Dissociation of impulsive traits by subthalamic metabotropic glutamate receptor 4

Elife. 2022 Jan 4:11:e62123. doi: 10.7554/eLife.62123.

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 remains 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 hotspot 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 bidirectionally 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.

Keywords: Go/No-Go task; STN; behavioral trait; fMRI; impulsivity; mGlu4; mouse; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basal Ganglia / physiology
  • Cell Line
  • Deep Brain Stimulation
  • Electrophysiology / methods
  • Impulsive Behavior*
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / physiology
  • Optogenetics / methods
  • Receptors, Metabotropic Glutamate / genetics*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Subthalamic Nucleus / physiology*

Substances

  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 4

Grants and funding

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