Modified viral-genetic mapping reveals local and global connectivity relationships of ventral tegmental area dopamine cells

  1. Kevin Beier  Is a corresponding author
  1. University of California, Irvine, United States

Abstract

Dopamine cells in the ventral tegmental area (VTADA) are critical for a variety of motivated behaviors. These cells receive synaptic inputs from over 100 anatomically-defined brain regions, which enables control from a distributed set of inputs across the brain. Extensive efforts have been made to map inputs to VTA cells based on neurochemical phenotype and output site. However, all of these studies have the same fundamental limitation that inputs local to the VTA cannot be properly assessed due to non-Cre-dependent uptake of EnvA-pseudotyped virus. Therefore, the quantitative contribution of local inputs to the VTA, including GABAergic, DAergic, and serotonergic, is not known. Here, I used a modified viral-genetic strategy that enables examination of both local as well as long-range inputs to VTADA cells in mice. I found that nearly half of the total inputs to VTADA cells are located locally, revealing a substantial portion of inputs that have been missed by previous analyses. The majority of inhibition to VTADA cells arises from the substantia nigra pars reticulata, with large contributions from the VTA and the substantia nigra pars compacta. In addition to receiving inputs from VTAGABA neurons, DA neurons are connected with other DA neurons within the VTA as well as the nearby retrorubal field. Lastly, I show that VTADA neurons receive inputs from distributed serotonergic neurons throughout the midbrain and hindbrain, with the majority arising from the dorsal raphe. My study highlights the importance of using the appropriate combination of viral-genetic reagents to unmask the complexity of connectivity relationships to defined cells in the brain.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Analysis of previously published data are included in Beier et al., Cell 2015 and Beier et al., Cell Reports 2019 (relevant for Figure 2).

The following previously published data sets were used

Article and author information

Author details

  1. Kevin Beier

    Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States
    For correspondence
    kbeier@uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4934-1338

Funding

National Institutes of Health (DP2-AG067666)

  • Kevin Beier

National Institutes of Health (R00-D041445)

  • Kevin Beier

National Institutes of Health (R01-DA054374)

  • Kevin Beier

Tobacco-Related Disease Research Program (T31KT1437)

  • Kevin Beier

Tobacco-Related Disease Research Program (T31IP1426)

  • Kevin Beier

One Mind (OM-5596678)

  • Kevin Beier

Alzheimer's Association (AARG-NTF-20-685694)

  • Kevin Beier

New Vision Research (CCAD2020-002)

  • Kevin Beier

American Parkinson Disease Association (APDA-5589562)

  • Kevin Beier

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

Reviewing Editor

  1. Jesse H Goldberg, Cornell University, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AUP-18-163) of the University of California, Irvine.. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: January 7, 2022
  2. Preprint posted: January 20, 2022 (view preprint)
  3. Accepted: May 20, 2022
  4. Accepted Manuscript published: May 23, 2022 (version 1)
  5. Version of Record published: June 7, 2022 (version 2)

Copyright

© 2022, Beier

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. Kevin Beier
(2022)
Modified viral-genetic mapping reveals local and global connectivity relationships of ventral tegmental area dopamine cells
eLife 11:e76886.
https://doi.org/10.7554/eLife.76886

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https://doi.org/10.7554/eLife.76886

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