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.
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© 2015 Published by Elsevier Inc.