L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans
Learning to be safe is central for adaptive behaviour when threats are no longer present. Detecting the absence of an expected threat is key for threat extinction learning and an essential process for the behavioural treatment of anxiety related disorders. One possible mechanism underlying extinction learning is a dopaminergic mismatch signal that encodes the absence of an expected threat. Here we show that such a dopamine-related pathway underlies extinction learning in humans. Dopaminergic enhancement via administration of L-DOPA (vs. Placebo) was associated with reduced retention of differential psychophysiological threat responses at later test, which was mediated by activity in the ventromedial prefrontal cortex that was specific to extinction learning. L-DOPA administration enhanced signals at the time-point of an expected, but omitted threat in extinction learning within the nucleus accumbens, which were functionally coupled with the ventral tegmental area and the amygdala. Computational modelling of threat expectancies further revealed prediction error encoding in nucleus accumbens that was reduced when L-DOPA was administered. Our results thereby provide evidence that extinction learning is influenced by L-DOPA and provide a mechanistic perspective to augment extinction learning by dopaminergic enhancement in humans.
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Deutsche Forschungsgemeinschaft (Project B10 (INST 211/755) of the Collaborative Research Center TRR58)
- Roland Esser
- Jan Haaker
Deutsche Forschungsgemeinschaft (HA 7470/3-1)
- Jan Haaker
Deutsche Forschungsgemeinschaft (collaborative research centre SFB TRR 169)
- Christoph W Korn
Deutsche Forschungsgemeinschaft (Emmy Noether Research Group (392443797))
- Christoph W Korn
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: The ethical approval was obtained by the ethics committee of the Ärztekammer Hamburg (PV5158)that approved the study. Participants gave their written, informed consent to participate in the study, for the collection of the data and consent to publish.
- Alexander Shackman, University of Maryland, United States
- Received: November 30, 2020
- Preprint posted: December 7, 2020 (view preprint)
- Accepted: September 1, 2021
- Accepted Manuscript published: September 2, 2021 (version 1)
- Version of Record published: September 15, 2021 (version 2)
© 2021, Esser 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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