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

Mingzheng Wu; Samuel Minkowicz; Vasin Dumrongprechachan; Pauline Hamilton; Lei Xiao; Yevgenia Kozorovitskiy

doi:10.7554/eLife.64041

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

Mingzheng Wu, Samuel Minkowicz, Vasin Dumrongprechachan, Pauline Hamilton, Lei Xiao, Yevgenia Kozorovitskiy^*

^*Corresponding author for this work

Neurobiology

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English (US)
Article number	e64041
Journal	eLife
Volume	10
DOIs	https://doi.org/10.7554/eLife.64041
State	Published - May 2021

Funding

The authors are grateful to Lindsey Butler for mouse colony management, Northwestern Biological Imaging Facility and Dr. Tiffany Schmidt for confocal microscope access. This work was supported by NINDS R01NS107539, NIMH R01MH117111, Rita Allen Foundation Scholar Award, Searle Scholar Award, Beckman Young Investigator Award, William and Bernice E Bumpus Young Innovator Award, NARSAD Young Investigator, and P&S Fund Grant (all YK). MW was supported as an affiliate fellow of the NIH T32 AG20506, SM is a fellow of the National Science Foundation Graduate Research Fellowship DGE-1842165, and VD is a predoctoral fellow of the American Heart Association (19PRE34380056).

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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title = "Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions",

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{\textquoteright}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{\textquoteright}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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AU - Kozorovitskiy, Yevgenia

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

Abstract

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ASJC Scopus subject areas

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