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Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis

View ORCID ProfileM Wu, S Minkowicz, View ORCID ProfileV Dumrongprechachan, P Hamilton, L Xiao, View ORCID ProfileY Kozorovitskiy
doi: https://doi.org/10.1101/2020.03.11.987818
M Wu
Department of Neurobiology, Northwestern University, Evanston, IL 60208
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S Minkowicz
Department of Neurobiology, Northwestern University, Evanston, IL 60208
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V Dumrongprechachan
Department of Neurobiology, Northwestern University, Evanston, IL 60208
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P Hamilton
Department of Neurobiology, Northwestern University, Evanston, IL 60208
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L Xiao
Department of Neurobiology, Northwestern University, Evanston, IL 60208
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Y Kozorovitskiy
Department of Neurobiology, Northwestern University, Evanston, IL 60208
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  • For correspondence: Yevgenia.Kozorovitskiy@northwestern.edu
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Abstract

Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters plasticity, neuromodulatory signaling, and neuronal activity in distributed networks, yet the field lacks a unifying framework for its varied consequences. Here we describe neuromodulatory and plasticity changes following aversive learning by using a learned helplessness paradigm, where ketamine restores escape behavior. Dopaminergic neuron activity in the ventral tegmental area systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine’s effects are blocked by chemogenetic inhibition of dopamine signaling and mimicked by optogenetic activation. We use 2-photon glutamate uncaging/imaging to interrogate structural plasticity in medial prefrontal cortex, revealing that dendritic spinogenesis on pyramidal neurons is both regulated by aversive experience and recovered by ketamine in a dopamine-dependent manner. Together, these data describe recurrent circuits that causally link neuromodulatory dynamics, aversive learning, and plasticity enhancements driven by a therapeutically promising antidepressant.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 24, 2020.
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Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis
M Wu, S Minkowicz, V Dumrongprechachan, P Hamilton, L Xiao, Y Kozorovitskiy
bioRxiv 2020.03.11.987818; doi: https://doi.org/10.1101/2020.03.11.987818
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Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis
M Wu, S Minkowicz, V Dumrongprechachan, P Hamilton, L Xiao, Y Kozorovitskiy
bioRxiv 2020.03.11.987818; doi: https://doi.org/10.1101/2020.03.11.987818

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