Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

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Abstract

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Ximena I Salinas-Hernández

Institute of Neurophysiology, Goethe University Frankfurt, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Pascal Vogel

Institute of Neurophysiology, Goethe University Frankfurt, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Sebastian Betz

Institute of Neurophysiology, Goethe University Frankfurt, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Raffael Kalisch

Neuroimaging Center, Johannes Gutenberg University, Mainz, Germany

Competing interests
The authors declare that no competing interests exist.
Torfi Sigurdsson

Institute of Neurophysiology, Goethe University Frankfurt, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Sevil Duvarci

Institute of Neurophysiology, Goethe University Frankfurt, Frankfurt, Germany

For correspondence
duvarci@med.uni-frankfurt.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4494-7741

Funding

Deutsche Forschungsgemeinschaft (SFB1193 Grant INST247/852-1)

Sevil Duvarci

Deutsche Forschungsgemeinschaft (SFB1193 Grant INST247/854-1)

Torfi Sigurdsson

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

Ethics

Animal experimentation: All procedures were conducted in accordance with the guidelines of the German Animal Protection Act and were approved by the local authorities (Regierungsprasidium Darmstadt; protocol number 1038). Every effort was made to minimize suffering.

Copyright

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.