Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age

  1. Lieke de Boer  Is a corresponding author
  2. Jan Axelsson
  3. Katrine Riklund
  4. Lars Nyberg
  5. Peter Dayan
  6. Lars Bäckman
  7. Marc Guitart-Masip  Is a corresponding author
  1. Karolinska Institute, Sweden
  2. Umeå University, Sweden
  3. University College London, United Kingdom

Abstract

Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanisms is associated with DA D1 receptor availability.

Article and author information

Author details

  1. Lieke de Boer

    Aging Research Center, Karolinska Institute, Stockholm, Sweden
    For correspondence
    liekelotte@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3381-2040
  2. Jan Axelsson

    Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  3. Katrine Riklund

    Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  4. Lars Nyberg

    Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter Dayan

    Gatsby Computational Neuroscience Unit, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3476-1839
  6. Lars Bäckman

    Aging Research Center, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  7. Marc Guitart-Masip

    Aging Research Center, Karolinska Institute, Stockholm, Sweden
    For correspondence
    marc.guitart-masip@ki.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2294-6492

Funding

Vetenskapsrådet (VR521-2013-2589)

  • Marc Guitart-Masip

Gatsby Charitable Foundation

  • Peter Dayan

Alexander von Humboldt-Stiftung (Humboldt Research Award)

  • Lars Bäckman

Stichting af Jochnick Foundation

  • Lars Bäckman

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

Reviewing Editor

  1. Wolfram Schultz, University of Cambridge, United Kingdom

Ethics

Human subjects: Ethical approval was obtained from the Umeå Ethical Review Board, identifier DNR 2014-251-31M. All participants provided written informed consent prior to commencing the study.

Version history

  1. Received: February 28, 2017
  2. Accepted: August 11, 2017
  3. Accepted Manuscript published: September 5, 2017 (version 1)
  4. Version of Record published: September 11, 2017 (version 2)

Copyright

© 2017, de Boer 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

  • 1,895
    Page views
  • 273
    Downloads
  • 33
    Citations

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

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. Lieke de Boer
  2. Jan Axelsson
  3. Katrine Riklund
  4. Lars Nyberg
  5. Peter Dayan
  6. Lars Bäckman
  7. Marc Guitart-Masip
(2017)
Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age
eLife 6:e26424.
https://doi.org/10.7554/eLife.26424

Share this article

https://doi.org/10.7554/eLife.26424

Further reading

    1. Developmental Biology
    2. Neuroscience
    Tariq Zaman, Daniel Vogt ... Michael R Williams
    Research Article

    The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.

    1. Neuroscience
    Hideo Hagihara, Hirotaka Shoji ... Tsuyoshi Miyakawa
    Research Article

    Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.