1. Neuroscience
Download icon

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

Research Article
  • Cited 0
  • Views 1,227
  • Annotations
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.

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.

Metrics

  • 1,227
    Page views
  • 199
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Neuroscience
    Daniela Saderi et al.
    Research Article Updated

    Both generalized arousal and engagement in a specific task influence sensory neural processing. To isolate effects of these state variables in the auditory system, we recorded single-unit activity from primary auditory cortex (A1) and inferior colliculus (IC) of ferrets during a tone detection task, while monitoring arousal via changes in pupil size. We used a generalized linear model to assess the influence of task engagement and pupil size on sound-evoked activity. In both areas, these two variables affected independent neural populations. Pupil size effects were more prominent in IC, while pupil and task engagement effects were equally likely in A1. Task engagement was correlated with larger pupil; thus, some apparent effects of task engagement should in fact be attributed to fluctuations in pupil size. These results indicate a hierarchy of auditory processing, where generalized arousal enhances activity in midbrain, and effects specific to task engagement become more prominent in cortex.

    1. Neuroscience
    Pratish Thakore et al.
    Research Article

    Cerebral blood flow is dynamically regulated by neurovascular coupling to meet the dynamic metabolic demands of the brain. We hypothesized that TRPA1 channels in capillary endothelial cells are stimulated by neuronal activity and instigate a propagating retrograde signal that dilates upstream parenchymal arterioles to initiate functional hyperemia. We find that activation of TRPA1 in capillary beds and post-arteriole transitional segments with mural cell coverage initiates retrograde signals that dilate upstream arterioles. These signals exhibit a unique mode of biphasic propagation. Slow, short-range intercellular Ca2+ signals in the capillary network are converted to rapid electrical signals in transitional segments that propagate to and dilate upstream arterioles. We further demonstrate that TRPA1 is necessary for functional hyperemia and neurovascular coupling within the somatosensory cortex of mice in vivo. These data establish endothelial cell TRPA1 channels as neuronal activity sensors that initiate microvascular vasodilatory responses to redirect blood to regions of metabolic demand.