Coupled Oscillations in Neural Control of Breathing

Abstract

The respiratory rhythm inmammals is generated by a respiratory central pattern generator (CPG) in the brainstem and encompasses both pons and medulla (see Fig. 1; Alheid and McCrimmon 2008; Smith et al. 2013). The pre-Botzinger complex (pre-BotC), located in the ventrolateral region of the medulla, is the putative kernel of rhythmic inspiratory activity. The pre-BotC interacts with the expiratory neurons of Botzinger complex (BotC) to generate primary respiratory oscillations. These oscillations are defined by both the intrinsic biophysical properties of neurons involved and the network interactions within and between the pre-BotC and BotC. Through the premotor neurons of the rostral ventral respiratory group (rVRG), these oscillations produce rhythmic drive to phrenic motoneurons that through the phrenic nerve (PN) control movements of the diaphragm and lung inflation. A distinct site of neural oscillations involved with the respiratory function, located more rostral to the pre-BotC, was identified in vitro, in the isolated brainstem-spinal cord preparation. The source of these oscillations, which was termed parafacial respiratory group (pFRG), was found to reside within the retrotrapezoid nucleus (RTN) or partially overlaps with it (Onimaru and Homma 2003; Janczewski and Feldman 2006). The pFRG oscillations emerge with increased metabolic demands (e.g., hypercapnia) and via abdominal nerve (AbN) drive abdominal muscles enabling forced lung deflation (active expiration). This rhythmic activity is coupled to the pre-BotC oscillations so that generated bursts represent late-expiratory (late-E) or sometimes biphasic (containing pre-inspiratory, pre-I, and post-inspiratory, post-I, components) discharges (Janczewski and Feldman 2006; Abdala et al. 2009). Several competing concepts concerning the appearance of RTN/pFRG oscillations and their physiological function have been suggested (Janczewski et al. 2002; Onimaru and Homma 2003; Abdala et al. 2009; Molkov et al. 2010). However, there are still heated debates on the exact physiological role of RTN/pFRG oscillations, the specific conditions for their emergence, and the nature and mechanisms of the interactions between the BotC/pre-BotC and RTN/pFRG oscillators.