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Light microscopy based approach for mapping connectivity with molecular specificity

Author

Listed:
  • Fred Y. Shen

    (University of Michigan
    University of Michigan)

  • Margaret M. Harrington

    (University of Michigan)

  • Logan A. Walker

    (University of Michigan)

  • Hon Pong Jimmy Cheng

    (University of Michigan)

  • Edward S. Boyden

    (Massachusetts Institute of Technology
    Howard Hughes Medical Institute)

  • Dawen Cai

    (University of Michigan
    University of Michigan
    University of Michigan)

Abstract

Mapping neuroanatomy is a foundational goal towards understanding brain function. Electron microscopy (EM) has been the gold standard for connectivity analysis because nanoscale resolution is necessary to unambiguously resolve synapses. However, molecular information that specifies cell types is often lost in EM reconstructions. To address this, we devise a light microscopy approach for connectivity analysis of defined cell types called spectral connectomics. We combine multicolor labeling (Brainbow) of neurons with multi-round immunostaining Expansion Microscopy (miriEx) to simultaneously interrogate morphology, molecular markers, and connectivity in the same brain section. We apply this strategy to directly link inhibitory neuron cell types with their morphologies. Furthermore, we show that correlative Brainbow and endogenous synaptic machinery immunostaining can define putative synaptic connections between neurons, as well as map putative inhibitory and excitatory inputs. We envision that spectral connectomics can be applied routinely in neurobiology labs to gain insights into normal and pathophysiological neuroanatomy.

Suggested Citation

  • Fred Y. Shen & Margaret M. Harrington & Logan A. Walker & Hon Pong Jimmy Cheng & Edward S. Boyden & Dawen Cai, 2020. "Light microscopy based approach for mapping connectivity with molecular specificity," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18422-8
    DOI: 10.1038/s41467-020-18422-8
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    Cited by:

    1. Jinyoung Kang & Margaret E. Schroeder & Youngmi Lee & Chaitanya Kapoor & Eunah Yu & Tyler B. Tarr & Kat Titterton & Menglong Zeng & Demian Park & Emily Niederst & Donglai Wei & Guoping Feng & Edward S, 2024. "Multiplexed expansion revealing for imaging multiprotein nanostructures in healthy and diseased brain," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. François G. C. Blot & Joshua J. White & Amy van Hattem & Licia Scotti & Vaishnavi Balaji & Youri Adolfs & R. Jeroen Pasterkamp & Chris I. De Zeeuw & Martijn Schonewille, 2023. "Purkinje cell microzones mediate distinct kinematics of a single movement," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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