Attenuated Dopamine Signaling After Aversive Learning is Restored by Ketamine to Rescue Escape Actions

Overview

Journal Elife

Specialty Biology

Date 2021 Apr 27

PMID 33904412

Citations 23

Authors

Mingzheng Wu

Samuel Minkowicz

Vasin Dumrongprechachan

Pauline Hamilton

Lei Xiao

Yevgenia Kozorovitskiy

Affiliations

Soon will be listed here.

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.

Citing Articles

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Lopez G, Lerner T Curr Opin Behav Sci. 2024; 61.

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Ketamine induces plasticity in a norepinephrine-astroglial circuit to promote behavioral perseverance.

Duque M, Chen A, Hsu E, Narayan S, Rymbek A, Begum S Neuron. 2024; 113(3):426-443.e5.

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Bergosh M, Medvidovic S, Zepeda N, Crown L, Ipe J, Debattista L Front Neurosci. 2024; 18:1389096.

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Xu P, Peng J, Yuan T, Chen Z, He H, Wu Z Elife. 2024; 13.

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Ma P, Chen P, Tilden E, Aggarwal S, Oldenborg A, Chen Y Sci Adv. 2024; 10(8):eadi0643.

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