Retrotrapezoid nucleus and parafacial respiratory group

Abstract

The rat retrotrapezoid nucleus (RTN) contains about 2000 Phox2b-expressing glutamatergic neurons (ccRTN neurons; 800 in mice) with a well-understood developmental lineage. ccRTN neuron development fails in mice carrying a Phox2b mutation commonly present in the congenital central hypoventilation syndrome. In adulthood, ccRTN neurons regulate the breathing rate and intensity, and may regulate active expiration along with other neighboring respiratory neurons. Prenatally, ccRTN neurons form an autonomous oscillator (embryonic parafacial group, e-pF) that activates and possibly paces inspiration. The pacemaker properties of the ccRTN neurons probably vanish after birth to be replaced by synaptic drives. The neonatal parafacial respiratory group (pfRG) may represent a transitional phase during which ccRTN neurons lose their group pacemaker properties. ccRTN neurons are activated by acidification via an intrinsic mechanism or via ATP released by glia. In summary, throughout life, ccRTN neurons seem to be a critical hub for the regulation of CO(2) via breathing.

Figure 1

RTN and pfRG A. Schematic parasagittal section through the pontomedullary region of the rodent brain showing the location of the ccRTN neurons (grey area) and the known projection of this cell group (Rosin et al., 2006; Abbott et al., 2009). Abbreviations: Amb, compact portion of nucleus ambiguus; KF, Kölliker-Fuse nucleus; LRN, lateral reticular nucleus; Mo5, trigeminal motor nucleus; NTS, nucleus of the solitary tract; PBN, parabrachial nuclei; SO, superior olive; tz, trapezoid body; VRC, ventral respiratory column. B: blow-up of the ventrolateral medulla showing the region that may contain the expiratory oscillator suggested by the experiments of Janczewski and Feldman (2006). Originally, the term parafacial respiratory group, pfRG, referred to neurons with a double pre-I/post-I discharge that were located under and caudal to the facial motor nucleus (Onimaru and Homma, 2003). The asterisk identifies some of the many neurons currently known to exhibit a double pre-I-post-I discharge in the Suzue preparation (neonate brainstem spinal cord in vitro) and / or in hypoxic adult rodent preparations (Onimaru et al., 2008; Fortuna and Guyenet, 2008; Abdala et al., 2009). The pound sign (#) identifies neurons that plausibly contribute inhibitory or excitatory inputs to the expiratory premotor neurons (E2 neurons of the caudal ventral respiratory group, cVRG). This population may include inhibitory neurons such as the expiratory decremental (E-DEC) neurons of the Bötzinger region and the inspiratory (I) neurons of the retrofacial region (Anders et al, 1991; Bainton and Kirkwood, 1979; Ballantyne and Richter, 1986; Iscoe, 1998) and excitatory neurons such as the ccRTN neurons and, perhaps, the newly described E2 neurons (Abbott et al., 2009; Abdala et al., 2009). Under specific circumstances these various neurons may form an expiratory oscillator that functions independently of the inspiratory oscillator. The inspiratory oscillator resides primarily in the pre-Bötzinger complex (pre-BötC) (Feldman and Del Negro, 2006). Pre-I, E-I, Ramp-I and late-I are respiratory-phasic neurons that contribute to the generation of the inspiratory motor outflow according to Smith et al. (2007). rVRG: rostral ventral respiratory group. C: example of one ccRTN neuron recorded at room temperature in a transverse slice obtained from a Phox2b-eGFP 8 day-old mouse (modified from Lazarenko et al., 2009). The record also shows the robust response of this neuron to 0.1 μM substance P. The acid sensitivity of the neuron illustrated in C (~1Hz / 0.1 pH unit) is typical of the ccRTN neurons. The average response to acid doubles at 37 degrees Celsius in the same neonate in vitro preparation and doubles again in vivo in the adult. D: schematic illustration of the hypothetical mechanisms responsible for the acid-sensitivity of ccRTN neurons. In the neonate in vitro, neuronal activation by acid results from the reduction of a background potassium conductance. The proton receptors may be potassium channels that are directly sensitive to intracellular or extracellular acidification. These channels are not identified. In the adult in vivo the acid sensitivity of RTN neurons may be further enhanced by the surrounding glia. The hypothesized mechanisms include the release of ATP and protons by a subset of glial cells depolarized by acid (Erlichman et al., 2008; Gourine et al., 2005).