Respiratory rhythm generation: triple oscillator hypothesis

Abstract

Breathing is vital for survival but also interesting from the perspective of rhythm generation. This rhythmic behavior is generated within the brainstem and is thought to emerge through the interaction between independent oscillatory neuronal networks. In mammals, breathing is composed of three phases - inspiration, post-inspiration, and active expiration - and this article discusses the concept that each phase is generated by anatomically distinct rhythm-generating networks: the preBötzinger complex (preBötC), the post-inspiratory complex (PiCo), and the lateral parafacial nucleus (pF _L), respectively. The preBötC was first discovered 25 years ago and was shown to be both necessary and sufficient for the generation of inspiration. More recently, networks have been described that are responsible for post-inspiration and active expiration. Here, we attempt to collate the current knowledge and hypotheses regarding how respiratory rhythms are generated, the role that inhibition plays, and the interactions between the medullary networks. Our considerations may have implications for rhythm generation in general.

Keywords: Oscillators; Postinspiration; Respiration; breathing; networks; pacemaker; preBotzinger complex; rhythm generation.

Figure 1.. Anatomical map of oscillators in the ventral respiratory column.

Schematic of the brainstem from a sagittal view illustrating the approximate anatomical locations of the three respiratory rhythm generators. Shapes in blue represent the three distinct oscillators (preBötzinger complex [preBötC], post-inspiratory complex [PiCo], and retrotrapezoid nucleus parafacial respiratory group [RTN/pFRG]) that are thought to individually control the three phases of respiration. The RTN/pFRG is further segregated into the lateral parafacial nucleus (pF _L), which is more lateral, dorsal, and rhythmogenic, and the ventral parafacial nucleus (pF _V), which is more medial, ventral, and not considered rhythmogenic. Shapes in gray represent motor nuclei, specifically VII N = facial nucleus and NA = nucleus ambiguus. Green represents neuronal populations that contribute to the respiratory rhythm but are not thought to be independent rhythm generators. The dotted lines indicate the approximate boundaries of the horizontal slice, while the pink and yellow boxes illustrate the approximate boundaries of transverse slices isolating preBötC and PiCo, respectively.

Figure 2.. Illustration of triple-oscillator hypothesis.

We propose that, at rest, the preBötzinger complex (preBötC) and post-inspiratory complex (PiCo) alternate activity to generate a two-phase rhythm, inspiration and post-inspiration. Under periods of high metabolic demand, for instance during exercise, a third oscillator is incorporated to create a three-phase rhythm. We propose that each of the three phases – inspiration, post-inspiration, and active expiration – are controlled by independent oscillators: the preBötC, PiCo, and lateral parafacial nucleus (pF _L), respectively. We further postulate that inhibition between these networks coordinates the phasing and timing of the rhythms.