Peripheral-central chemoreceptor interaction and the significance of a critical period in the development of respiratory control

Abstract

Respiratory control entails coordinated activities of peripheral chemoreceptors (mainly the carotid bodies) and central chemosensors within the brain stem respiratory network. Candidates for central chemoreceptors include Phox2b-containing neurons of the retrotrapezoid nucleus, serotonergic neurons of the medullary raphé, and/or multiple sites within the brain stem. Extensive interconnections among respiratory-related nuclei enable central chemosensitive relay. Both peripheral and central respiratory centers are not mature at birth, but undergo considerable development during the first two postnatal weeks in rats. A critical period of respiratory development (∼P12-P13 in the rat) exists when abrupt neurochemical, metabolic, ventilatory, and electrophysiological changes occur. Environmental perturbations, including hypoxia, intermittent hypoxia, hypercapnia, and hyperoxia alter the development of the respiratory system. Carotid body denervation during the first two postnatal weeks in the rat profoundly affects the development and functions of central respiratory-related nuclei. Such denervation delays and prolongs the critical period, but does not eliminate it, suggesting that the critical period may be intrinsically and genetically determined.

Fig. 1

Schematic diagram of connections linking the peripheral chemoreceptor carotid body directly and indirectly to many mediators of central chemosensitivity within the respiratory network. All connections are based on published papers, but not all published reports are included. XII, hypoglossal nucleus; Amb, nucleus ambiguus; BötC, Bötzinger complex; CB, carotid body; cVRG, caudal ventral respiratory group; DMNX, dorsal motor nucleus of the vagus; DRG, dorsal respiratory group; K–F, Kölliker-Fuse nucleus; LC, locus coeruleus; LPGi, lateral paragigantocellular nucleus; NTS, nucleus tractus solitarius (including the commissural [NTS_COM], dorsolateral [NTS_DL], medial (NTS_M], and ventrolateral [NTS_VL] subnuclei); PBC, pre-Bötzinger complex; PB_L, PB_M, lateral and medial parabrachial nuclei; pPy, parapyramidal region; PRG, pontine respiratory group; RM, raphé magnus, ROb, raphé obscurus, RP, raphé pallidus; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group; VRG, ventral respiratory group (cVRG, rVRG, caudal and rostral VRG); VMS, ventral medullary surface; VRC, ventral respiratory column. The term “ventrolateral medulla or VLM” is not included here because it is loosely used by different investigators to mean one or more nuclear groups separately listed here.

Fig. 2

Optical densitometric measurements of immunoreaction product in individual neurons of various brain stem nuclei from P2 to P21. Data points are mean ± SEM. A. Tryptophan hydroxylase (TPH); B. serotonin transporter (SERT); C. 5-HT_1A receptor; D. 5-HT_1B receptor; E. 5-HT_2A receptor; and F. 5-HT_1A, 5-HT_1B, and 5-HT_2A receptors and SERT in the non-respiratory cuneate nucleus (CN) for comparison. The key for various nuclei is the same as in Fig. 1. Tukey’s tests comparing one age group with its immediately adjacent younger age group showed that P12 was the only time point in the first 3 postnatal weeks that a significant was found (*P < 0.05). (Modified from Liu and Wong-Riley, 2010a, b). For ease of comparison, the highest value of each graph in the original was adjusted to 1, and all of the other values were adjusted accordingly.

Fig. 3

Postnatal trends of metabolic rate (V̇O₂ and V̇CO₂) (A and B) and V̇_E/V̇O₂ and V̇_E/V̇CO₂ ratios (C and D) in hypoxia as compared to normoxia in rats from P0 to P21. Normoxic values were adjusted to 1 for comparison. Tukey’s tests comparing one age group with its immediately adjacent younger age group indicated that P13 was the only time point in the entire 3 postnatal weeks that a day-to-day significance was found (*P < 0.05; **P < 0.01; ***P < 0.001). See text for details. (Modified from Liu et al., 2009).

Fig. 4

Patch clamp recordings of hypoglossal motoneurons in normal rats from P0 to P16. A. Charge transfer of mEPSCs was significantly reduced at P12. B. Amplitude of sEPSCs was significantly reduced at P12–P13. C. Frequency of sEPSCs was significantly reduced at P12–P13 and rose again at P14. The frequency of sEPSCs at P7 was also significantly higher than that at P2. D. Charge transfer of mIPSCs was significantly increased at P12, the only time point when a day-to-day difference was found. E. The amplitude of sIPSCs was significantly increased at P12 and P15. F. The frequency of sIPSCs was significantly increased at P12. (*P < 0.05; **P < 0.01). See text for details. (Modified from Gao et al., 2011).