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Expansion-Assisted Iterative-FISH defines lateral hypothalamus spatio-molecular organization

View ORCID ProfileYuhan Wang, Mark Eddison, View ORCID ProfileGreg Fleishman, View ORCID ProfileMartin Weigert, View ORCID ProfileShengjin Xu, View ORCID ProfileFredrick E. Henry, Tim Wang, View ORCID ProfileAndrew L. Lemire, Uwe Schmidt, Hui Yang, View ORCID ProfileKonrad Rokicki, View ORCID ProfileCristian Goina, Karel Svoboda, View ORCID ProfileEugene W. Myers, View ORCID ProfileStephan Saalfeld, View ORCID ProfileWyatt Korff, View ORCID ProfileScott M. Sternson, View ORCID ProfilePaul W. Tillberg
doi: https://doi.org/10.1101/2021.03.08.434304
Yuhan Wang
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Mark Eddison
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Greg Fleishman
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Martin Weigert
2Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany
3Institute of Bioengineering, School of Life Sciences, EPFL, Lausanne CH1015, Switzerland
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Shengjin Xu
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Fredrick E. Henry
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Tim Wang
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Andrew L. Lemire
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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  • ORCID record for Andrew L. Lemire
Uwe Schmidt
2Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany
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Hui Yang
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
4Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA
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Konrad Rokicki
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Cristian Goina
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Karel Svoboda
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Eugene W. Myers
2Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Saxony 01307, Germany
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  • ORCID record for Eugene W. Myers
Stephan Saalfeld
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Wyatt Korff
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Scott M. Sternson
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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  • For correspondence: sternsons@janelia.hhmi.org tillbergp@janelia.hhmi.org
Paul W. Tillberg
1Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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  • ORCID record for Paul W. Tillberg
  • For correspondence: sternsons@janelia.hhmi.org tillbergp@janelia.hhmi.org
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Abstract

Determining the spatial organization and morphological characteristics of molecularly defined cell types is a major bottleneck for characterizing the architecture underpinning brain function. We developed Expansion-Assisted Iterative Fluorescence In Situ Hybridization (EASI-FISH) to survey gene expression in brain tissue, as well as a turnkey computational pipeline to rapidly process large EASI-FISH image datasets. EASI-FISH was optimized for thick brain sections (300 µm) to facilitate reconstruction of spatio-molecular domains that generalize across brains. Using the EASI-FISH pipeline, we investigated the spatial distribution of dozens of molecularly defined cell types in the lateral hypothalamic area (LHA), a brain region with poorly defined anatomical organization. Mapping cell types in the LHA revealed nine novel spatially and molecularly defined subregions. EASI-FISH also facilitates iterative re-analysis of scRNA-Seq datasets to determine marker-genes that further dissociated spatial and morphological heterogeneity. The EASI-FISH pipeline democratizes mapping molecularly defined cell types, enabling discoveries about brain organization.

Highlights

  • - EASI-FISH enables robust gene expression profiling in thick brain slices

  • - A turnkey analysis pipeline for facile analysis of large EASI-FISH image datasets

  • - EASI-FISH reveals novel subregions of the lateral hypothalamus

  • - Identification of rare cell types based on morphological and spatial heterogeneity

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵5 These authors jointly supervised this work.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Expansion-Assisted Iterative-FISH defines lateral hypothalamus spatio-molecular organization
Yuhan Wang, Mark Eddison, Greg Fleishman, Martin Weigert, Shengjin Xu, Fredrick E. Henry, Tim Wang, Andrew L. Lemire, Uwe Schmidt, Hui Yang, Konrad Rokicki, Cristian Goina, Karel Svoboda, Eugene W. Myers, Stephan Saalfeld, Wyatt Korff, Scott M. Sternson, Paul W. Tillberg
bioRxiv 2021.03.08.434304; doi: https://doi.org/10.1101/2021.03.08.434304
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Expansion-Assisted Iterative-FISH defines lateral hypothalamus spatio-molecular organization
Yuhan Wang, Mark Eddison, Greg Fleishman, Martin Weigert, Shengjin Xu, Fredrick E. Henry, Tim Wang, Andrew L. Lemire, Uwe Schmidt, Hui Yang, Konrad Rokicki, Cristian Goina, Karel Svoboda, Eugene W. Myers, Stephan Saalfeld, Wyatt Korff, Scott M. Sternson, Paul W. Tillberg
bioRxiv 2021.03.08.434304; doi: https://doi.org/10.1101/2021.03.08.434304

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