Abstract

Obstructive sleep apnea (OSA) is characterized by sporadic collapse of the upper airway leading to periodic disruptions in breathing. Upper airway patency is governed by genioglossal nerve activity that originates from the hypoglossal motor nucleus. Mice with targeted deletion of the gene Hmox2, encoding the carbon monoxide (CO) producing enzyme, heme oxygenase-2 (HO-2), exhibit OSA, yet the contribution of central HO-2 dysregulation to the phenomenon is unknown. Using the rhythmic brainstem slice preparation that contains the preBötzinger complex (preBötC) and the hypoglossal nucleus, we tested the hypothesis that central HO-2 dysregulation weakens hypoglossal motoneuron output. Disrupting HO-2 activity increased the occurrence of subnetwork activity from the preBötC, which was associated with an increased irregularity of rhythmogenesis. These phenomena were also associated with the intermittent inability of the preBötC rhythm to drive output from the hypoglossal nucleus (i.e., transmission failures), and a reduction in the input-output relationship between the preBötC and the motor nucleus. HO-2 dysregulation reduced excitatory synaptic currents and intrinsic excitability in inspiratory hypoglossal neurons. Inhibiting activity of the CO-regulated H2S producing enzyme, cystathionine-g-lyase (CSE), reduced transmission failures in HO-2 null brainstem slices, which also normalized excitatory synaptic currents and intrinsic excitability of hypoglossal motoneurons. These findings demonstrate a hitherto uncharacterized modulation of hypoglossal activity through mutual interaction of HO‑2/CO and CSE/H2S, and support the potential importance of centrally‑derived gasotransmitter activity in regulating upper airway control.

Data availability

Numerical data used to generate figures is uploaded to Dryad. Source Data file names refer to current figure panels.

The following data sets were generated

Article and author information

Author details

  1. Brigitte M Browe

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ying-Jie Peng

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jayasri Nanduri

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nanduri R Prabhakar

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alfredo J Garcia III

    Institute for Integrative Physiology, University of Chicago, Chicago, United States
    For correspondence
    ajgarcia3@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5620-7519

Funding

National Heart, Lung, and Blood Institute (P01 HL144454)

  • Nanduri R Prabhakar

National Institute of Neurological Disorders and Stroke (R01NS107421)

  • Alfredo J Garcia III

National Institute on Drug Abuse (R01DA057767)

  • Alfredo J Garcia III

National Heart, Lung, and Blood Institute (R01HL163965)

  • Alfredo J Garcia III

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

Ethics

Animal experimentation: In accordance with National Institutes of Health guidelines, all animal protocols were performed with the approval of the Institute of Animal Care and Use Committee at The University of Chicago (ACUP 72486, ACUP 71811).

Copyright

© 2023, Browe 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

  • 595
    views
  • 114
    downloads
  • 2
    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. Brigitte M Browe
  2. Ying-Jie Peng
  3. Jayasri Nanduri
  4. Nanduri R Prabhakar
  5. Alfredo J Garcia III
(2023)
Gasotransmitter modulation of hypoglossal motoneuron activity
eLife 12:e81978.
https://doi.org/10.7554/eLife.81978

Share this article

https://doi.org/10.7554/eLife.81978

Further reading

    1. Neuroscience
    Cassandra Avila, Martin Sarter
    Research Article

    Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned cue-associated action rules. Cortico-striatal projections are an essential part of the brain’s attention–motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic–DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign-trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In STs, turn cue-locked glutamate concentrations frequently peaked twice or three times, contrasting with predominately single peaks in GTs. In GTs, but not STs, inhibition of prelimbic–DMS projections attenuated turn rates and turn cue-evoked glutamate concentrations and increased the number of turn cue-locked glutamate peaks. These findings indicate that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking. As cortico-striatal dysfunction has been hypothesized to contribute to a wide range of disorders, including complex movement control deficits in Parkinson’s disease and compulsive drug taking, the demonstration of phenotypic contrasts in cortico-striatal control implies the presence of individual vulnerabilities for such disorders.

    1. Neuroscience
    Célian Bimbard, Flóra Takács ... Philip Coen
    Tools and Resources

    Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) allow reuse of the probes after explantation; (3) be light enough for use in mice. Here, we present the ‘Apollo Implant’, an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a ‘payload’ module which is attached to the probe and is recoverable, and a ‘docking’ module which is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across eight labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.