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.

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.

Metrics

  • 10,239
    views
  • 1,045
    downloads
  • 35
    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. 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

Share this article

https://doi.org/10.7554/eLife.48983

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.