1. Neuroscience

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
https://doi.org/10.7554/eLife.62123
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

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.

Metrics

  • 1,515
    views
  • 202
    downloads
  • 7
    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. 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

Categories and tags

Research organism

Further reading

    1. Neuroscience

    A chromatic feature detector in the retina signals visual context changes

    Larissa Höfling, Klaudia P Szatko ... Thomas Euler
    Research Article

    The retina transforms patterns of light into visual feature representations supporting behaviour. These representations are distributed across various types of retinal ganglion cells (RGCs), whose spatial and temporal tuning properties have been studied extensively in many model organisms, including the mouse. However, it has been difficult to link the potentially nonlinear retinal transformations of natural visual inputs to specific ethological purposes. Here, we discover a nonlinear selectivity to chromatic contrast in an RGC type that allows the detection of changes in visual context. We trained a convolutional neural network (CNN) model on large-scale functional recordings of RGC responses to natural mouse movies, and then used this model to search in silico for stimuli that maximally excite distinct types of RGCs. This procedure predicted centre colour opponency in transient suppressed-by-contrast (tSbC) RGCs, a cell type whose function is being debated. We confirmed experimentally that these cells indeed responded very selectively to Green-OFF, UV-ON contrasts. This type of chromatic contrast was characteristic of transitions from ground to sky in the visual scene, as might be elicited by head or eye movements across the horizon. Because tSbC cells performed best among all RGC types at reliably detecting these transitions, we suggest a role for this RGC type in providing contextual information (i.e. sky or ground) necessary for the selection of appropriate behavioural responses to other stimuli, such as looming objects. Our work showcases how a combination of experiments with natural stimuli and computational modelling allows discovering novel types of stimulus selectivity and identifying their potential ethological relevance.

    1. Neuroscience

    Recording γ-secretase activity in living mouse brains

    Steven S Hou, Yuya Ikegawa ... Masato Maesako
    Tools and Resources

    γ-Secretase plays a pivotal role in the central nervous system. Our recent development of genetically encoded Förster resonance energy transfer (FRET)-based biosensors has enabled the spatiotemporal recording of γ-secretase activity on a cell-by-cell basis in live neurons in culture. Nevertheless, how γ-secretase activity is regulated in vivo remains unclear. Here, we employ the near-infrared (NIR) C99 720–670 biosensor and NIR confocal microscopy to quantitatively record γ-secretase activity in individual neurons in living mouse brains. Intriguingly, we uncovered that γ-secretase activity may influence the activity of γ-secretase in neighboring neurons, suggesting a potential ‘cell non-autonomous’ regulation of γ-secretase in mouse brains. Given that γ-secretase plays critical roles in important biological events and various diseases, our new assay in vivo would become a new platform that enables dissecting the essential roles of γ-secretase in normal health and diseases.

    1. Neuroscience

    Dopamine: Making memories

    Francesco Longo
    Insight

    The neurotransmitter dopamine helps form long-term memories by increasing the production of proteins through a unique signaling pathway.