{"doi":"10.7554/elife.91136.2.sa1","title":"Reviewer #2 (Public Review): Functional Diversity of Dopamine Axons in Prefrontal Cortex During Classical Conditioning","abstract":"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.Two-photon calcium imaging revealed that many mesocortical dopamine axons show enhanced selectivity for aversive cue processing during classical conditioning.","journal":null,"year":2024,"id":496725,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1025694,"name":"Yuki Kambe","orcid":"0000-0003-1484-0628","position":1,"is_corresponding":false},{"id":1122393,"name":"Kei Majima","orcid":"0000-0002-2405-4113","position":2,"is_corresponding":false},{"id":1122394,"name":"Zijing Hu","orcid":"0009-0000-4367-4580","position":3,"is_corresponding":false},{"id":1122395,"name":"Makoto Ohtake","orcid":"0000-0003-1084-2482","position":4,"is_corresponding":false},{"id":1122396,"name":"Ali Momennezhad","orcid":"0000-0002-8046-4387","position":5,"is_corresponding":false},{"id":1122397,"name":"Hideki Izumi","orcid":"0000-0003-0080-7106","position":6,"is_corresponding":false},{"id":1122398,"name":"Takuma Tanaka","orcid":"0000-0003-1898-8064","position":7,"is_corresponding":false},{"id":1122850,"name":"Ashley Matunis","orcid":null,"position":8,"is_corresponding":false},{"id":1122851,"name":"Emma Stacy","orcid":null,"position":9,"is_corresponding":false},{"id":1122399,"name":"Takahide Itokazu","orcid":"0000-0003-2977-7190","position":10,"is_corresponding":false},{"id":1122400,"name":"Takashi Sato","orcid":"0000-0002-7623-9021","position":11,"is_corresponding":false},{"id":1122401,"name":"Tatsuo K. Sato","orcid":"0000-0002-1279-5125","position":12,"is_corresponding":false},{"id":1122392,"name":"Kenta Abe","orcid":"0000-0002-1634-7469","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:09:27.134858Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}