Is plasticity within the retrotrapezoid nucleus responsible for the recovery of the PCO2 set-point after carotid body denervation in rats?

Carotid body denervation (CBD) causes hypoventilation and increases the arterial PCO2 set-point; these effects eventually subside. The hypoventilation is attributed to reduced CB afferent activity and the PCO2 set-point recovery to CNS plasticity. In the present study, we investigated whether the retrotrapezoid nucleus (RTN), a group of non-catecholaminergic Phox2b-expressing central respiratory chemoreceptors (CCRs), is the site of such plasticity. We evaluated the contribution of the RTN to breathing frequency (FR ), tidal volume (VT ) and minute volume (VE ) by inhibiting this nucleus optogenetically for 10 s (archaerhodopsinT3.0) in unanaesthetized rats breathing various levels of O2 and/or CO2 . The measurements were made in seven rats before and 6-7 days after CBD and were repeated in seven sham-operated rats. Seven days post-CBD, blood gases and ventilation in 21% O2 were normal, whereas the hypoxic ventilatory reflex was still depressed (95.3%) and hypoxia no longer evoked sighs. Sham surgery had no effect. In normoxia or hypoxia, RTN inhibition produced a more sustained hypopnoea post-CBD than before; in hyperoxia, the responses were identical. Post-CBD, RTN inhibition reduced FR and VE in proportion to arterial pH or PCO2 (ΔVE : 3.3 ± 1.5% resting VE /0.01 pHa). In these rats, 20.7 ± 8.9% of RTN neurons expressed archaerhodopsinT3.0. Hypercapnia (3-6% FiCO2 ) increased FR and VT in CBD rats (n = 4). In conclusion, RTN regulates FR and VE in a pH-dependent manner after CBD, consistent with its postulated CCR function. RTN inhibition produces a more sustained hypopnoea after CBD than before, although this change may simply result from the loss of the fast feedback action of the CBs.