Retrotrapezoid nucleus and central chemoreception.
Patrice G. Guyenet1, E. Colombari2, Ana C. Takakura2 and T.S. Moreira2
1
Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA;
Department of Physiology, UNIFESP-EPM, São Paulo, SP, 04023-060, Brazil.
2
Central respiratory chemoreception (CRC) is the mechanism by which brain pCO2
regulates breathing. CRC contributes to blood gas homeostasis at all times. CRC is especially
important to sustain breathing during sleep and alterations of central and peripheral
chemoreflexes probably underlie many forms of sleep-disordered breathing. CRC is mediated by
changes in brain pH but its mechanisms are otherwise unclear. Lower brainstem neurons
commonly exhibit some pH-sensitivity in vitro and topical acidification of many lower brainstem
regions in vivo alters breathing to some degree. Accordingly, several investigators have proposed
that CRC is a highly distributed property of the central respiratory pattern generating network
(CPG). The alternative viewpoint is that the exquisite sensitivity of the respiratory network to
CO2 relies on specialized pH-sensitive neurons that drive the CPG (bona fide central
chemoreceptors). This second theory also implies that the widespread intrinsic pH-sensitivity of
CPG and other brainstem neurons is insufficient to account for CRC. However, the existence of
the postulated bona fide central chemoreceptors has not been definitively demonstrated. In this
talk, I shall consider whether such central respiratory chemoreceptors are located within the
retrotrapezoid nucleus (RTN).
RTN resides at the ventral medullary surface (VMS) in a region suggested as early as the
1960s to be of critical importance to CRC. RTN neurons are strongly activated by CO2 in vivo,
their CO2 threshold is markedly lower that of the respiratory motor outflows and their response to
CO2 is virtually insensitive to treatments that silence the CPG such as administration of opiate
agonists or antagonists of ionotropic glutamatergic receptors. RTN neurons are propriobulbar
interneurons and have the capacity to release glutamate. They selectively innervate the ventral
respiratory column plus selected regions of the dorsolateral pons and the nucleus of the solitary
tract (NTS). RTN neurons express Phox2b, a transcription factor whose mutation in man
produces a severe form of sleep apnea and loss of CRC. RTN lesions eliminate breathing under
anesthesia and its stimulation by CO2. In slices, RTN neurons encode pCO2 via pH in a manner
that resembles their response under anesthesia in vivo. Both in vivo and in slices, RTN neurons
are silent at pH 7.5 and are vigorously and almost linearly excited by acidification down to pH
7.2 and, at physiological temperature, the dynamic range of their response to pH is comparable in
vitro and in vivo. Under conditions of reduced synaptic activity in vitro, acidification closes a
resting potassium conductance in RTN neurons.
RTN neurons are not merely CO2 detectors, however. In vivo, these neurons are also
strongly activated by stimulation of the carotid bodies. Accordingly, RTN functions as a
chemosensory integrating center that responds to both brain pCO2 and to changes in arterial blood
gases (CO2 and O2). Furthermore, RTN neurons receive independent inhibitory inputs from the
CPG and from slowly-adapting lung stretch afferents (SARs). The existence of such inputs
suggests that the activity of the RTN is down-regulated under conditions when the CPG is already
being vigorously stimulated by factors other than blood gases. Such conditions may prevail when
the animal is alert or exercising, conditions during which breathing is less dependent on CRC
than during sleep.
In conclusion, RTN neurons are a pCO2-regulated source of excitatory drive to the CPG
and have properties consistent with specialized central respiratory chemoreceptors. These neurons
seem critical to maintain breathing under anesthesia and may be the VMS chemoreceptors whose
existence was postulated since the 1960s. RTN neurons may also be essential to breathe during
sleep although this hypothesis must be more thoroughly investigated.