{"doi":"10.20517/and.2025.26","title":"Subtype-specific roles of nigrostriatal dopaminergic neurons in motor and associative learning","abstract":"Aim: Define the subtype-specific contributions of nigrostriatal dopaminergic neurons (DANs) to motor and non-motor behaviors by comparing Calbindin 1-positive (Calb1<sup>+</sup>) and Aldehyde dehydrogenase 1a1-positive (Aldh1a1<sup>+</sup>) DANs. Methods: Intersectional genetic strategy and chemogenetic inhibition were applied to selectively silence Calb1<sup>+</sup> or Aldh1a1<sup>+</sup> DANs in mice. An adeno-associated viral vector (AAV-CreOn-FlpOn-hM4Di-P2A-mCherry) was stereotactically delivered into the substantia nigra pars compacta of double knock-in lines Th<sup>Flp</sup>; Calb1<sup>IRESCre</sup> or Th<sup>Flp</sup>; Aldh1a1<sup>CreERT2</sup>. Following expression, subtype-specific neuronal inhibition was induced with a designer receptor exclusively activated by designer drugs (DREADD) ligand, and the mice were assessed in assays of voluntary movement, motor skill learning, and early associative learning behavior. Results: Chemogenetic inhibition of either Calb1<sup>+</sup> or Aldh1a1<sup>+</sup> DANs produced a marked reduction in voluntary movement and impaired acquisition of motor skills, indicating that both subtypes are necessary for normal motor function and learning. In contrast, only inhibition of Calb1<sup>+</sup> DANs altered early associative-learning performance, revealing a dissociable, subtype-specific role for Calb1<sup>+</sup> neurons in reinforcement-related behavior that was not observed with Aldh1a1<sup>+</sup> neuron inhibition. Conclusion: Both Calb1<sup>+</sup> and Aldh1a1<sup>+</sup> nigrostriatal DANs are key regulators of movement and motor learning, with Calb1<sup>+</sup> neurons additionally modulating reward-based associative learning. These findings highlight the functional heterogeneity of nigrostriatal DAN subtypes and identify potential therapeutic targets for addressing motor and non-motor deficits in Parkinson’s disease.","journal":"Ageing and Neurodegenerative Diseases","year":2025,"id":581809,"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":0.9437,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1459277,"name":"Gavin Riccobono","orcid":null,"position":1,"is_corresponding":false},{"id":35911,"name":"Lulu Tian","orcid":"0000-0001-5820-0337","position":2,"is_corresponding":false},{"id":1351743,"name":"Disa Basu","orcid":null,"position":3,"is_corresponding":false},{"id":461659,"name":"Lixin Sun","orcid":"0000-0001-8203-0841","position":4,"is_corresponding":false},{"id":461661,"name":"Lisa Chang","orcid":"0009-0008-8879-9246","position":5,"is_corresponding":false},{"id":1367541,"name":"Victor M. Martinez Smith","orcid":null,"position":6,"is_corresponding":false},{"id":294249,"name":"Lupeng Wang","orcid":"0000-0002-3706-4564","position":7,"is_corresponding":false},{"id":397727,"name":"Weidong Le","orcid":"0000-0001-7459-2705","position":8,"is_corresponding":false},{"id":397726,"name":"Huaibin Cai","orcid":"0000-0002-8596-6108","position":9,"is_corresponding":false},{"id":1458852,"name":"Ahsan Habib","orcid":"0000-0001-9496-3681","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":null,"created_at":"2026-07-19T02:58:51.328454Z","pmid":"41541494","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":[]}