1. Computational and Systems Biology
  2. Neuroscience

High-resolution volumetric imaging constrains compartmental models to explore synaptic integration and temporal processing by cochlear nucleus globular bushy cells

  1. George A Spirou  Is a corresponding author
  2. Matthew G Kersting
  3. Sean Carr
  4. Bayan Razzaq
  5. Carolyna Yamamoto Alves Pinto
  6. Mariah Dawson
  7. Mark H Ellisman
  8. Paul B Manis  Is a corresponding author
  1. University of South Florida, United States
  2. West Virginia University, United States
  3. University of California, San Diego, United States
  4. University of North Carolina at Chapel Hill, United States
https://doi.org/10.7554/eLife.83393
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Cite this article
  1. George A Spirou
  2. Matthew G Kersting
  3. Sean Carr
  4. Bayan Razzaq
  5. Carolyna Yamamoto Alves Pinto
  6. Mariah Dawson
  7. Mark H Ellisman
  8. Paul B Manis
(2023)
High-resolution volumetric imaging constrains compartmental models to explore synaptic integration and temporal processing by cochlear nucleus globular bushy cells
eLife 12:e83393.
https://doi.org/10.7554/eLife.83393
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Abstract

Globular bushy cells (GBCs) of the cochlear nucleus play central roles in the temporal processing of sound. Despite investigation over many decades, fundamental questions remain about their dendrite structure, afferent innervation, and integration of synaptic inputs. Here, we use volume electron microscopy (EM) of the mouse cochlear nucleus to construct synaptic maps that precisely specify convergence ratios and synaptic weights for auditory- nerve innervation and accurate surface areas of all postsynaptic compartments. Detailed biophysically-based compartmental models can help develop hypotheses regarding how GBCs integrate inputs to yield their recorded responses to sound. We established a pipeline to export a precise reconstruction of auditory nerve axons and their endbulb terminals together with high-resolution dendrite, soma, and axon reconstructions into biophysically-detailed compartmental models that could be activated by a standard cochlear transduction model. With these constraints, the models predict auditory nerve input profiles whereby all endbulbs onto a GBC are subthreshold (coincidence detection mode), or one or two inputs are suprathreshold (mixed mode). The models also predict the relative importance of dendrite geometry, soma size, and axon initial segment length in setting action potential threshold and generating heterogeneity in sound-evoked responses, and thereby propose mechanisms by which GBCs may homeostatically adjust their excitability. Volume EM also reveals new dendritic structures and dendrites that lack innervation. This framework defines a pathway from subcellular morphology to synaptic connectivity, and facilitates investigation into the roles of specific cellular features in sound encoding. We also clarify the need for new experimental measurements to provide missing cellular parameters, and predict responses to sound for further in vivo studies, thereby serving as a template for investigation of other neuron classes.

Data availability

The serial blockface electron microscope volume will be uploaded to BossDB (bossdb.org).The modeling code is publicly available on GitHub (https://github.com/pbmanis/vcnmodel; https://github.com/cnmodel).The main Simulation result files used to generate the figures in this manuscript have been uploaded to Dryad, and can be accessed at https://doi.org/10.5061/dryad.4j0zpc8g1. This repository includes:Simulation figures and figure panels can be generated using the DataTables script in the VCNModel package after downloading the simulation result files. All simulations shown in the paper, and/or their analyses, are included in the Dryad repository. They can be regenerated from the VCNModel package (above, on GitHub) using supplied scripts.Code and Data for Figure2-Figure Supplement 1 is in the file Figure2_Suppl1.py in the VCNModel GitHub repository.Code and data for Figure5-Figure Supplement 2 is in pattern_summary.py in the VCNModel GitHub repository.Figures 1E, F, 2C, D, 3C,D,F,G, 7H and K, 8H were generated using Matlab code. The tables (Excel) and Matlab code are at www.github.com/gaspirou/pub_file_share.

The following data sets were generated

Article and author information

Author details

  1. George A Spirou

    Department of Medical Engineering, University of South Florida, Tampa, United States
    For correspondence
    gspirou@usf.edu
    Competing interests
    The authors declare that no competing interests exist.

  2. Matthew G Kersting

    Department of Medical Engineering, University of South Florida, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Sean Carr

    Department of Medical Engineering, University of South Florida, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6757-9104

  4. Bayan Razzaq

    Department of Otolaryngology, Head and Neck Surgery, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Carolyna Yamamoto Alves Pinto

    Department of Medical Engineering, University of South Florida, Tampa, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6735-045X

  6. Mariah Dawson

    Department of Otolaryngology, Head and Neck Surgery, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Mark H Ellisman

    Department of Neurosciences, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Paul B Manis

    Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    pmanis@med.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0131-8961

Funding

National Institute on Deafness and Other Communication Disorders (R01 DC015901)

  • George A Spirou
  • Mark H Ellisman
  • Paul B Manis

National Institute on Deafness and Other Communication Disorders (R01 DC004551)

  • Paul B Manis

National Institute of General Medical Sciences (R01 GM082949)

  • Mark H Ellisman

National Institute of Neurological Disorders and Stroke (U24 NS120055)

  • Mark H Ellisman

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Reviewing Editor

  1. Catherine Emily Carr, University of Maryland, United States

Ethics

Animal experimentation: All procedures involving animals were approved by the West Virginia University (WVU) InstitutionalAnimal Care and Use Committee, protocol #15-1201 (G.A. Spirou, PI) and were in accordance with policies of the United States Public Health Service. No animal procedures in this study were performed at other institutions. The perfusion of the mouse was performed under avertin anesthesia.

Version history

  1. Preprint posted: September 10, 2022 (view preprint)
  2. Received: September 14, 2022
  3. Accepted: June 7, 2023
  4. Accepted Manuscript published: June 8, 2023 (version 1)
  5. Version of Record published: August 17, 2023 (version 2)

Copyright

© 2023, Spirou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. George A Spirou
  2. Matthew G Kersting
  3. Sean Carr
  4. Bayan Razzaq
  5. Carolyna Yamamoto Alves Pinto
  6. Mariah Dawson
  7. Mark H Ellisman
  8. Paul B Manis
(2023)
High-resolution volumetric imaging constrains compartmental models to explore synaptic integration and temporal processing by cochlear nucleus globular bushy cells
eLife 12:e83393.
https://doi.org/10.7554/eLife.83393

Share this article

https://doi.org/10.7554/eLife.83393

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