{"doi":"10.1101/2025.10.24.684445","title":"Interregional human assembloids recapitulate fetal brain morphologies and enhance neuronal complexity","abstract":"<jats:title>SUMMARY</jats:title>\n                <jats:p>Neuronal morphology governs how neurons connect, integrate, and process information, offering critical insights into the functional architecture of the brain. Characterizing the three-dimensional (3D) morphology of individual neurons is key not only for mapping circuit connectivity but also for understanding the cellular diversity that emerges during development. Neural organoids are valuable models of human brain development and disease, yet their morphological complexity remains poorly characterized despite advances in single-cell transcriptomics. Here, we use 3D confocal imaging and manual reconstruction of 735 neurons to analyze forebrain (dorsal and ventral) and thalamic (dorsal and ventral) organoids, as well as forebrain, thalamic, and corticothalamic assembloids. We find that organoids and assembloids exhibit distinct morphologies resembling fetal brain neurons, including immature pyramidal-like, double-bouquet, and bushy-like neurons. Interregional assembloids show greater neuronal morphological complexity than individual organoids, with more extensive dendritic branching, longer projections, and diverse soma shapes. Corticothalamic assembloids further display features of emerging connectivity. We observe dendritic spines with excitatory and inhibitory profiles and varicosities, indicative of maturing synaptic architecture. Together, our work makes an initial effort in describing the diversity of neuronal morphology in human neural organoids and assembloids. It further establishes structural phenotyping as a critical dimension for validating human neural models and underscores their value for modeling morphofunctional disorders.</jats:p>","journal":null,"year":null,"id":636694,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1652717,"name":"Maria Carolina Pedro Athié","orcid":"0000-0002-6649-9065","position":1,"is_corresponding":false},{"id":1652718,"name":"Ana Clara Caznok Silveira","orcid":"0009-0000-2637-7349","position":2,"is_corresponding":false},{"id":1652719,"name":"Josué Renner","orcid":"0000-0002-3605-7952","position":3,"is_corresponding":false},{"id":773362,"name":"Elayne Vieira Dias","orcid":"0000-0003-0567-8390","position":4,"is_corresponding":false},{"id":1652720,"name":"João Victor Ribeiro dos Santos","orcid":"0009-0000-6643-0327","position":5,"is_corresponding":false},{"id":1652721,"name":"Branka Hrvoj-Mihic","orcid":"0009-0005-4132-5666","position":6,"is_corresponding":false},{"id":1652723,"name":"Camila Canateli","orcid":"0000-0002-5482-4625","position":7,"is_corresponding":false},{"id":1652725,"name":"João Meidanis","orcid":"0000-0001-7878-4990","position":8,"is_corresponding":false},{"id":2997,"name":"Alysson R. Muotri","orcid":"0000-0003-0867-2875","position":9,"is_corresponding":false},{"id":1652726,"name":"Alberto Antônio Rasia-Filho","orcid":"0000-0003-4623-5916","position":10,"is_corresponding":false},{"id":852501,"name":"Simoni Helena Avansini","orcid":"0000-0002-2490-7438","position":11,"is_corresponding":false},{"id":1652716,"name":"André Saraiva Leão Marcelo Antunes","orcid":"0000-0002-0692-8948","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Interregional human assembloids recapitulate fetal brain morphologies and enhance neuronal complexity","abstract":"<jats:title>SUMMARY</jats:title>\n                <jats:p>Neuronal morphology governs how neurons connect, integrate, and process information, offering critical insights into the functional architecture of the brain. Characterizing the three-dimensional (3D) morphology of individual neurons is key not only for mapping circuit connectivity but also for understanding the cellular diversity that emerges during development. Neural organoids are valuable models of human brain development and disease, yet their morphological complexity remains poorly characterized despite advances in single-cell transcriptomics. Here, we use 3D confocal imaging and manual reconstruction of 735 neurons to analyze forebrain (dorsal and ventral) and thalamic (dorsal and ventral) organoids, as well as forebrain, thalamic, and corticothalamic assembloids. We find that organoids and assembloids exhibit distinct morphologies resembling fetal brain neurons, including immature pyramidal-like, double-bouquet, and bushy-like neurons. Interregional assembloids show greater neuronal morphological complexity than individual organoids, with more extensive dendritic branching, longer projections, and diverse soma shapes. Corticothalamic assembloids further display features of emerging connectivity. We observe dendritic spines with excitatory and inhibitory profiles and varicosities, indicative of maturing synaptic architecture. Together, our work makes an initial effort in describing the diversity of neuronal morphology in human neural organoids and assembloids. It further establishes structural phenotyping as a critical dimension for validating human neural models and underscores their value for modeling morphofunctional disorders.</jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41278870","pmcid":null,"openalex_id":"https://openalex.org/W4415542279","authors":[],"funders":[{"funder_name":"NIH","grant_id":"R01MH100175, R01NS123642, R01AG078959, R01107788, R01AG084030, R01MH127077, R01DA056908, and R01MH123828","title":null},{"funder_name":"DoD grant","grant_id":"W81XWH2110306","title":null},{"funder_name":"CNPq/Brazil fellowship","grant_id":"#314352/2020-1","title":null},{"funder_name":"FAPESP grant","grant_id":"2024/01200-8","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"R01 MH127077","title":null},{"funder_name":"NIDA NIH HHS","grant_id":"R01 DA056908","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"R01 MH123828","title":null},{"funder_name":"NIMH NIH HHS","grant_id":"R01 MH100175","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS123642","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG078959","title":null},{"funder_name":"NIA NIH HHS","grant_id":"RF1 AG084030","title":null},{"funder_name":"The International Brain Research Organization (IBRO)","grant_id":"","title":null}],"total_grants":12,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"green","license":"cc-by-nc-nd","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/10/25/2025.10.24.684445.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2025/10/25/2025.10.24.684445.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2025.10.24.684445","host_type":"publisher"},{"url":"https://doi.org/10.1101/2025.10.24.684445","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41278870","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12633276","host_type":"repository"}],"fields_of_study":["Fetal and Pediatric Neurological Disorders"],"mesh_terms":[],"keywords":["Soma","Dendritic spine","Forebrain","Human brain","Hippocampal formation","Biological neural network","Neuroplasticity","Basal forebrain","Dendrite (mathematics)","Neuron"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T17:33:06.590428Z","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":[]}