Dopamine (DA) neurons are thought to facilitate learning by signaling reward prediction errors (RPEs), the discrepancy between actual and expected reward. However, how RPEs are calculated remains unknown. It has been hypothesized that DA neurons receive RPE signals from the lateral habenula. Here, we tested how lesions of the habenular complex affect the response of optogenetically identified DA neurons in mice. We found that lesions impaired specific aspects of RPE signaling in DA neurons. The inhibitory responses caused by reward omission were greatly diminished while inhibitory responses to aversive stimuli, such as air puff-predictive cues or air puff, remained unimpaired. Furthermore, we found that after habenula lesions, DA neurons' ability to signal graded levels of positive RPEs became unreliable, yet significant excitatory responses still remained. These results demonstrate that the habenula plays a critical role in DA RPE signaling but suggest that it is not the exclusive source of RPE signals.
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