Contributions of carotid bodies, retrotrapezoid nucleus neurons and preBotzinger complex astrocytes to the CO₂-sensitive drive for breathing

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 preBotzinger complex (preBotC). 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 preBotC 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, preBotC astrocytes were targeted to express the tetanus toxin light chain (TeLC). Bilateral expression of TeLC in preBotC astrocytes was associated with similar to 20% and similar to 30% reduction of the respiratory response to CO2 in conscious and anaesthetized animals, respectively. Carotid body denervation reduced the CO2 respiratory response by similar to 25%. Bilateral inhibition of RTN neurons transduced to express Gi-coupled designer receptors exclusively activated by designer drug (DREADD(Gi)) by application of clozapine-N-oxide reduced the CO2 response by similar to 20% and similar to 40% in conscious and anaesthetized rats, respectively. Combined blockade of astroglial signalling in the preBotC, inhibition of RTN neurons and carotid body denervation reduced the CO2-induced respiratory response by similar to 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 preBotC 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 preBotC network excitability to chemosensory inputs. image