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Whole-neuron morphology and genetic identity define cell types and reveal principles of brain-wide connectivity

Year: 2026
Type: article
Abstract: Neocortex contains diverse excitatory neurons whose dendritic and axonal architectures shape computation and long-range communication, yet a unified framework linking neuronal structure, molecular identity, and brain-wide connectivity is lacking. Here, we combine complete whole-neuron morphology (WNM) reconstructions with paired genetic identities across 15 mouse cortical areas to define organizing principles of cortical wiring at single-cell resolution. We identify 10 stable excitatory cell types with conserved morphology and predominant genetic correspondence. Their full axonal target spectra reveal four output architectures and cell-type-resolved principles of corticocortical and cortico-subcortical organization, including modular convergence in downstream targets, distinct spatial topographical rules across corticocortical and corticofugal pathways, and hierarchical organization better predicted by targeting probability and projection distribution than projection strength, while refining bulk-derived projectomes by resolving artifacts from bulk approaches. Together, these findings establish WNM as a principled axis for defining cortical cell types as building blocks of large-scale connectomes.
Source: Cell Reports
DOI: 10.1016/j.celrep.2026.117469
Authors: Yun Wang, Hsien-Chi Kuo, Xiuli Kuang, Shenqin Yao, Phil Lesnar, Lydia Ng, Yaoyao Li, Laila El-Hifnawi, Natalie Chen, Kasey Zhang, Eric M. Li, Yoav Ben-Simon, Song-Lin Ding, Quanxin Wang, Totte Karlsson, Rachel Dalley, Grace Williams, Wei Xiong, Chao Chen, Kai Chen, Zili Huang, Zhi-Feng Yu, Wen-Jie Xu, Leila Ahmadinia, Sarah Walling-Bell, Julia Andrade, Olga Gliko, Matt Mallory, Colin Farrel, Ben Sutton, Kelly Jin, Zizhen Yao, Carliana Halterman, Kara Ronellenfitch, Luke Esposito, Susan Sunkin, Lauren Kruse, Qingming Luo, Hui Gong, Anan Li, Xiangning Li, Jia Qu, Hannah Choi, Stefan Mihalas, Jun Zhuang, Staci Sorensen
Institutions: Allen Institute for Brain Science, Wenzhou Medical University, Affiliated Eye Hospital of Wenzhou Medical College, Georgia Institute of Technology, Hainan University, Jiangsu Industry Technology Research Institute
Language: English
Open Access status: gold
Estimated APC paid: $5,620
Funders: Wenzhou Medical University, Allen Institute, National Institute of Mental Health and Neurosciences, École Polytechnique Fédérale de Lausanne, National Natural Science Foundation of China, National Institutes of Health, National Institute of Mental Health
OpenAlex ID: W7164946090
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Cites: 81
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Related to: 10