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Nat Neurosci. 2018 Apr;21(4):625-637. doi: 10.1038/s41593-018-0109-1. Epub 2018 Mar 5.

A three-dimensional single-cell-resolution whole-brain atlas using CUBIC-X expansion microscopy and tissue clearing.

Author information

1
Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Tokyo, Japan.
3
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
4
Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, Osaka, Japan.
5
Department of Systems Science, School of Engineering Science, Osaka University, Osaka, Japan.
6
Department of Neurology, Graduate School of Medicine, Osaka University, Osaka, Japan.
7
Department of Kampo Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
8
Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
9
Laboratory for Cell-Free Protein Synthesis, RIKEN Quantitative Biology Center, Osaka, Japan.
10
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
11
Animal Resource Development Unit and Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, Japan.
12
Division of Cellular and Molecular Pharmacology, Nihon University School of Medicine, Tokyo, Japan.
13
Brain Research Institute, Niigata University, Niigata, Japan.
14
Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. uedah-tky@umin.ac.jp.
15
International Research Center for Neurointelligence (WPI-IRCN), UTIAS, The University of Tokyo, Tokyo, Japan. uedah-tky@umin.ac.jp.
16
Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, Osaka, Japan. uedah-tky@umin.ac.jp.

Abstract

A three-dimensional single-cell-resolution mammalian brain atlas will accelerate systems-level identification and analysis of cellular circuits underlying various brain functions. However, its construction requires efficient subcellular-resolution imaging throughout the entire brain. To address this challenge, we developed a fluorescent-protein-compatible, whole-organ clearing and homogeneous expansion protocol based on an aqueous chemical solution (CUBIC-X). The expanded, well-cleared brain enabled us to construct a point-based mouse brain atlas with single-cell annotation (CUBIC-Atlas). CUBIC-Atlas reflects inhomogeneous whole-brain development, revealing a significant decrease in the cerebral visual and somatosensory cortical areas during postnatal development. Probabilistic activity mapping of pharmacologically stimulated Arc-dVenus reporter mouse brains onto CUBIC-Atlas revealed the existence of distinct functional structures in the hippocampal dentate gyrus. CUBIC-Atlas is shareable by an open-source web-based viewer, providing a new platform for whole-brain cell profiling.

PMID:
29507408
DOI:
10.1038/s41593-018-0109-1

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