Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain

Abstract

Understanding the principles governing neuronal diversity is a fundamental goal for neuroscience. Here we provide an anatomical and transcriptomic database of nearly 200 genetically identified cell populations. By separately analyzing the robustness and pattern of expression differences across these cell populations, we identify two gene classes contributing distinctly to neuronal diversity. Short homeobox transcription factors distinguish neuronal populations combinatorially, and exhibit extremely low transcriptional noise, enabling highly robust expression differences. Long neuronal effector genes, such as channels and cell adhesion molecules, contribute disproportionately to neuronal diversity, based on their patterns rather than robustness of expression differences. By linking transcriptional identity to genetic strains and anatomical atlases we provide an extensive resource for further investigation of mouse neuronal cell types.

Data availability

Sequencing data have been deposited in NCBI GEO under accession number GSE79238.

The following data sets were generated
The following previously published data sets were used
    1. Tasic B et al
    (2018) Cell Diversity in the Mouse Cortex
    Available at http://celltypes.brain-map.org/rnaseq.

Article and author information

Author details

  1. Ken Sugino

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    For correspondence
    ken.sugino@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5795-0635
  2. Erin Clark

    Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4013-325X
  3. Anton Schulmann

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yasuyuki Shima

    Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lihua Wang

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. David L Hunt

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Bryan M Hooks

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0135-4284
  8. Dimitri Traenkner

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jayaram Chandrashekar

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6412-0114
  10. Serge Picard

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Andrew L Lemire

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Nelson Spruston

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3118-1636
  13. Adam W Hantman

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Sacha B Nelson

    Brandeis University, Waltham, United States
    For correspondence
    nelson@brandeis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0108-8599

Funding

Howard Hughes Medical Institute

  • Ken Sugino
  • Anton Schulmann
  • Lihua Wang
  • David L Hunt
  • Bryan M Hooks
  • Dimitri Traenkner
  • Jayaram Chandrashekar
  • Andrew L Lemire
  • Nelson Spruston
  • Adam W Hantman
  • Sacha B Nelson

National Eye Institute (EY022360)

  • Erin Clark
  • Yasuyuki Shima
  • Sacha B Nelson

National Institute of Mental Health (MH105949)

  • Erin Clark
  • Yasuyuki Shima
  • Sacha B Nelson

National Institute of Neurological Disorders and Stroke (NS075007)

  • Erin Clark
  • Yasuyuki Shima
  • Sacha B Nelson

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

Ethics

Animal experimentation: All experiments were conducted in accordance with the requirements of theInstitutional Animal Care and Use Committees at Janelia Research Campus (protocol# not available) and Brandeis University (protocol#17001).

Copyright

© 2019, Sugino 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.

Metrics

  • 73
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ken Sugino
  2. Erin Clark
  3. Anton Schulmann
  4. Yasuyuki Shima
  5. Lihua Wang
  6. David L Hunt
  7. Bryan M Hooks
  8. Dimitri Traenkner
  9. Jayaram Chandrashekar
  10. Serge Picard
  11. Andrew L Lemire
  12. Nelson Spruston
  13. Adam W Hantman
  14. Sacha B Nelson
(2019)
Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain
eLife 8:e38619.
https://doi.org/10.7554/eLife.38619

Share this article

https://doi.org/10.7554/eLife.38619

Further reading

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

    1. Neuroscience
    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.