@article{discovery10178233,
            note = {Copyright {\copyright} 2023 The Authors. The Journal of Physiology published by John Wiley \& Sons Ltd on behalf of The Physiological Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.},
       publisher = {Wiley},
           month = {September},
            year = {2023},
           title = {Contributions of carotid bodies, retrotrapezoid nucleus neurons and preB{\"o}tzinger complex astrocytes to the CO2-sensitive drive for breathing},
         journal = {The Journal of Physiology},
            issn = {0022-3751},
        keywords = {Astrocyte; carotid body; chemosensitivity; designer receptors exclusively activated by designer drug; hypercapnia; preB{\"o}tzinger complex; retrotrapezoid nucleus},
          author = {SheikhBahaei, Shahriar and Marina, Nephtali and Rajani, Vishaal and Kasparov, Sergey and Funk, Gregory D and Smith, Jeffrey C and Gourine, Alexander V},
             url = {https://doi.org/10.1113/JP283534},
        abstract = {Current models of respiratory CO2 chemosensitivity are centred around the function of a specific population of neurons residing in the medullary retrotrapezoid nucleus (RTN). However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm-generating region of the medulla oblongata - the preB{\"o}tzinger complex (preB{\"o}tC). There is also evidence that astrocytes, non-neuronal brain cells, contribute to central CO2 chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preB{\"o}tC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO2 in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preB{\"o}tC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preB{\"o}tC astrocytes was associated with {$\sim$}20\% and {$\sim$}30\% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by {$\sim$}25\%. Bilateral inhibition of RTN neurons transduced to express Gi-coupled designer receptors exclusively activated by designer drug (DREADDGi) by application of clozapine-N-oxide reduced the CO2 response by {$\sim$}20\% and {$\sim$}40\% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preB{\"o}tC, inhibition of RTN neurons and carotid body denervation reduced the CO2-induced respiratory response by {$\sim$}70\%. These data further support the hypothesis that the CO2-sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preB{\"o}tC level, astrocytes modulate the activity of the respiratory network in response to CO2, either by relaying chemosensory information (i.e. they act as CO2 sensors) or by enhancing the preB{\"o}tC network excitability to chemosensory inputs.}
}