1. Neuroscience

Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization

  1. Valerie Michael
  2. Jack Goffinet
  3. John Pearson
  4. Fan Wang
  5. Katherine Tschida  Is a corresponding author
  6. Richard Mooney  Is a corresponding author
  1. Duke University Medical Center, United States
  2. Duke University Medical Centre, United States
  3. Cornell University, United States
https://doi.org/10.7554/eLife.63493
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  1. Valerie Michael
  2. Jack Goffinet
  3. John Pearson
  4. Fan Wang
  5. Katherine Tschida
  6. Richard Mooney
(2020)
Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization
eLife 9:e63493.
https://doi.org/10.7554/eLife.63493
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Abstract

Animals vocalize only in certain behavioral contexts, but the circuits and synapses through which forebrain neurons trigger or suppress vocalization remain unknown. Here we used transsynaptic tracing to identify two populations of inhibitory neurons that lie upstream of neurons in the periaqueductal gray that gate the production of ultrasonic vocalizations in mice (i.e., PAG-USV neurons). Activating PAG-projecting neurons in the preoptic hypothalamus (POAPAG neurons) elicited USV production in the absence of social cues. In contrast, activating PAG-projecting neurons in the central-medial boundary zone of the amygdala (AmgC/M-PAG neurons) transiently suppressed USV production without disrupting non-vocal social behavior. Optogenetics-assisted circuit mapping in brain slices revealed that POAPAG neurons directly inhibit PAG interneurons, which in turn inhibit PAG-USV neurons, whereas AmgC/M-PAG neurons directly inhibit PAG-USV neurons. These experiments identify two major forebrain inputs to the PAG that trigger and suppress vocalization, respectively, while also establishing the synaptic mechanisms through which these neurons exert opposing behavioral effects.

Data availability

Data have been deposited to the Duke Research Data Repository, under the DOI: 10.7924/r4cz38d99. We have deposited 4 types of data in the repository: (1) confocal microscope images of in situ hybridization, (2) audio and video files from the mice used in this study, (3) slice electrophysiology data, and (4) custom Matlab codes used for data analysis. All other data analyzed in this study are included in the manuscript and supporting files.

The following data sets were generated

Article and author information

Author details

  1. Valerie Michael

    Neurobiology, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Jack Goffinet

    Biostatistics and Bioinformatics, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6729-0848

  3. John Pearson

    Biostatistics & Bioinformatics, Neurobiology, Center for Cognitive Neuroscience, Psychology and Neuroscience, Electrical and Computer Engineering, Duke University Medical Center, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9876-7837

  4. Fan Wang

    Department of Neurobiology, Department of Cell Biology, Duke University Medical Centre, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Katherine Tschida

    Psychology, Cornell University, Ithaca, United States
    For correspondence
    kat227@cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8171-1722

  6. Richard Mooney

    Department of Neurobiology, Duke University Medical Center, Durham, United States
    For correspondence
    mooney@neuro.duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3308-1367

Funding

National Institutes of Health (R01 DC013826)

  • Richard Mooney

National Institutes of Health (R01 MH117778)

  • Fan Wang
  • Richard Mooney

National Institutes of Health (F31DC017879)

  • Valerie Michael

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 experiments were conducted according to protocols approved by the Duke University Institutional Animal Care and Use Committee protocol (# A227-17-09).

Copyright

© 2020, Michael 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. Valerie Michael
  2. Jack Goffinet
  3. John Pearson
  4. Fan Wang
  5. Katherine Tschida
  6. Richard Mooney
(2020)
Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization
eLife 9:e63493.
https://doi.org/10.7554/eLife.63493

Share this article

https://doi.org/10.7554/eLife.63493

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Further reading

    1. Neuroscience

    Nested circuits mediate the decision to vocalize

    Shuyun Xiao, Valerie Michael, Richard Mooney
    Research Advance Updated

    Vocalizations facilitate mating and social affiliation but may also inadvertently alert predators and rivals. Consequently, the decision to vocalize depends on brain circuits that can weigh and compare these potential benefits and risks. Male mice produce ultrasonic vocalizations (USVs) during courtship to facilitate mating, and previously isolated female mice produce USVs during social encounters with novel females. Earlier we showed that a specialized set of neurons in the midbrain periaqueductal gray (PAG-USV neurons) are an obligatory gate for USV production in both male and female mice, and that both PAG-USV neurons and USVs can be switched on by their inputs from the preoptic area (POA) of the hypothalamus and switched off by their inputs from neurons on the border between the central and medial amygdala (AmgC/M-PAG neurons) (Michael et al., 2020). Here, we show that the USV-suppressing AmgC/M-PAG neurons are strongly activated by predator cues or during social contexts that suppress USV production in male and female mice. Further, we explored how vocal promoting and vocal suppressing drives are weighed in the brain to influence vocal production in male mice, where the drive and courtship function for USVs are better understood. We found that AmgC/M-PAG neurons receive monosynaptic inhibitory input from POA neurons that also project to the PAG, that these inhibitory inputs are active in USV-promoting social contexts, and that optogenetic activation of POA cell bodies that make divergent axonal projections to the amygdala and PAG is sufficient to elicit USV production in socially isolated male mice. Accordingly, AmgC/M-PAG neurons, along with POAPAG and PAG-USV neurons, form a nested hierarchical circuit in which environmental and social information converges to influence the decision to vocalize.