Interdependent feedback regulation of breathing by the carotid bodies and the retrotrapezoid nucleus

• Published in: The Journal of physiology Vol. 596; no. 15; pp. 3029 - 3042
• Main Authors: Guyenet, Patrice G., Bayliss, Douglas A., Stornetta, Ruth L., Kanbar, Roy, Shi, Yingtang, Holloway, Benjamin B., Souza, George M. P. R., Basting, Tyler M., Abbott, Stephen B. G., Wenker, Ian C.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.08.2018; John Wiley and Sons Inc
• Subjects: Alkalosis; Apnea; Automation; Brain stem; Carbon dioxide; Carotid body; central respiratory chemoreceptor; Chemoreceptors (internal); Feedback; Gases; Glutamatergic transmission; Heart diseases; Homeostasis; Hypoxia; Neurons; NREM sleep; optogenetics; Paracrine signalling; Respiration; Retrotrapezoid nucleus; Reviews; Sleep disorders; Solitary tract nucleus; Symposium Review; central respiratory chemoreceptor; carotid body; optogenetics
• ISSN: 0022-3751; 1469-7793; 1469-7793
• DOI: 10.1113/JP274357

The retrotrapezoid nucleus (RTN) regulates breathing in a CO2‐ and state‐dependent manner. RTN neurons are glutamatergic and innervate principally the respiratory pattern generator; they regulate multiple aspects of breathing, including active expiration, and maintain breathing automaticity during non‐REM sleep. RTN neurons encode arterial PCO2/pH via cell‐autonomous and paracrine mechanisms, and via input from other CO2‐responsive neurons. In short, RTN neurons are a pivotal structure for breathing automaticity and arterial PCO2 homeostasis. The carotid bodies stimulate the respiratory pattern generator directly and indirectly by activating RTN via a neuronal projection originating within the solitary tract nucleus. The indirect pathway operates under normo‐ or hypercapnic conditions; under respiratory alkalosis (e.g. hypoxia) RTN neurons are silent and the excitatory input from the carotid bodies is suppressed. Also, silencing RTN neurons optogenetically quickly triggers a compensatory increase in carotid body activity. Thus, in conscious mammals, breathing is subject to a dual and interdependent feedback regulation by chemoreceptors. Depending on the circumstance, the activity of the carotid bodies and that of RTN vary in the same or the opposite directions, producing additive or countervailing effects on breathing. These interactions are mediated either via changes in blood gases or by brainstem neuronal connections, but their ultimate effect is invariably to minimize arterial PCO2 fluctuations. We discuss the potential relevance of this dual chemoreceptor feedback to cardiorespiratory abnormalities present in diseases in which the carotid bodies are hyperactive at rest, e.g. essential hypertension, obstructive sleep apnoea and heart failure.  This schematic diagram is an attempt to explain why, in humans, obstructive sleep apnoea (OSA), essential hypertension or mild congestive heart failure (CHF) produce a chronic elevation of sympathetic tone (SNA) without concomitant change in breathing (frequency (fR) or tidal volume (VT)) and arterial PCO2 (P aC O2). All three conditions are associated with increased carotid body activity which might be expected a priori to increase both breathing and SNA. At rest, breathing is unchanged, however, whereas SNA is elevated. We speculate that the reason why breathing is unchanged is the powerful countervailing influence of a reduction in central chemoreceptor activity (RTN) which restores PCO2 homeostasis despite increased carotid body activity. By contrast, SNA might be chronically enhanced because its main buffering influence, the baroreflex, is actually reduced when the carotid bodies are activated. Because of the lack of breathing stimulation reported in humans, the present interpretation deliberately de‐emphasizes the importance of increased cardiorespiratory coupling (the excitatory influence of the respiratory pattern generator on the circuits responsible for SNA generation) in causing the increase in SNA. Instead, a previously described direct excitatory pathway from second‐order carotid body afferents (located within nucleus tractus solitarii (NTS)) to bulbospinal presympathetic neurons (RVLM) is invoked along with a reduced activity of the largely respiration‐independent baroreflex feedback pathway between NTS and RVLM neurons. The present schematic diagram does not adequately describe the cardiorespiratory changes observed in animal models of OSA or CHF, especially in reduced preparations, or the cardiorespiratory status of humans with end‐stage CHF, situations in which breathing is enhanced and/or irregular at rest. Under such conditions, increased cardiorespiratory coupling does contribute to the rise in SNA. Green arrows, pathway facilitated; red arrows, inhibitory pathway; red cross symbolizes the inhibitory effect of carotid body stimulation on the sympathetic baroreflex pathway.