Modified viral-genetic mapping reveals local and global connectivity relationships of ventral tegmental area dopamine cells
- 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).
Article and author information
Author details
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.
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.
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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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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