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Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions

Research Article
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Cite this article as: eLife 2021;10:e64041 doi: 10.7554/eLife.64041

Abstract

Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters neuronal activity and neuromodulatory signaling in distributed networks, modifying behavior. Here we describe changes in dopaminergic neuron activity and signaling following aversive learning in a learned helplessness paradigm in mice. A single dose of ketamine suffices to restore escape behavior after aversive learning. Dopaminergic neuron activity in the ventral tegmental area (VTA) systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine's effects are blocked by chemogenetic inhibition of dopamine signaling. Rather than directly altering the activity of dopaminergic neurons, ketamine appears to rescue dopamine dynamics through actions in the medial prefrontal cortex (mPFC). Chemogenetic activation of Drd1 receptor positive mPFC neurons mimics ketamine's effects on behavior. Together, our data link neuromodulatory dynamics in mPFC-VTA circuits, aversive learning, and the effects of ketamine.

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All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files are provided for each figure.

Article and author information

Author details

  1. Mingzheng Wu

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4415-6296
  2. Samuel Minkowicz

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1555-1158
  3. Vasin Dumrongprechachan

    Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5890-6778
  4. Pauline Hamilton

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Lei Xiao

    Department of Neurobiology, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1640-9690
  6. Yevgenia Kozorovitskiy

    Department of Neurobiology, Northwestern University, Evanston, United States
    For correspondence
    Yevgenia.Kozorovitskiy@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3710-1484

Funding

Rita Allen Foundation (Rita Allen Foundation Scholar Award)

  • Yevgenia Kozorovitskiy

National Institutes of Health (R01NS107539)

  • Yevgenia Kozorovitskiy

Kinship Foundation (Searle Scholar Award)

  • Yevgenia Kozorovitskiy

Arnold and Mabel Beckman Foundation (Beckman Young Investigator Award)

  • Yevgenia Kozorovitskiy

Brain and Behavior Research Foundation (NARSAD and P&S Fund Award)

  • Yevgenia Kozorovitskiy

National Institutes of Health (T32 AG20506 affiliate fellow)

  • Mingzheng Wu

National Science Foundation (GRFP DGE-1842165)

  • Samuel Minkowicz

American Heart Association (19PRE34380056 predoctoral fellowship)

  • Vasin Dumrongprechachan

National Institutes of Health (R01MH117111)

  • Yevgenia Kozorovitskiy

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

Ethics

Animal experimentation: Animals were handled according to protocols approved by the Northwestern University Animal Care and Use Committee (IS00000707).

Reviewing Editor

  1. Mario Penzo, National Institute of Mental Health, United States

Publication history

  1. Received: October 15, 2020
  2. Accepted: April 26, 2021
  3. Accepted Manuscript published: April 27, 2021 (version 1)
  4. Version of Record published: June 17, 2021 (version 2)

Copyright

© 2021, Wu 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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