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A prefrontal-bed nucleus of the stria terminalis circuit limits fear to uncertain threat

Research Article
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Cite this article as: eLife 2020;9:e60812 doi: 10.7554/eLife.60812

Abstract

In many cases of trauma, the same environmental stimuli that become associated with aversive events are experienced on other occasions without adverse consequence. We examined neural circuits underlying partially reinforced fear (PRF), whereby mice received tone-shock pairings on half of conditioning trials. Tone-elicited freezing was lower after PRF conditioning than fully reinforced fear (FRF) conditioning, despite an equivalent number of tone-shock pairings. PRF preferentially activated medial prefrontal cortex (mPFC) and bed nucleus of the stria terminalis (BNST). Chemogenetic inhibition of BNST-projecting mPFC neurons increased PRF, not FRF, freezing. Multiplexing chemogenetics with in vivo neuronal recordings showed elevated infralimbic cortex (IL) neuronal activity during CS-onset and freezing-cessation; these neural correlates were abolished by chemogenetic mPFC®BNST inhibition. These data suggest mPFC®BNST neurons limit fear to threats with a history of partial association with an aversive stimulus, with potential implications for understanding the neural basis of trauma-related disorders.

Data availability

Some of the data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1.

Article and author information

Author details

  1. Lucas R Glover

    LBGN, NIH, Rockville, United States
    For correspondence
    lucasglover@email.gwu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1127-3819
  2. Kerry M McFadden

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Max Bjorni

    Department of Psychology, Santa Clara University, Santa Clara, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sawyer R Smith

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Natalie G Rovero

    Department of Psychology, Santa Clara University, Santa Clara, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarvar Oreizi-Esfahani

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Takayuki Yoshida

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Abagail F Postle

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Mio Nonaka

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Lindsay R Halladay

    Department of Psychology, Santa Clara University, Santa Clara, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Andrew Holmes

    LBGN, NIH, Rockville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7308-1129

Funding

National Institute on Alcohol Abuse and Alcoholism (NIAAA-IRP)

  • Andrew Holmes

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

Ethics

Animal experimentation: All experimental procedures were approved by the NIAAA (protocol # LBGN-AH-01) and Santa Clara University (SCU AWA: D18-01042) Animal Care and Use Committees and followed the NIH guidelines outlined in 'Using Animals in Intramural Research' and the local Animal Care and Use Committees.

Reviewing Editor

  1. Mihaela D Iordanova, Concordia University, Canada

Publication history

  1. Received: July 7, 2020
  2. Accepted: December 11, 2020
  3. Accepted Manuscript published: December 15, 2020 (version 1)
  4. Version of Record published: February 22, 2021 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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