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.

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.

Metrics

  • 3,653
    views
  • 592
    downloads
  • 68
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  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

Share this article

https://doi.org/10.7554/eLife.59799

Further reading

    1. Neuroscience
    Sven Ohl, Martin Rolfs
    Research Article

    Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e. feature-invariant) or specialized (i.e. feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e. the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e. a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speeds. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.

    1. Neuroscience
    Gergely F Turi, Sasa Teng ... Yueqing Peng
    Research Article

    Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.