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However, there is significant evidence suggesting that chemosensitive neurons exist in other brainstem areas, including the rhythm\u2010generating region of the medulla oblongata \u2013 the preB\u00f6tzinger complex (preB\u00f6tC). There is also evidence that astrocytes, non\u2010neuronal brain cells, contribute to central CO\n                      <jats:sub>2<\/jats:sub>\n                      chemosensitivity. In this study, we reevaluated the relative contributions of the RTN neurons, the preB\u00f6tC astrocytes, and the carotid body chemoreceptors in mediating the respiratory responses to CO\n                      <jats:sub>2<\/jats:sub>\n                      in experimental animals (adult laboratory rats). To block astroglial signalling via exocytotic release of transmitters, preB\u00f6tC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preB\u00f6tC astrocytes was associated with \u223c20% and \u223c30% reduction of the respiratory response to CO\n                      <jats:sub>2<\/jats:sub>\n                      in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO\n                      <jats:sub>2<\/jats:sub>\n                      respiratory response by \u223c25%. Bilateral inhibition of RTN neurons transduced to express Gi\u2010coupled designer receptors exclusively activated by designer drug (DREADD\n                      <jats:sub>Gi<\/jats:sub>\n                      ) by application of clozapine\u2010\n                      <jats:italic>N<\/jats:italic>\n                      \u2010oxide reduced the CO\n                      <jats:sub>2<\/jats:sub>\n                      response by \u223c20% and \u223c40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preB\u00f6tC, inhibition of RTN neurons and carotid body denervation reduced the CO\n                      <jats:sub>2<\/jats:sub>\n                      \u2010induced respiratory response by \u223c70%. These data further support the hypothesis that the CO\n                      <jats:sub>2<\/jats:sub>\n                      \u2010sensitive drive to breathe requires inputs from the peripheral chemoreceptors and several central chemoreceptor sites. At the preB\u00f6tC level, astrocytes modulate the activity of the respiratory network in response to CO\n                      <jats:sub>2<\/jats:sub>\n                      , either by relaying chemosensory information (i.e. they act as CO\n                      <jats:sub>2<\/jats:sub>\n                      \u00a0sensors) or by enhancing the preB\u00f6tC network excitability to chemosensory inputs.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15743-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>\n                            This study reevaluated the roles played by the carotid bodies, neurons of the retrotrapezoid nucleus (RTN) and astrocytes of the preB\u00f6tC in mediating the CO\n                            <jats:sub>2<\/jats:sub>\n                            \u2010sensitive drive to breathe.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>The data obtained show that disruption of preB\u00f6tC astroglial signalling, blockade of inputs from the peripheral chemoreceptors or inhibition of RTN neurons similarly reduce the respiratory response to hypercapnia.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            These data provide further support for the hypothesis that the CO\n                            <jats:sub>2<\/jats:sub>\n                            \u2010sensitive drive to breathe is mediated by the inputs from the peripheral chemoreceptors and several central chemoreceptor sites.\n                          <\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp283534","type":"journal-article","created":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T05:19:56Z","timestamp":1695532796000},"page":"223-240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Contributions of carotid bodies, retrotrapezoid nucleus neurons and preB\u00f6tzinger complex astrocytes to the CO\n                    <sub>2<\/sub>\n                    \u2010sensitive drive for breathing"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-9979","authenticated-orcid":false,"given":"Shahriar","family":"SheikhBahaei","sequence":"first","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Research Department of Neuroscience, Physiology and Pharmacology University College London  London UK"},{"name":"Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH)  Bethesda Maryland USA"},{"name":"Neuron\u2010Glia Signaling and Circuits Unit, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH)  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nephtali","family":"Marina","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Research Department of Neuroscience, Physiology and Pharmacology 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