Neural bases for the genesis and CO2 therapy of periodic Cheyne-Stokes breathing in neonatal male connexin-36 knockout mice

Ana M Casarrubios; Leonel F Pérez-Atencio; Cristina Martín; José M Ibarz; Eva Mañas; David L Paul; Luis C Barrio

doi:10.3389/fnins.2023.1045269

Neural bases for the genesis and CO₂ therapy of periodic Cheyne-Stokes breathing in neonatal male connexin-36 knockout mice

Front Neurosci. 2023 Feb 8:17:1045269. doi: 10.3389/fnins.2023.1045269. eCollection 2023.

Authors

Ana M Casarrubios^{1

2}, Leonel F Pérez-Atencio¹, Cristina Martín¹, José M Ibarz¹, Eva Mañas³, David L Paul⁴, Luis C Barrio^{1

5}

Affiliations

¹ Units of Experimental Neurology and Sleep Apnea, Hospital "Ramón y Cajal" (IRYCIS), Madrid, Spain.
² Ph.D. Program in Neuroscience, Autonoma de Madrid University-Cajal Institute, Madrid, Spain.
³ Sleep Apnea Unit, Respiratory Department, Hospital "Ramón y Cajal" (IRYCIS), Madrid, Spain.
⁴ Department of Neurobiology, Medical School, Harvard University, Boston, MA, United States.
⁵ Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain.

Abstract

Periodic Cheyne-Stokes breathing (CSB) oscillating between apnea and crescendo-decrescendo hyperpnea is the most common central apnea. Currently, there is no proven therapy for CSB, probably because the fundamental pathophysiological question of how the respiratory center generates this form of breathing instability is still unresolved. Therefore, we aimed to determine the respiratory motor pattern of CSB resulting from the interaction of inspiratory and expiratory oscillators and identify the neural mechanism responsible for breathing regularization induced by the supplemental CO₂ administration. Analysis of the inspiratory and expiratory motor pattern in a transgenic mouse model lacking connexin-36 electrical synapses, the neonatal (P14) Cx36 knockout male mouse, with a persistent CSB, revealed that the reconfigurations recurrent between apnea and hyperpnea and vice versa result from cyclical turn on/off of active expiration driven by the expiratory oscillator, which acts as a master pacemaker of respiration and entrains the inspiratory oscillator to restore ventilation. The results also showed that the suppression of CSB by supplemental 12% CO₂ in inhaled air is due to the stabilization of coupling between expiratory and inspiratory oscillators, which causes the regularization of respiration. CSB rebooted after washout of CO₂ excess when the inspiratory activity depressed again profoundly, indicating that the disability of the inspiratory oscillator to sustain ventilation is the triggering factor of CSB. Under these circumstances, the expiratory oscillator activated by the cyclic increase of CO₂ behaves as an "anti-apnea" center generating the crescendo-decrescendo hyperpnea and periodic breathing. The neurogenic mechanism of CSB identified highlights the plasticity of the two-oscillator system in the neural control of respiration and provides a rationale base for CO₂ therapy.

Keywords: carbon dioxide; central sleep apnea; coupled oscillators; periodic breathing; respiratory oscillators.

Grants and funding

This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (BUF2015-71078-P and BFU2015-70067-REDC) to LB. AC had a contract with the Program for Youth Employment Initiative of the Community of Madrid (PEJD-2018-PRE/BMD-8019).