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Published September 23, 2019 | Published + Supplemental Material
Journal Article Open

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


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.

Additional Information

© 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. Received: 02 June 2019; Accepted: 21 September 2019; Published: 23 September 2019. We acknowledge Dr. Ginger Milne and the Vanderbilt Neurochemistry Core (Vanderbilt University School of Medicine) for HPLC analysis; Dr. Markus Meister for expertise in conducting the looming stimulus assay; Dr. Daniel Wagenaar and the Caltech Neurotechnology Center (California Institute of Technology) for technical assistance; George R Hudson for assistance with Th-VAST experiments; Varun Wadia and Jaeyoung Kang for assistance with fear conditioning and social preference assays; Aditya Nair for image analysis; and the Beckman Institute for CLARITY, Optogenetics and Vector Engineering Research (CLOVER, California Institute of Technology, clover.caltech.edu) for assistance with vector design and production. This work is funded by NIH Director's New Innovator Award IDP20D017782-01, NIH Presidential Early Career Award for Scientists and Engineers (PECASE), NIH BRAIN RF1MH117069, NSF NeuroNex Technology Hub 1707316, the Heritage Medical Research Institute, and the Tianqiao and Chrissy Chen Institute for Neuroscience (VG); NIH Awards U01NS103522 and DP2MH107056 (LT); Children's Tumor Foundation Young Investigator Award 2016-01-006 (JER); and a PGS-D from the National Science and Engineering Research Council (NSERC) of Canada (GMC). Data and Materials 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 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. The authors have no competing interests to declare.

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August 19, 2023
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