Dopamine neurons are thought to facilitate learning by comparing actual and expected reward1,2. Despite two decades of investigation, little is known about how this comparison is made. To determine how dopamine neurons calculate prediction error, we combined optogenetic manipulations with extracellular recordings in the ventral tegmental area (VTA) while mice engaged in classical conditioning. By manipulating the temporal expectation of reward, we demonstrate that dopamine neurons perform subtraction, a computation that is ideal for reinforcement learning but rarely observed in the brain. Furthermore, selectively exciting and inhibiting neighbouring GABA neurons in the VTA reveals that these neurons are a source of subtraction: they inhibit dopamine neurons when reward is expected, causally contributing to prediction error calculations. Finally, bilaterally stimulating VTA GABA neurons dramatically reduces anticipatory licking to conditioned odours, consistent with an important role for these neurons in reinforcement learning. Together, our results uncover the arithmetic and local circuitry underlying dopamine prediction errors.

In odorant-rich environments, animals must be able to detect specific odorants of interest against variable backgrounds. However, several studies have suggested that both humans and rodents are very poor at analyzing the components of odorant mixtures, leading to the idea that olfaction is a synthetic sense in which mixtures are perceived holistically. We have developed a behavioral task to directly measure the ability of mice to perceive mixture components and found that mice can be easily trained to detect target odorants embedded in unpredictable and variable mixtures. We imaged the responses of olfactory bulb glomeruli to the individual odors used in the task in mice expressing the Ca++ indicator GCaMP3 in olfactory receptor neurons. By relating behavioral performance to the glomerular response patterns, we found that the difficulty of segregating the target from the background was strongly dependent on the extent of overlap between the representations of the target and the background odors by olfactory receptors. Our study indicates that the olfactory system has powerful analytic abilities that are constrained by the limits of combinatorial neural representation of odorants at the level of the olfactory receptors.

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