C1 neurons are part of the circuitry that recruits active expiration in response to peripheral chemoreceptors activation

Abstract

Breathing results from the interaction of three distinct oscillators: the pre-Bötzinger Complex (preBötC), driving inspiration, the post-inspiratory complex (PiCo), driving post-inspiration, and the lateral parafacial region (pFRG), driving active expiration. The pFRG is silent at rest and becomes rhythmically active during stimulation of peripheral chemoreceptors, which also activates adrenergic C1 cells. We postulated that the C1 cells and the pFRG may constitute functionally distinct but interacting populations for controlling expiratory activity during hypoxia. We found in rats that a) C1 neurons are activated by hypoxia and project to the pFRG region; b) active expiration elicited by hypoxia was blunted after blockade of ionotropic glutamatergic receptors at the level of the pFRG; and c) selective depletion of C1 neurons eliminated the active expiration elicited by hypoxia. These results suggest that C1 cells may regulate the respiratory cycle, including active expiration, under hypoxic conditions.

Data availability

All data generated or analyzed during this study are included in the manuscript

Article and author information

Author details

  1. Milene R Malheiros-Lima

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  2. Josiane N Silva

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  3. Felipe C Souza

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  4. Ana C Takakura

    Department of Pharmacology, University of São Paulo, São Paulo, Brazil
    Competing interests
    The authors declare that no competing interests exist.
  5. Thiago S Moreira

    Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil
    For correspondence
    tmoreira@icb.usp.br
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9789-8296

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (Graduate Student Fellowship)

  • Milene R Malheiros-Lima

Fundação de Amparo à Pesquisa do Estado de São Paulo (2016/23281-3)

  • Ana C Takakura

Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/23376-1)

  • Thiago S Moreira

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Finance Code 001)

  • Thiago S Moreira

Conselho Nacional de Desenvolvimento Científico e Tecnológico (301219/2016-8)

  • Ana C Takakura

Conselho Nacional de Desenvolvimento Científico e Tecnológico (301904/2015-4)

  • Thiago S Moreira

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

Reviewing Editor

  1. Ronald L Calabrese, Emory University, United States

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 (#07-2014) of the Institute of Biomedical Science of the University of São Paulo. All surgery was performed under anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: October 8, 2019
  2. Accepted: January 21, 2020
  3. Accepted Manuscript published: January 23, 2020 (version 1)
  4. Version of Record published: February 10, 2020 (version 2)

Copyright

© 2020, Malheiros-Lima 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

  • 1,739
    Page views
  • 243
    Downloads
  • 20
    Citations

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

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. Milene R Malheiros-Lima
  2. Josiane N Silva
  3. Felipe C Souza
  4. Ana C Takakura
  5. Thiago S Moreira
(2020)
C1 neurons are part of the circuitry that recruits active expiration in response to peripheral chemoreceptors activation
eLife 9:e52572.
https://doi.org/10.7554/eLife.52572

Share this article

https://doi.org/10.7554/eLife.52572

Further reading

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

    1. Medicine
    2. Neuroscience
    Luisa Fassi, Shachar Hochman ... Roi Cohen Kadosh
    Research Article

    In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individual’s subjective experience of the type of treatment she or he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment - the thought of receiving the active or placebo condition during an experiment - can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N = 387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Studies 1 and 2; transcranial direct current stimulation: Studies 3 and 4). Our findings show that the inclusion of subjective treatment can provide a better model fit either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive, and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants’ subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions.