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.

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

  • 1,579
    views
  • 211
    downloads
  • 9
    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

Further reading

    1. Neuroscience
    Ulrike Pech, Jasper Janssens ... Patrik Verstreken
    Research Article

    The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.

    1. Neuroscience
    Sven Ohl, Martin Rolfs
    Research Article

    Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e. feature-invariant) or specialized (i.e. feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e. the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e. a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speeds. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.