Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1

  1. J Elliott Robinson
  2. Gerard M Coughlin
  3. Acacia M Hori
  4. Jounhong Ryan Cho
  5. Elisha D Mackey
  6. Zeynep Turan
  7. Tommaso Patriarchi
  8. Lin Tian
  9. Viviana Gradinaru  Is a corresponding author
  1. California Institute of Technology, United States
  2. University of California, Davis, United States

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose neurodevelopmental symptoms include impaired executive function, attention, and spatial learning that could be due to perturbed mesolimbic dopaminergic circuitry. However, these circuits have never been directly assayed in vivo. We employed the genetically encoded optical dopamine sensor dLight1 to monitor dopaminergic neurotransmission in the ventral striatum of NF1 mice during motivated behavior. Additionally, we developed novel systemic AAV vectors to facilitate morphological reconstruction of dopaminergic populations in cleared tissue. We found that NF1 mice exhibit reduced spontaneous dopaminergic neurotransmission that was associated with excitation/inhibition imbalance in the ventral tegmental area and abnormal neuronal morphology. NF1 mice also had more robust dopaminergic and behavioral responses to salient visual stimuli, which were stimulus-dependent, independent of learning, and rescued by optogenetic inhibition of non-dopaminergic neurons in the VTA. Overall, these studies provide a first in vivo characterization of dopaminergic circuit function in the context of NF1 and reveal novel pathophysiological mechanisms.

Data availability

Viral vector plasmids used in this study are available on Addgene at http://www.addgene.org/Viviana_Gradinaru/. Codes used for fiber photometry signal extraction and analysis are available at https://github.com/GradinaruLab/dLight1. Source data is available at www.doi.org/10.7303/syn18904024.

The following data sets were generated

Article and author information

Author details

  1. J Elliott Robinson

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9417-3938
  2. Gerard M Coughlin

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Acacia M Hori

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jounhong Ryan Cho

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elisha D Mackey

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Zeynep Turan

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tommaso Patriarchi

    Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lin Tian

    Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7012-6926
  9. Viviana Gradinaru

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    viviana@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5868-348X

Funding

National Institutes of Health (IDP20D017782-01)

  • Viviana Gradinaru

National Science and Engineering Research Council of Canada (Postgraduate Scholarship-Doctoral)

  • Gerard M Coughlin

National Institutes of Health (PECASE)

  • Viviana Gradinaru

National Institutes of Health (RF1MH117069)

  • Viviana Gradinaru

National Science Foundation (1707316)

  • Viviana Gradinaru

Heritage Medical Research Institute

  • Viviana Gradinaru

Tianqiao and Chrissy Chen Institute for Neuroscience

  • Viviana Gradinaru

National Institutes of Health (U01NS103522)

  • Lin Tian

National Institutes of Health (DP2MH107056)

  • Lin Tian

Children's Tumor Foundation (Young Investigator Award 2016-01-00)

  • J Elliott Robinson

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

Ethics

Animal experimentation: Animal husbandry and experimental procedures involving animal subjects were conducted in compliance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the Institutional Animal Care and Use Committee (IACUC) and by the Office of Laboratory Animal Resources at the California Institute of Technology under IACUC protocol 1730.

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Publication history

  1. Received: June 2, 2019
  2. Accepted: September 21, 2019
  3. Accepted Manuscript published: September 23, 2019 (version 1)
  4. Version of Record published: October 29, 2019 (version 2)
  5. Version of Record updated: November 8, 2019 (version 3)
  6. Version of Record updated: November 26, 2019 (version 4)
  7. Version of Record updated: January 20, 2020 (version 5)

Copyright

© 2019, Robinson 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. J Elliott Robinson
  2. Gerard M Coughlin
  3. Acacia M Hori
  4. Jounhong Ryan Cho
  5. Elisha D Mackey
  6. Zeynep Turan
  7. Tommaso Patriarchi
  8. Lin Tian
  9. Viviana Gradinaru
(2019)
Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1
eLife 8:e48983.
https://doi.org/10.7554/eLife.48983

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