Mesoscale volumetric fluorescence imaging at nanoscale resolution by photochemical sectioning

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-10-16 DOI:10.1126/science.adr9109

Wei Wang, Xiongtao Ruan, Gaoxiang Liu, Daniel E. Milkie, Wenping Li, Eric Betzig, Srigokul Upadhyayula, Ruixuan Gao

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Abstract

Optical nanoscopy of intact biological specimens has been transformed by recent advancements in hydrogel-based tissue clearing and expansion, enabling the imaging of cellular and subcellular structures with molecular contrast. However, existing high-resolution fluorescence microscopes are physically limited by objective-to-specimen distance, which prevents the study of whole-mount specimens without physical sectioning. To address this challenge, we developed a photochemical strategy for spatially precise sectioning of specimens. By combining serial photochemical sectioning with lattice light-sheet imaging and petabyte-scale computation, we imaged and reconstructed axons and myelin sheaths across entire mouse olfactory bulbs at nanoscale resolution. An olfactory bulb–wide analysis of myelinated and unmyelinated axons revealed distinctive patterns of axon degeneration and de-/dysmyelination in the neurodegenerative brain, highlighting the potential for peta- to exabyte-scale super-resolution studies using this approach.

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光化学切片的纳米分辨率中尺度体积荧光成像

近年来，基于水凝胶的组织清除和扩张技术的进步改变了完整生物标本的光学纳米显微镜，使细胞和亚细胞结构的成像与分子对比成为可能。然而，现有的高分辨率荧光显微镜受到物镜到标本距离的物理限制，这阻碍了不进行物理切片的整片标本的研究。为了应对这一挑战，我们开发了一种光化学策略，用于对标本进行空间精确切片。通过将连续光化学切片与点阵光片成像和pb级计算相结合，我们以纳米级分辨率对整个小鼠嗅球的轴突和髓鞘进行了成像和重建。对有髓鞘和无髓鞘轴突的嗅球分析揭示了神经退行性脑中轴突变性和去髓鞘/髓鞘异常的独特模式，强调了使用这种方法进行peta到eb级超分辨率研究的潜力。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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