1. Neuroscience
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HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

  1. Peng Zhong
  2. Casey R Vickstrom
  3. Xiaojie Liu
  4. Ying Hu
  5. Laikang Yu
  6. Han-Gang Yu
  7. Qing-song Liu  Is a corresponding author
  1. Medical College of Wisconsin, United States
  2. West Virginia University, United States
Research Article
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Cite this article as: eLife 2017;6:e32420 doi: 10.7554/eLife.32420

Abstract

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

Article and author information

Author details

  1. Peng Zhong

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Casey R Vickstrom

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaojie Liu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ying Hu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Laikang Yu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Han-Gang Yu

    Department of Physiology and Pharmacology, West Virginia University, Morgantown, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6838-8310
  7. Qing-song Liu

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, United States
    For correspondence
    qsliu@mcw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1858-1504

Funding

National Institute on Drug Abuse (DA035217)

  • Qing-song Liu

National Institute of Mental Health (MH101146)

  • Qing-song Liu

National Institute of Mental Health (F30MH115536)

  • Casey R Vickstrom

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 maintenance and use were in accordance with protocols approved by the Institutional Animal Care and Use Committee of the Medical College of Wisconsin (#1166, #2420).

Reviewing Editor

  1. Olivier Manzoni, Inmed, INSERM, Marseilles, France

Publication history

  1. Received: October 1, 2017
  2. Accepted: December 18, 2017
  3. Accepted Manuscript published: December 19, 2017 (version 1)
  4. Version of Record published: January 2, 2018 (version 2)

Copyright

© 2017, Zhong 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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