Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons

  1. Anna J Bowen
  2. Jane Y Chen
  3. Y. Waterlily Huang
  4. Nathan A Baertsch
  5. Sekun Park
  6. Richard D Palmiter  Is a corresponding author
  1. Howard Hughes Medical Institute, University of Washington, United States
  2. Seattle Children's Research Institute, United States
  3. University of Washington, United States

Abstract

Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses in mice, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRPPBN neurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRPPBN neurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar projections elicit assorted unconditioned threat responses including autonomic arousal, anxiety, and freezing behavior, while thalamic and basal forebrain projections generate freezing behavior and, unexpectedly, contribute to associative fear learning. Moreover, the unconditioned responses generated by individual projections are complementary, with simultaneous activation of multiple sites driving profound freezing behavior and bradycardia that are not elicited by any individual projection. This semi-parallel, scalable connectivity schema likely contributes to flexible control of threat responses in unpredictable environments.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Anna J Bowen

    Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8911-2572
  2. Jane Y Chen

    Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3986-8785
  3. Y. Waterlily Huang

    Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  4. Nathan A Baertsch

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1589-5575
  5. Sekun Park

    Department of Biochemistry, University of Washington, Seattle, United States
    Competing interests
    No competing interests declared.
  6. Richard D Palmiter

    Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, United States
    For correspondence
    palmiter@u.washington.edu
    Competing interests
    Richard D Palmiter, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6587-0582

Funding

National Institutes of Health (T32NS099578)

  • Anna J Bowen

National Institutes of Health (R01-DA24908)

  • Richard D Palmiter

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2183-02) of the University of Washington. All surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Joshua Johansen, RIKEN Center for Brain Science, Japan

Publication history

  1. Received: June 8, 2020
  2. Accepted: August 28, 2020
  3. Accepted Manuscript published: August 28, 2020 (version 1)
  4. Version of Record published: September 10, 2020 (version 2)

Copyright

© 2020, Bowen 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.

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  1. Anna J Bowen
  2. Jane Y Chen
  3. Y. Waterlily Huang
  4. Nathan A Baertsch
  5. Sekun Park
  6. Richard D Palmiter
(2020)
Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons
eLife 9:e59799.
https://doi.org/10.7554/eLife.59799
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