1. Neuroscience
Download icon

Ventrolateral periaqueductal gray neurons prioritize threat probability over fear output

  1. Kristina M Wright  Is a corresponding author
  2. Michael A McDannald  Is a corresponding author
  1. Boston College, United States
Research Article
  • Cited 7
  • Views 2,201
  • Annotations
Cite this article as: eLife 2019;8:e45013 doi: 10.7554/eLife.45013


Faced with potential harm, individuals must estimate the probability of threat and initiate an appropriate fear response. In the prevailing view, threat probability estimates are relayed to the ventrolateral periaqueductal gray (vlPAG), to organize fear output. A straightforward prediction is that vlPAG single-unit activity reflects fear output, invariant of threat probability. We recorded vlPAG single-unit activity in male, Long Evans rats undergoing fear discrimination. Three 10-s auditory cues predicted unique foot shock probabilities: danger (p = 1.00), uncertainty (p = 0.375) and safety (p = 0.00). Fear output was measured by suppression of reward seeking over the entire cue and in one-second cue intervals. Cued fear non-linearly scaled to threat probability and cue-responsive vlPAG single-units scaled their firing on one of two timescales: at onset or ramping toward shock delivery. VlPAG onset activity reflected threat probability, invariant of fear output, while ramping activity reflected both signals with threat probability prioritized.

Article and author information

Author details

  1. Kristina M Wright

    Department of Psychology, Boston College, Chestnut Hill, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
  2. Michael A McDannald

    Department of Psychology, Boston College, Chestnut Hill, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8525-1260


National Institutes of Health (MH117791)

  • Michael A McDannald

National Institutes of Health (DA034010)

  • Michael A McDannald

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


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 (#2018-002) of Boston College. All surgery was performed under isofluorane anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Geoffrey Schoenbaum, National Institute on Drug Abuse, National Institutes of Health, United States

Publication history

  1. Received: January 9, 2019
  2. Accepted: March 4, 2019
  3. Accepted Manuscript published: March 7, 2019 (version 1)
  4. Version of Record published: March 26, 2019 (version 2)


© 2019, Wright & McDannald

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.


  • 2,201
    Page views
  • 298
  • 7

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

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
    Seung-Eon Roh et al.
    Research Article Updated

    Climbing fibers (CFs) generate complex spikes (CS) and Ca2+ transients in cerebellar Purkinje cells (PCs), serving as instructive signals. The so-called 'all-or-none' character of CSs has been questioned since the CF burst was described. Although recent studies have indicated a sensory-driven enhancement of PC Ca2+ signals, how CF responds to sensory events and contributes to PC dendritic Ca2+ and CS remains unexplored. Here, single or simultaneous Ca2+ imaging of CFs and PCs in awake mice revealed the presynaptic CF Ca2+ amplitude encoded the sensory input’s strength and directly influenced post-synaptic PC dendritic Ca2+ amplitude. The sensory-driven variability in CF Ca2+ amplitude depended on the number of spikes in the CF burst. Finally, the spike number of the CF burst determined the PC Ca2+ influx and CS properties. These results reveal the direct translation of sensory information-coding CF inputs into PC Ca2+, suggesting the sophisticated role of CFs as error signals.

    1. Genetics and Genomics
    2. Neuroscience
    Marina Kovalenko et al.
    Research Article Updated

    Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in HttQ111 mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the HttQ111 allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in medium-spiny neurons and highlight a complex relationship between the expanded Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.