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

Abstract

The retrotrapezoid nucleus (RTN) regulates breathing in a CO - 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 /pH via cell-autonomous and paracrine mechanisms, and via input from other CO -responsive neurons. In short, RTN neurons are a pivotal structure for breathing automaticity and arterial 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 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.

Breathing regulation and blood gas homeostasis after near complete lesions of the retrotrapezoid nucleus in adult rats

“…Also, hypoxia inhibits the RTN via alkalosis (Basting et al . 2015), which normally opposes the direct breathing stimulation elicited by the RTN‐independent effect of carotid body stimulation on the respiratory pattern generator (Guyenet et al . 2018).…”

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…To mount an effective response to changes in blood gases, O 2 sensing mechanisms within the CNS must be tightly coordinated with inputs derived from peripheral chemosensory mechanisms Wilson & Teppema, 2016;Guyenet et al 2018). Exactly how these peripheral mechanisms are integrated within the central neuronal networks in the brainstem is not fully understood, and is a source of controversy (as reviewed in Smith et al 2010).…”

“…; Wilson & Teppema, ; Guyenet et al . ). Exactly how these peripheral mechanisms are integrated within the central neuronal networks in the brainstem is not fully understood, and is a source of controversy (as reviewed in Smith et al .…”

Advances in cellular and integrative control of oxygen and carbon dioxide homeostasis

“…The review by Guyenet et al . () discusses the functionally important interactions that occur between the carotid bodies and the central CO 2 ‐sensitive neurons in the retrotrapezoid nucleus in the control of breathing in various conditions.…”

“…The carotid bodies play an important role as the main oxygen sensor for arterial oxygen homeostasis in the body, but they also coordinate their central input with central chemoreceptor pathways for the maintenance of arterial CO 2 homeostasis. The review by Guyenet et al (2018) discusses the functionally important interactions that occur between the carotid bodies and the central CO 2 -sensitive neurons in the retrotrapezoid nucleus in the control of breathing in various conditions. Ramirez et al (2018) extend this discussion with insights into central neural mechanisms of oxygen sensing and homeostasis and the emergent role of central astrocytes as differential modulators of central chemosensory networks.…”