Late-Expiratory Activity: Emergence and Interactions With the Respiratory CPG

Abstract

The respiratory rhythm and motor pattern are hypothesized to be generated by a brain stem respiratory network with a rhythmogenic core consisting of neural populations interacting within and between the pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes and controlled by drives from other brain stem compartments. Our previous large-scale computational model reproduced the behavior of this network under many different conditions but did not consider neural oscillations that were proposed to emerge within the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and drive preinspiratory (or late-expiratory, late-E) discharges in the abdominal motor output. Here we extend the analysis of our previously published data and consider new data on the generation of abdominal late-E activity as the basis for extending our computational model. The extended model incorporates an additional late-E population in RTN/pFRG, representing a source of late-E oscillatory activity. In the proposed model, under normal metabolic conditions, this RTN/pFRG oscillator is inhibited by BötC/pre-BötC circuits, and the late-E oscillations can be released by either hypercapnia-evoked activation of RTN/pFRG or by hypoxia-dependent suppression of RTN/pFRG inhibition by BötC/pre-BötC. The proposed interactions between BötC/pre-BötC and RTN/pFRG allow the model to reproduce several experimentally observed behaviors, including quantal acceleration of abdominal late-E oscillations with progressive hypercapnia and quantal slowing of phrenic activity with progressive suppression of pre-BötC excitability, as well as to predict a release of late-E oscillations by disinhibition of RTN/pFRG under normal conditions. The extended model proposes mechanistic explanations for the emergence of RTN/pFRG oscillations and their interaction with the brain stem respiratory network.

Sympathoexcitation during chemoreflex active expiration is mediated byl-glutamate in the RVLM/Bötzinger complex of rats

“…These results are consistent with the previous studies performed in vivo showing that suppression of the inspiratory activity did not change the overall expiratory activity (Janczewski and Feldman 2006). Similarly to working models presented in different studies (Abdala et al 2009;Molkov et al 2010), suppression of the inspiratory activity (in the present study after microinjection of KYN into the RVLM/pre-BötC) eliminates inspiratory inhibition of expiratory neurons, which converts the biphasic activity of AbN during baseline to a prolonged monophasic discharge. These findings suggest a separate generator of expiratory activity, which interacts with the pre-BötC inspiratory oscillator and seems to be essential for respiratory pattern generation.…”

“…On the other hand, the expiratory activity during baseline seems to be generated mainly by expiratory neurons of BötC (Ezure et al 2003a,b,c;Tian et al 1999) while during high respiratory drive, such as in conditions of hypercapnia/hypoxia, a distinct expiratory generator located at the retrotrapezoid/parafacial respiratory group (RTN/pFRG) is activated and plays a critical role in the generation of active expiration (Abdala et al 2009;Molkov et al 2010Molkov et al , 2011. Intermingled with the BötC and pre-BötC neurons are the presympathetic neurons of the RVLM, which anteroposterior distribution is as long as 700 m from the caudal end of the facial nucleus to the caudal ventrolateral medulla (CVLM) (Dobbins and Feldman 1994;Wang et al 2002Wang et al , 2009).…”

Patterns of inspiratory phase-dependent activity in the in vitro respiratory network

“…Characterization of the typical firing behavior of single neurons with respect to the respiratory cycle has been central to models of respiratory rhythm generation (Molkov et al 2010;Rubin et al 2009;Rybak et al 2007;Smith et al 2007). Categorization of this behavior into different types has provided the substrate for understanding rhythmogenesis as arising from antagonistic pools of neurons with characteristic firing patterns.…”

“…In the respiratory and locomotor networks, catalogs of 5-20 different firing patterns and their hypothesized connections have been incorporated into increasingly complex models of rhythm generation with the idea that they can potentially explain how these networks generate rhythmicity (Molkov et al 2010;Ogilvie et al 1992;Rubin et al 2009;Rybak et al 1997aRybak et al , 1997bRybak et al , 1997cRybak et al , 2007Rybak et al , 2008Sherwood et al 2011;Smith et al 2007). Yet, despite the reliance of current models on the concept of different physiological categories, the quantitative basis for these categories has not been rigorously established, nor have the criteria that specify inclusion into one or another cell class been described in detail.…”

Neural mechanisms underlying respiratory rhythm generation in the lamprey

“…Onimaru et al, 2009;Thoby-Brisson et al, 2009;Guyenet and Mulkey, 2010;Feldman et al, 2013;Smith et al, 2013). This oscillator may display burst activity involving endogenous I NaP -dependent properties, as it occurs in the preBötC ThobyBrisson et al, 2009;Molkov et al, 2010). In addition, it contains glutamatergic neurons that express NK1 receptors, but it is not sensitive to opioids (Mulkey et al, 2004;Onimaru et al, 2008;Takakura et al, 2008;Lazarenko et al, 2009;Thoby-Brisson et al, 2009; for reviews, see Feldman et al, 2013;Guyenet and Mulkey, 2010).…”