Reflexively inhibiting respiratory drive

Breathing is a voluntary somatomotor activity that depends on the integration of a chemosensory drive, arising from central and peripheral chemoreceptors, with dynamic feedback from airway afferents and with the respiratory rhythm generator. In this issue of The Journal of Physiology, as part of a continuing series of investigations into the chemosensory role of the retrotrapezoid nucleus (RTN; Mulkey et al. 2004; Guyenet et al. 2005), Moreira et al. (2007) provide evidence that RTN neurons integrate chemosensory information with inhibitory afferent input arising in the pathway from slowly adapting pulmonary stretch receptors (SARs). Chemosensory properties of brain regions on or near the ventrolateral surface of the medulla and caudal pons were originally observed in studies by Loeschcke, Schlaefke, Mitchell and their colleagues (Schlaefke, 1981). Subsequently, Smith et al. (1989) identified the RTN as a cluster of neurons close to the brainstem surface just below the facial nucleus (just caudal to the level of the trapezoid body) that projected to medullary regions containing respiratory neurons. The location of the RTN neurons near the ventral surface and their extensive projections to respiratory neurons suggested to Smith et al. (1989) that these neurons could be the chemoreceptors described by the earlier investigations. In the ensuing decades, numerous studies have demonstrated the general importance of this region in chemoreception using a variety of approaches including chemical activation or inactivation and general or neurotransmitter specific lesions (Nattie & Li, 2006). Interactions between central chemoreceptors and peripheral respiratory afferents have also long been recognized. For example, lung inflation activates SARs eliciting a variety of cardiorespiratory responses that includes lengthening expiratory duration. The effectiveness of the expiratory lengthening is, however, inversely related to the magnitude of the central chemoreceptor stimulation (Mitchell et al. 1980). Moreira et al. (2007) show that at least an aspect of SAR and central chemoreceptor interaction can occur in the retrotrapezoid nucleus. This site is significant in that it is upstream of respiratory neurons involved in inspiratory rhythm generation as well as those sculpting the rhythm into patterns of activity on motor nerves to respiratory muscles. Thus, as pointed out by Moreira et al. (2007) this can provide a mechanism for modulating a tonic excitatory drive to the respiratory system. The interaction documented by Moreira et al. (2007) is an inhibition of chemosensitive neurons in the RTN by lung inflation. The authors interpret this as a negative feedback suppression of a central chemoreceptor excitatory drive to inspiratory neurons. Inhibiting the chemoreceptor drive would facilitate the inhibiting effects of SAR activation on inspiratory neurons in rhythm-generating regions of the ventral respiratory column (VRC). Deflation-activated receptors (DARs) are an additional lung volume-related afferent that could also contribute to the modulation of RTN activity. These receptors are particularly prevalent in rats and second order neurons in the DAR afferent pathway are thought to be excitatory and project to the vicinity of the RTN (Otake et al. 2001). DAR can be activated at resting end-expiratory lung volumes in rats (Ho et al. 2001). Consequently they could contribute to the increase in activity of RTN neurons observed by Moreira et al. (2007) between lung inflations. An important related issue is the postulated existence of an expiratory rhythm-generating circuit in the RTN region ventral to the facial nucleus (Onimaru & Homma, 2003; Janczewski & Feldman, 2006). Activation of SARs by lung inflation in juvenile rats excites the expiratory oscillator while DAR receptors inhibit expiration (Janczewski & Feldman, 2006). Thus, the demonstrated effects of SARs (Moreira et al. 2007) and the postulated effects of DAR afferent inputs on RTN chemoreceptive neurons in adult rats appear to be opposite to those on expiratory rhythm-generating neurons demonstrated in neonatal and juvenile rats. The potential coincidence of chemoreceptor neurons and an expiratory oscillator in the RTN region and its persistence into adults will be a continuing hot issue for the neurobiology of breathing. Unravelling this ontogenetic puzzle and understanding the multiple roles neurons in this parafacial region play in the regulation of breathing will be particularly important for the current theoretical debate. This is also significant because developmental abnormalities in chemosensitivity at the ventral surface of human brains are postulated to play a critical role in the aetiology of diseases including sudden infant death syndrome.