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Light microscopy based approach for mapping connectivity with molecular specificity

Fred Y. Shen, Margaret M. Harrington, View ORCID ProfileLogan A. Walker, Hon Pong Jimmy Cheng, View ORCID ProfileEdward S. Boyden, View ORCID ProfileDawen Cai
doi: https://doi.org/10.1101/2020.02.24.963538
Fred Y. Shen
1Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA
2Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA
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Margaret M. Harrington
3Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
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Logan A. Walker
4LS&A, Program in Biophysics, University of Michigan, Ann Arbor, Michigan, USA
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Hon Pong Jimmy Cheng
3Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
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Edward S. Boyden
5McGovern Institute, Media Lab, Department of Biological Engineering, and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Dawen Cai
2Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA
3Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
4LS&A, Program in Biophysics, University of Michigan, Ann Arbor, Michigan, USA
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  • For correspondence: dwcai@umich.edu
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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 chemical and electrical synapses. However, molecular information that specifies cell types is often lost in EM reconstructions. To address this, we devised a light microscopy approach for connectivity analysis of defined cell types called spectral connectomics. We combined multicolor genetic labeling (Brainbow) of neurons with a multi-round immunostaining Expansion Microscopy (miriEx) strategy to simultaneously interrogate morphology, molecular markers, and connectivity in the same brain section. We applied our multimodal profiling strategy to directly link inhibitory neuron cell types with their network morphologies. Furthermore, we showed that correlative Brainbow and endogenous synaptic machinery immunostaining can be used to define putative synaptic connections between spectrally unique 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 across multiple animals and time points.

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Posted February 25, 2020.
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Light microscopy based approach for mapping connectivity with molecular specificity
Fred Y. Shen, Margaret M. Harrington, Logan A. Walker, Hon Pong Jimmy Cheng, Edward S. Boyden, Dawen Cai
bioRxiv 2020.02.24.963538; doi: https://doi.org/10.1101/2020.02.24.963538
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Light microscopy based approach for mapping connectivity with molecular specificity
Fred Y. Shen, Margaret M. Harrington, Logan A. Walker, Hon Pong Jimmy Cheng, Edward S. Boyden, Dawen Cai
bioRxiv 2020.02.24.963538; doi: https://doi.org/10.1101/2020.02.24.963538

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