The respiratory chemoreception conundrum: light at the end of the tunnel?

Arterial PCO₂ is tightly regulated via changes in breathing. A rise in PCO₂ activates the carotid bodies and exerts additional effects on neurons located within the CNS, causing an increase in lung ventilation. Central respiratory chemoreception refers to the component of this homeostatic reflex that is triggered by activation of receptors located within the brain (central chemoreceptors). Throughout the body, CO₂ generally operates via the proxy of pH. Since countless proteins, ion channels and neurons display some degree of pH-sensitivity, the notion that central respiratory chemoreception could rely on a few specialized neurons seems a priori counter-intuitive. Yet, two types of neurons currently stand out as critically important for breathing regulation by CO₂: the retrotrapezoid nucleus (RTN) and the raphe. RTN neurons are glutamatergic, strongly activated by hypercapnia in vivo and by CO₂ or protons in slices. These neurons target selectively the pontomedullary regions implicated in generating the respiratory rhythm and pattern. Their response to CO₂ seems to involve both cell-autonomous and paracrine effects of CO₂, the latter presumably mediated by the surrounding glia. The specific connections that these excitatory neurons establish with the rest of the breathing network are likely to be the main explanation of their importance to respiratory chemoreception. Serotonergic neurons have a powerful stimulatory effect on breathing, they facilitate the chemoreflexes and a subset of them likely function as CO₂ sensors. Opto- and pharmacogenetic methods have played an important role in assessing the contribution of RTN and serotonergic neurons as well as glial cells to respiration. These particular experiments are emphasized here for thematic reasons although the current perception of the importance of the RTN and serotonergic cells to respiratory chemoreception also relies on many other types of evidence. A small portion of this evidence is presented as background. This article is part of a Special Issue entitled Optogenetics (7th BRES).