1. Neuroscience

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
https://doi.org/10.7554/eLife.65280
Share this article
Cite this article
  1. Roland Esser
  2. Christoph W Korn
  3. Florian Ganzer
  4. Jan Haaker
(2021)
L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans
eLife 10:e65280.
https://doi.org/10.7554/eLife.65280
  2. Download BibTeX
  3. Download .RIS

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.

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

  • 1,182
    views
  • 159
    downloads
  • 34
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Roland Esser
  2. Christoph W Korn
  3. Florian Ganzer
  4. Jan Haaker
(2021)
L-DOPA modulates activity in the vmPFC, Nucleus Accumbens and VTA during threat extinction learning in humans
eLife 10:e65280.
https://doi.org/10.7554/eLife.65280

Share this article

https://doi.org/10.7554/eLife.65280

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Accelerated signal propagation speed in human neocortical dendrites

    Gáspár Oláh, Rajmund Lákovics ... Gábor Tamás
    Research Article

    Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Axonal and dendritic recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Experimentally-based detailed biophysical models have shown that the key factor responsible for the accelerated EPSP propagation in human cortical dendrites is the large conductance load imposed at the soma by the large basal dendritic tree. Additionally, larger dendritic diameters and differences in cable and ion channel properties in humans contribute to enhanced signal propagation. Our integrative experimental and modeling study provides new insights into the scaling rules that help maintain information processing speed albeit the large and sparse neurons in the human cortex.

    1. Neuroscience

    Cognition: When working memory works for our goals

    Jacob A Miller
    Insight

    When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.

    1. Neuroscience

    Stimulus representation in human frontal cortex supports flexible control in working memory

    Zhujun Shao, Mengya Zhang, Qing Yu
    Research Article

    When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.