Retrotrapezoid nucleus and central chemoreception

Abstract

The 'distributed chemoreception theory' attributes the central chemoreflex (the stimulation of breathing by CNS acidification) to the cumulative effects of pH on multiple classes of respiratory neurons as well as on their tonic sources of drive. Opinions differ as to how many classes of pH-sensitive neurons contribute to the central chemoreflex but the number of candidates is high and growing fast. The 'specialized chemoreceptor theory', endorsed here, attributes the chemoreflex to a limited number of specialized neurons. These neurons (the central chemoreceptors) would drive a respiratory pattern generator that is not or minimally activated by acidification. In this review we first describe the properties of the retrotrapezoid nucleus (RTN) and argue that this nucleus may contain the most important central chemoreceptors. Next, we subject the assumptions that underlie the distributed chemoreception theory to a critical analysis. We propose several explanations for the apparent contradiction between the two competing theories of central chemoreception. We attribute much of the current controversy to premature extrapolations of the effects of acidification on neurons recorded in vitro (chemosensitivity) and to a semantic confusion between chemosensitivity and chemoreception (the mechanism by which CO(2) or pH activates breathing in vivo).

Figure 1. RTN and a few of its connections

CPG, central respiratory pattern generator; NTS, nucleus of the solitary tract; iNTS, interstitial subnucleus; comNTS, commissural subnucleus; SARs, slowly adapting lung stretch receptors; VRC, ventral respiratory column. Acidification activates RTN neurons by reducing an unidentified potassium conductance. There is no evidence that this potassium channel is directly proton sensitive. Whether protons act intra or extracellularly is also unknown, and therefore both possibilities are represented. RTN neurons receive an oligosynaptic excitatory input from the carotid body. It is important to realize that these neurons are not just chemoreceptors. RTN neurons also receive inhibitory inputs from the CPG and from several types of pulmonary receptors. These inhibitory inputs are tentatively interpreted as feedbacks that limit the activity of the CPG under conditions when this network is already vigorously activated by sources of drive other than of chemosensory origin. RTN neurons are activated by brainstem serotonergic neurons that release serotonin, thyrotropin-releasing hormone (TRH) and substance P. These inputs presumably contribute to the ability of serotonergic neurons to stimulate breathing and to facilitate the central chemoreflex. Glutamatergic neurons are in green, inhibitory neurons (GABA or glycine) are in red. The CPG consists of vast numbers of interconnected neurons located primarily within the VRC and the dorsal pons.