Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions
- Northwestern University, United States
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.
Data availability
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
Vasin Dumrongprechachan
Yevgenia Kozorovitskiy
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.
Reviewing Editor
- Mario Penzo, National Institute of Mental Health, United States
Ethics
Animal experimentation: Animals were handled according to protocols approved by the Northwestern University Animal Care and Use Committee (IS00000707).
Version history
- Received: October 15, 2020
- Accepted: April 26, 2021
- Accepted Manuscript published: April 27, 2021 (version 1)
- 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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Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions
eLife 10:e64041.
https://doi.org/10.7554/eLife.64041
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