Neural control of breathing and CO₂ homeostasis

I will focus on recent advances regarding how the brain detects CO₂ to regulate breathing (central respiratory chemoreception) and I will replace the findings in the general context of CO₂/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO₂ and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN, and a subset of serotonergic neurons located in raphe magnus) are activated by small changes in PCO₂ and contribute importantly to the chemoreflexes. RTN neurons are glutamatergic and innervate selectively the pontomedullary respiratory centers; in conscious rats these neurons regulate multiple aspect of breathing (frequency, inspiratory amplitude, airway patency and active expiration). In such rats, RTN inhibition reduces breathing in direct proportion to arterial pH. RTN neurons detect PCO₂ via synaptic input from peripheral chemoreceptors, signals from astrocytes and intrinsic proton receptors (TASK-2, GPR4). Deleting TASK-2 or GPR4 greatly diminishes the pH-sensitivity of RTN neurons in vitro and reduces the central chemoreflex by ~65%; deleting both virtually eliminates the central chemoreflex. Reintroducing GPR4 selectively in RTN neurons restores the reflex entirely. RTN neurons respond to countless modulators (serotonin, orexin, TRH, etc.) which operate via pH-independent mechanisms but have the potential to strongly bias the chemoreflexes at RTN level and elsewhere. RTN neuron development depends on transcription factors Atoh-1, Egr-2 and Phox2b. Mice carrying a Phox2b mutation that causes congenital central hypoventilation syndrome are born without RTN and recapitulate the respiratory deficits seen in this disease, particularly the loss of the central chemoreflex. In conscious rats, hypoxia causes respiratory alkalosis which switches off RTN. RTN can be reactivated by administration of CO₂ or acetazolamide, a respiratory stimulant. RTN and the carotid bodies cooperate in sustaining breathing in conscious rats i.e. the respiratory depressant effects of carotid body denervation or hyperoxia are quickly compensated by an increase in RTN activity. Respiratory chemoreflexes are arousal state-dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. The effects of RTN on breathing are highly dependent on the state of vigilance. For example, breathing frequency is no longer regulated by RTN during REM sleep and RTN elicits active expiration only during waking. These characteristics probably result from changes in the release of serotonin and other state-dependent modulators, within RTN and elsewhere in the breathing network. Abrupt and severe hypercapnia, hypoxia, or both, produce arousal; the arousal occurs partly via activation of dorsolateral pontine regions by carotid bodies and the above mentioned central chemoreceptors but it may also result from more diffuse effects of [H+] on the brain. During exercise, “central command” and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO₂ and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation.