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.

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.

Metrics

  • 1,972
    views
  • 513
    downloads
  • 11
    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. 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

Share this article

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

Further reading

    1. Neuroscience
    François Kroll, Joshua Donnelly ... Jason Rihel
    Research Article

    By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer’s risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer’s risk genes tested. We developed an online tool, ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3677 compounds. ZOLTAR successfully predicted that sorl1 mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep of presenilin-2 knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.

    1. Neuroscience
    Kaspar E Vogt, Ashwinikumar Kulkarni ... Robert W Greene
    Research Article

    Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response. We report an increased AMPA/NMDA EPSC ratio in frontal-cortical pyramidal neurons of layers 2–3. Silent synapses are absent, decreasing the plastic potential to convert silent NMDA to active AMPA synapses. These sleep loss changes are recovered by sleep. Sleep genes are enriched for synaptic shaping cellular components controlling glutamate synapse phenotype, overlap with autism risk genes, and are primarily observed in excitatory pyramidal neurons projecting intra-telencephalically. These genes are enriched with genes controlled by the transcription factor, MEF2c, and its repressor, HDAC4. Sleep genes can thus provide a framework within which motor learning and training occur mediated by the sleep-dependent oscillation of glutamate-synaptic phenotypes.