Abstract

Learning from experience depends at least in part on changes in neuronal connections. We present the largest map of connectivity to date between cortical neurons of a defined type (L2/3 pyramidal cells in mouse primary visual cortex), which was enabled by automated analysis of serial section electron microscopy images with improved handling of image defects (250×140×90 μm3 volume). We used the map to identify constraints on the learning algorithms employed by the cortex. Previous cortical studies modeled a continuum of synapse sizes by a log-normal distribution. A continuum is consistent with most neural network models of learning, in which synaptic strength is a continuously graded analog variable. Here we show that synapse size, when restricted to synapses between L2/3 pyramidal cells, is well-modeled by the sum of a binary variable and an analog variable drawn from a log-normal distribution. Two synapses sharing the same presynaptic and postsynaptic cells are known to be correlated in size . We show that the binary variables of the two synapses are highly correlated, while the analog variables are not. Binary variation could be the outcome of a Hebbian or other synaptic plasticity rule depending on activity signals that are relatively uniform across neuronal arbors, while analog variation may be dominated by other influences such as spontaneous dynamical fluctuations. We discuss the implications for the longstanding hypothesis that activity-dependent plasticity switches synapses between bistable states.

Data availability

All data acquired and produced for this project are available on https://www.microns-explorer.org/phase1

The following data sets were generated

Article and author information

Author details

  1. Sven Dorkenwald

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    For correspondence
    svenmd@princeton.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2352-319X
  2. Nicholas L Turner

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  3. Thomas Macrina

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    Thomas Macrina, discloses financial interests in Zetta AI LLC.
  4. Kisuk Lee

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  5. Ran Lu

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  6. Jingpeng Wu

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  7. Agnes L Bodor

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  8. Adam A Bleckert

    Allen Institute for Brain Science, Seatttle, United States
    Competing interests
    No competing interests declared.
  9. Derrick Brittain

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  10. Nico Kemnitz

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  11. William M Silversmith

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  12. Dodam Ih

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  13. Jonathan Zung

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  14. Aleksandar Zlateski

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  15. Ignacio Tartavull

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  16. Szi-Chieh Yu

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  17. Sergiy Popovych

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  18. William Wong

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  19. Manuel Castro

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  20. Chris S Jordan

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  21. Alyssa M Wilson

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    Competing interests
    No competing interests declared.
  22. Emmanouil Froudarakis

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3249-3845
  23. JoAnn Buchanan

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  24. Marc M Takeno

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8384-7500
  25. Russel Torres

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2876-4382
  26. Gayathri Mahalingam

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  27. Forrest Collman

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0280-7022
  28. Casey M Schneider-Mizell

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9477-3853
  29. Daniel J Bumbarger

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  30. Yang Li

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  31. Lynne Becker

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
  32. Shelby Suckow

    Allen Institute for Brain Science, Seattle, WA, United States
    Competing interests
    No competing interests declared.
  33. Jacob Reimer

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    Jacob Reimer, discloses financial interests in Vathes LLC.
  34. Andreas Savas Tolias

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    Andreas Savas Tolias, discloses financial interests in Vathes LLC.
  35. Nuno Macarico da Costa

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2001-4568
  36. R Clay Reid

    Allen Institute for Brain Science, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8697-6797
  37. H Sebastian Seung

    Princeton Neuroscience Institute, Princeton University, Princeton, United States
    For correspondence
    sseung@princeton.edu
    Competing interests
    H Sebastian Seung, discloses financial interests in Zetta AI LLC.

Funding

Intelligence Advanced Research Projects Activity (D16PC00003)

  • Sven Dorkenwald
  • Nicholas L Turner
  • Thomas Macrina
  • Kisuk Lee
  • Ran Lu
  • Jingpeng Wu
  • Agnes L Bodor
  • Adam A Bleckert
  • Derrick Brittain
  • Nico Kemnitz
  • William M Silversmith
  • Dodam Ih
  • Jonathan Zung
  • Aleksandar Zlateski
  • Ignacio Tartavull
  • Szi-Chieh Yu
  • Sergiy Popovych
  • William Wong
  • Manuel Castro
  • Chris S Jordan
  • Alyssa M Wilson
  • Emmanouil Froudarakis
  • JoAnn Buchanan
  • Marc M Takeno
  • Russel Torres
  • Gayathri Mahalingam
  • Forrest Collman
  • Casey M Schneider-Mizell
  • Daniel J Bumbarger
  • Yang Li
  • Lynne Becker
  • Shelby Suckow
  • Jacob Reimer
  • Andreas Savas Tolias
  • Nuno Macarico da Costa
  • R Clay Reid
  • H Sebastian Seung

G. Harold and Leila Y. Mathers Foundation

  • H Sebastian Seung

Intelligence Advanced Research Projects Activity (D16PC00004)

