{"doi":"10.1038/s41592-024-02275-w","title":"Large-scale deep tissue voltage imaging with targeted-illumination confocal microscopy","abstract":"Voltage imaging with cellular specificity has been made possible by advances in genetically encoded voltage indicators. However, the kilohertz rates required for voltage imaging lead to weak signals. Moreover, out-of-focus fluorescence and tissue scattering produce background that both undermines the signal-to-noise ratio and induces crosstalk between cells, making reliable in vivo imaging in densely labeled tissue highly challenging. We describe a microscope that combines the distinct advantages of targeted illumination and confocal gating while also maximizing signal detection efficiency. The resulting benefits in signal-to-noise ratio and crosstalk reduction are quantified experimentally and theoretically. Our microscope provides a versatile solution for enabling high-fidelity in vivo voltage imaging at large scales and penetration depths, which we demonstrate across a wide range of imaging conditions and different genetically encoded voltage indicator classes. In targeted-illumination confocal microscopy, the combination of targeted illumination with confocal detection allows one-photon voltage imaging across large fields of view with a high signal-to-noise ratio.","journal":"Nature Methods","year":2024,"id":420660,"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":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"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":1162579,"name":"W. J. Cunningham","orcid":"0000-0002-0936-5642","position":1,"is_corresponding":false},{"id":288328,"name":"Krishnakanth Kondabolu","orcid":"0000-0002-9453-1499","position":2,"is_corresponding":false},{"id":289745,"name":"Eric Lowet","orcid":"0000-0002-9793-0639","position":3,"is_corresponding":false},{"id":813479,"name":"Maria V. Moya","orcid":"0000-0003-2310-1990","position":4,"is_corresponding":false},{"id":334830,"name":"Rebecca A. Mount","orcid":"0000-0002-8962-1641","position":5,"is_corresponding":false},{"id":1000495,"name":"Cara Ravasio","orcid":"0009-0005-6412-5755","position":6,"is_corresponding":false},{"id":714256,"name":"Emma Bortz","orcid":"0000-0001-7442-8825","position":7,"is_corresponding":false},{"id":1175255,"name":"Dana Shaw","orcid":"0000-0003-1828-9191","position":8,"is_corresponding":false},{"id":660080,"name":"Michael N. Economo","orcid":"0000-0001-9893-1505","position":9,"is_corresponding":false},{"id":261782,"name":"Xue Han","orcid":"0000-0003-3896-4609","position":10,"is_corresponding":false},{"id":317889,"name":"Jérôme Mertz","orcid":"0000-0002-6343-9155","position":11,"is_corresponding":false},{"id":317888,"name":"Sheng Xiao","orcid":"0000-0001-8959-2388","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T01:57:31.041511Z","pmid":"38840033","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":[]}