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Related Experiment Video

Updated: Oct 24, 2025

Using the Threat Probability Task to Assess Anxiety and Fear During Uncertain and Certain Threat
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A midbrain dynorphin circuit promotes threat generalization.

Lizz Fellinger1, Yong S Jo2, Avery C Hunker3

  • 1University of Amsterdam, Amsterdam, the Netherlands; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

Current Biology : CB
|August 13, 2021
PubMed
Summary

Threat generalization is mediated by kappa opioid receptor (KOR) and dynorphin (Dyn) signaling in the midbrain. This pathway promotes generalized threat responses as threat intensity increases, impacting anxiety and discrimination.

Keywords:
CRISPRdopaminedorsal raphedynorphinfeargeneralizationkappa opioid receptor

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Area of Science:

  • Neuroscience
  • Behavioral Neuroscience
  • Molecular Psychiatry

Background:

  • Threat generalization, where responses to a threat extend to similar but non-threatening stimuli, is a hallmark of anxiety disorders.
  • The neural circuits and molecular mechanisms underlying the shift from threat discrimination to generalization are not fully understood.
  • The kappa opioid receptor (KOR) system, involving dynorphin (Dyn), is implicated in stress and dysphoria, suggesting a potential role in threat processing.

Purpose of the Study:

  • To investigate the role of kappa opioid receptor (KOR) and dynorphin (Dyn) signaling in the ventral tegmental area (VTA) in regulating threat generalization.
  • To identify specific neural inputs to the VTA that contribute to threat generalization and anxiety-like behaviors.
  • To elucidate the relationship between threat intensity, discrimination, and generalization.

Main Methods:

  • Utilized rodent models to assess behavioral responses to varying threat intensities.
  • Employed molecular and circuit-level techniques to examine KOR/Dyn signaling within the VTA.
  • Investigated the contribution of specific afferent pathways, including the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN), to VTA function.

Main Results:

  • Found that KOR/Dyn signaling in the VTA is crucial for promoting threat generalization.
  • Demonstrated that projections from the BNST and DRN to the VTA differentially influence anxiety-like behavior and threat generalization.
  • Observed an inverted "U" relationship between threat intensity and conditioned threat discrimination, with generalization increasing at higher intensities.

Conclusions:

  • KOR/Dyn signaling in the midbrain VTA is a key mechanism driving threat generalization.
  • Specific neural pathways projecting to the VTA play distinct roles in anxiety and threat generalization.
  • Understanding these mechanisms offers potential therapeutic targets for anxiety disorders characterized by threat generalization.