  • Sven Dorkenwald
  • Nicholas L Turner
  • Thomas Macrina
  • Kisuk Lee
  • Ran Lu
  • Jingpeng Wu
  • Agnes L Bodor
  • Adam A Bleckert
  • Derrick Brittain
  • Nico Kemnitz
  • William M Silversmith
  • Dodam Ih
  • Jonathan Zung
  • Aleksandar Zlateski
  • Ignacio Tartavull
  • Szi-Chieh Yu
  • Sergiy Popovych
  • William Wong
  • Manuel Castro
  • Chris S Jordan
  • Alyssa M Wilson
  • Emmanouil Froudarakis
  • JoAnn Buchanan
  • Marc M Takeno
  • Russel Torres
  • Gayathri Mahalingam
  • Forrest Collman
  • Casey M Schneider-Mizell
  • Daniel J Bumbarger
  • Yang Li
  • Lynne Becker
  • Shelby Suckow
  • Jacob Reimer
  • Andreas Savas Tolias
  • Nuno Macarico da Costa
  • R Clay Reid
  • H Sebastian Seung

Intelligence Advanced Research Projects Activity (D16PC00005)

  • Sven Dorkenwald
  • Nicholas L Turner
  • Thomas Macrina
  • Kisuk Lee
  • Ran Lu
  • Jingpeng Wu
  • Agnes L Bodor
  • Adam A Bleckert
  • Derrick Brittain
  • Nico Kemnitz
  • William M Silversmith
  • Dodam Ih
  • Jonathan Zung
  • Aleksandar Zlateski
  • Ignacio Tartavull
  • Szi-Chieh Yu
  • Sergiy Popovych
  • William Wong
  • Manuel Castro
  • Chris S Jordan
  • Alyssa M Wilson
  • Emmanouil Froudarakis
  • JoAnn Buchanan
  • Marc M Takeno
  • Russel Torres
  • Gayathri Mahalingam
  • Forrest Collman
  • Casey M Schneider-Mizell
  • Daniel J Bumbarger
  • Yang Li
  • Lynne Becker
  • Shelby Suckow
  • Jacob Reimer
  • Andreas Savas Tolias
  • Nuno Macarico da Costa
  • R Clay Reid
  • H Sebastian Seung

National Institute of Neurological Disorders and Stroke (U19 NS104648)

  • H Sebastian Seung

Army Research Office (W911NF-12-1-0594)

  • H Sebastian Seung

National Eye Institute (R01 EY027036)

  • H Sebastian Seung

National Institute of Mental Health (U01 MH114824)

  • H Sebastian Seung

National Institute of Neurological Disorders and Stroke (R01 NS104926)

  • H Sebastian Seung

National Institute of Mental Health (RF1MH117815)

  • H Sebastian Seung

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Timothy O'Leary, University of Cambridge, United Kingdom

Ethics

Animal experimentation: All animal procedures were approved by the Institutional Animal Care and Use Committee at the Allen Institute for Brain Science (1503 and 1804) or Baylor College of Medicine (AN-4703).

Version history

  1. Preprint posted: December 31, 2019 (view preprint)
  2. Received: December 13, 2021
  3. Accepted: November 15, 2022
  4. Accepted Manuscript published: November 16, 2022 (version 1)
  5. Version of Record published: November 28, 2022 (version 2)

Copyright

© 2022, Dorkenwald 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. Sven Dorkenwald
  2. Nicholas L Turner
  3. Thomas Macrina
  4. Kisuk Lee
  5. Ran Lu
  6. Jingpeng Wu
  7. Agnes L Bodor
  8. Adam A Bleckert
  9. Derrick Brittain
  10. Nico Kemnitz
  11. William M Silversmith
  12. Dodam Ih
  13. Jonathan Zung
  14. Aleksandar Zlateski
  15. Ignacio Tartavull
  16. Szi-Chieh Yu
  17. Sergiy Popovych
  18. William Wong
  19. Manuel Castro
  20. Chris S Jordan
  21. Alyssa M Wilson
  22. Emmanouil Froudarakis
  23. JoAnn Buchanan
  24. Marc M Takeno
  25. Russel Torres
  26. Gayathri Mahalingam
  27. Forrest Collman
  28. Casey M Schneider-Mizell
  29. Daniel J Bumbarger
  30. Yang Li
  31. Lynne Becker
  32. Shelby Suckow
  33. Jacob Reimer
  34. Andreas Savas Tolias
  35. Nuno Macarico da Costa
  36. R Clay Reid
  37. H Sebastian Seung
(2022)
Binary and analog variation of synapses between cortical pyramidal neurons
eLife 11:e76120.
https://doi.org/10.7554/eLife.76120

Share this article

https://doi.org/10.7554/eLife.76120

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