Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1
- California Institute of Technology, United States
- 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.
Article and author information
Author details
J Elliott Robinson
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.
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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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