SeeThrough: a rationally designed skull clearing technique for in vivo brain imaging

Xinyi Liu, Motokazu Uchigashima, Ikumi Oomoto, Yoshihito Saito, Hitoshi Uchida, Shinya Oginezawa, Keiko Masuda, Daisuke Satoh, Manabu Abe, Kenji Sakimura, Yoshihiro Shimizu, Masanori Murayama (), Kazuki Tainaka () and Takayasu Mikuni ()
Additional contact information
Xinyi Liu: Niigata University
Motokazu Uchigashima: Niigata University
Ikumi Oomoto: Wako
Yoshihito Saito: Wako
Hitoshi Uchida: Niigata University
Shinya Oginezawa: Niigata University
Keiko Masuda: Kobe
Daisuke Satoh: Niigata University
Manabu Abe: Niigata University
Kenji Sakimura: Niigata University
Yoshihiro Shimizu: Kobe
Masanori Murayama: Wako
Kazuki Tainaka: Niigata University
Takayasu Mikuni: Niigata University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Light scattering in the skull limits optical access to the brain. Here we present SeeThrough, a skull-clearing technique that enables simple, high-resolution, and minimally-invasive brain imaging without skull removal. Through systematic screening of over 1600 chemicals, we rationally developed a refractive index-matching solution that combines water- and organic solvent-based components, achieving both high clearing efficiency and biocompatibility. The reagents exhibit minimal brain penetration, maintain tissue integrity, and avoid inflammatory responses. Notably, SeeThrough provides imaging sensitivity and contrast comparable to open-skull window imaging, while permitting minimally-invasive monitoring of brain border macrophages as well as blood and cerebrospinal fluid dynamics. Combined with two-photon imaging, SeeThrough enables spatially and temporally scalable imaging applications in the mouse brain, including ~400 µm deep imaging, one-month longitudinal imaging, and mesoscale, cellular-resolution monitoring of brain activity for network-level analysis. Thus, SeeThrough offers a broadly accessible platform for high-throughput, physiology-preserving imaging of the brain parenchyma and brain-skull interface.

Date: 2025
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DOI: 10.1038/s41467-025-62836-1

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