Connectomics, the comprehensive mapping of neural circuits at nanoscale resolution, has historically relied on electron microscopy (EM), both transmission (TEM) and scanning (SEM). However, as connectomics scales towards larger brain volumes and whole mammalian brains, substantial technical challenges emerge. Here, we highlight key challenges and advancing approaches that hold promise, particularly those that integrate three-dimensional, multi-resolution and time-resolved imaging to capture both long-range and local wiring, down to supramolecular resolution.
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Acknowledgements
We thank G. Park for figure illustrations; M. Ellisman, A. Pacureanu, J. Petrillo, Y. Zhang for comments on the piece and members of the Lee laboratory for helpful discussions; D. Zhou for providing the calcium imaging sample image; and W. Xiang and K. Delgado for providing the APEX labeling EM cutout.
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Harvard University has filed a patent application regarding GridTape (WO2017184621A1) on behalf of the inventors including W.-C.A.L., and negotiated licensing agreements with interested partners.
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Khajeh, R., Lee, WC.A. Connectomics beyond electron microscopy. Nat Methods 22, 2487–2489 (2025). https://doi.org/10.1038/s41592-025-02943-5
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DOI: https://doi.org/10.1038/s41592-025-02943-5
