
Mesocortical dopamine axons show diverse preferences for rewarding and aversive stimuli, with a strong bias toward aversive processing. During classical conditioning, the selectivity for aversive cues is enhanced in aversive-preferring dopamine axons, but not in reward-preferring axons.


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Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.

Impact statement Two-photon calcium imaging revealed that many mesocortical dopamine axons show enhanced selectivity for aversive cue processing during classical conditioning.

### Competing Interest Statement

The authors have declared no competing interest.

Functional Diversity of Dopamine Axons in Prefrontal Cortex During Classical Conditioning

enhanced-selectivity-for-aversive-cues-in-dopamine-axons-projecting-to-the-medial-prefrontal-cortex-during-classical-conditioning


Enhanced Selectivity for Aversive Cues in Dopamine Axons Projecting to the Medial Prefrontal Cortex During Classical Conditioning
