1. Neuroscience
Download icon

L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans

  1. Roland Esser
  2. Christoph W Korn
  3. Florian Ganzer
  4. Jan Haaker  Is a corresponding author
  1. University Medical Center Hamburg-Eppendorf, Germany
Research Article
  • Cited 0
  • Views 613
  • Annotations
Cite this article as: eLife 2021;10:e65280 doi: 10.7554/eLife.65280

Abstract

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.

Data availability

All data for analyses and figures in this study are provided in the within the Open Science Framework

The following data sets were generated

Article and author information

Author details

  1. Roland Esser

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Christoph W Korn

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Florian Ganzer

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Jan Haaker

    Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    For correspondence
    j.haaker@uke.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8366-9559

Funding

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.

Ethics

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.

Reviewing Editor

  1. Alexander Shackman, University of Maryland, United States

Publication history

  1. Received: November 30, 2020
  2. Preprint posted: December 7, 2020 (view preprint)
  3. Accepted: September 1, 2021
  4. Accepted Manuscript published: September 2, 2021 (version 1)
  5. Version of Record published: September 15, 2021 (version 2)

Copyright

© 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.

Metrics

  • 613
    Page views
  • 88
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Neuroscience
    2. Structural Biology and Molecular Biophysics
    Johannes Elferich et al.
    Research Article Updated

    Mechanosensory transduction (MT), the conversion of mechanical stimuli into electrical signals, underpins hearing and balance and is carried out within hair cells in the inner ear. Hair cells harbor actin-filled stereocilia, arranged in rows of descending heights, where the tips of stereocilia are connected to their taller neighbors by a filament composed of protocadherin 15 (PCDH15) and cadherin 23 (CDH23), deemed the ‘tip link.’ Tension exerted on the tip link opens an ion channel at the tip of the shorter stereocilia, thus converting mechanical force into an electrical signal. While biochemical and structural studies have provided insights into the molecular composition and structure of isolated portions of the tip link, the architecture, location, and conformational states of intact tip links, on stereocilia, remains unknown. Here, we report in situ cryo-electron microscopy imaging of the tip link in mouse stereocilia. We observe individual PCDH15 molecules at the tip and shaft of stereocilia and determine their stoichiometry, conformational heterogeneity, and their complexes with other filamentous proteins, perhaps including CDH23. The PCDH15 complexes occur in clusters, frequently with more than one copy of PCDH15 at the tip of stereocilia, suggesting that tip links might consist of more than one copy of PCDH15 complexes and, by extension, might include multiple MT complexes.

    1. Neuroscience
    Thomas Akam et al.
    Research Article

    Laboratory behavioural tasks are an essential research tool. As questions asked of behaviour and brain activity become more sophisticated, the ability to specify and run richly structured tasks becomes more important. An increasing focus on reproducibility also necessitates accurate communication of task logic to other researchers. To these ends, we developed pyControl, a system of open-source hardware and software for controlling behavioural experiments comprising a simple yet flexible Python-based syntax for specifying tasks as extended state machines, hardware modules for building behavioural setups, and a graphical user interface designed for efficiently running high-throughput experiments on many setups in parallel, all with extensive online documentation. These tools make it quicker, easier, and cheaper to implement rich behavioural tasks at scale. As important, pyControl facilitates communication and reproducibility of behavioural experiments through a highly readable task definition syntax and self-documenting features. Here, we outline the system’s design and rationale, present validation experiments characterising system performance, and demonstrate example applications in freely moving and head-fixed mouse behaviour.