopamine signals sequence-specific prediction errors for action-outcome associations, such that dopamine activity would be suppressed when a reward is the expected result of a learned action or action sequence.

Methods: The authors trained mice expressing channelrhodopsin in dopamine neurons to perform lever-pressing tasks for optogenetic intracranial self-stimulation (opto-ICSS) while recording subsecond dopamine release with fast-scan cyclic voltammetry and fiber photometry (FP3002). They compared dopamine responses during self-initiated stimulation and temporally matched passive playback sessions. Additional tests included omission, delay and magnitude probe trials, as well as a left-right lever-press sequence task to assess hierarchical control of learned actions.

Results: Dopamine release was markedly lower when stimulation resulted from the mouse’s own action than when delivered noncontingently. Omission of expected outcomes produced transient dopamine dips below baseline, consistent with negative prediction errors. These effects were action-specific, temporally restricted to the expected outcome and extended to learned action sequences, showing suppression only for reinforced sequences and not for other movements.

Conclusions: Nigrostriatal dopamine encodes action-outcome prediction errors that are specific to learned actions and sequences. This hierarchical and temporally precise modulation suggests dopamine contributes to goal-directed learning and behavioral control.