Dissociation of impulsive traits by subthalamic metabotropic glutamate receptor 4

  1. Lukasz Piszczek
  2. Andreea Constantinescu
  3. Dominic Kargl
  4. Jelena Lazovic
  5. Anton Pekcec
  6. Janet R Nicholson
  7. Wulf Haubensak  Is a corresponding author
  1. Vienna Biocenter, Austria
  2. Vienna BioCenter Core Facilities (VBCF), Austria
  3. Boehringer Ingelheim, Germany

Abstract

Behavioral strategies require gating of premature responses to optimize outcomes. Several brain areas control impulsive actions, but the neuronal basis of natural variation in impulsivity between individuals remain largely unknown. Here, by combining a Go/No-Go behavioral assay with resting state (rs) functional MRI in mice, we identified the subthalamic nucleus (STN), a known gate for motor control in the basal ganglia, as a major hot spot for trait impulsivity. In vivo recorded STN neural activity encoded impulsive action as a separable state from basic motor control, characterized by decoupled STN/Substantia nigra pars reticulata (SNr) mesoscale networks. Optogenetic modulation of STN activity bi-directionally controlled impulsive behavior. Pharmacological and genetic manipulations showed that these impulsive actions are modulated by metabotropic glutamate receptor 4 (mGlu4) function in STN and its coupling to SNr in a behavioral trait-dependent manner, and independently of general motor function. In conclusion, STN circuitry multiplexes motor control and trait impulsivity, which are molecularly dissociated by mGlu4. This provides a potential mechanism for the genetic modulation of impulsive behavior, a clinically relevant predictor for developing psychiatric disorders associated with impulsivity.

Data availability

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

Article and author information

Author details

  1. Lukasz Piszczek

    The Research Institute of Molecular Pathology (IMP), Department of Neuroscience, Vienna Biocenter, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2017-8853
  2. Andreea Constantinescu

    The Research Institute of Molecular Pathology (IMP), Department of Neuroscience, Vienna Biocenter, Vienna, Austria
    Competing interests
    No competing interests declared.
  3. Dominic Kargl

    The Research Institute of Molecular Pathology (IMP), Department of Neuroscience, Vienna Biocenter, Vienna, Austria
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7206-1708
  4. Jelena Lazovic

    Preclinical Imaging Facility, Vienna BioCenter Core Facilities (VBCF), Vienna, Austria
    Competing interests
    No competing interests declared.
  5. Anton Pekcec

    Div Research Germany, Boehringer Ingelheim, Biberach an der Riss, Germany
    Competing interests
    Anton Pekcec, is affiliated with Boehringer Ingelheim Pharma GmbH and Co. The author has no competing and/or financial interests to declare..
  6. Janet R Nicholson

    Div Research Germany, Boehringer Ingelheim, Biberach an der Riss, Germany
    Competing interests
    Janet R Nicholson, is affiliated with Boehringer Ingelheim Pharma GmbH and Co. The author has no competing and/or financial interests to declare..
  7. Wulf Haubensak

    The Research Institute of Molecular Pathology (IMP), Department of Neuroscience, Vienna Biocenter, Vienna, Austria
    For correspondence
    wulf.haubensak@imp.ac.at
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2034-9184

Funding

H2020 European Research Council (311701)

  • Wulf Haubensak

Boehringer Ingelheim

  • Wulf Haubensak

Österreichische Forschungsförderungsgesellschaft

  • Wulf Haubensak

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

Reviewing Editor

  1. Alicia Izquierdo, University of California, Los Angeles, United States

Ethics

Animal experimentation: Animal procedures were performed in accordance with institutional guidelines and were approved by the 4 respective Austrian (BGBl nr. 501/1988, idF BGBl I no. 162/2005) and European authorities (Directive 86/609/EEC of 24 November 1986, European Community) and covered by the license M58/002220/2011/9.

Version history

  1. Received: August 14, 2020
  2. Accepted: December 31, 2021
  3. Accepted Manuscript published: January 4, 2022 (version 1)
  4. Version of Record published: January 31, 2022 (version 2)

Copyright

© 2022, Piszczek 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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  1. Lukasz Piszczek
  2. Andreea Constantinescu
  3. Dominic Kargl
  4. Jelena Lazovic
  5. Anton Pekcec
  6. Janet R Nicholson
  7. Wulf Haubensak
(2022)
Dissociation of impulsive traits by subthalamic metabotropic glutamate receptor 4
eLife 11:e62123.
https://doi.org/10.7554/eLife.62123

Share this article

https://doi.org/10.7554/eLife.62123

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