Novel Data Supporting the Two Respiratory Rhythm Oscillator Hypothesis. Focus on “Respiration-Related Rhythmic Activity in the Rostral Medulla of Newborn Rats”

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EDITORIAL FOCUSNovel Data Supporting the Two Respiratory Rhythm Oscillator Hypothesis. Focus on “Respiration-Related Rhythmic Activity in the Rostral Medulla of Newborn Rats”Wiktor A. Janczewski, and Jack L. FeldmanWiktor A. Janczewski, and Jack L. FeldmanPublished Online:01 Jul 2006https://doi.org/10.1152/jn.00246.2006This is the final version - click for previous versionMoreSectionsPDF (35 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Among the most rewarding moments in scientific discovery are when the pieces of a puzzle provided by different laboratories start to fall into place, forming a coherent and new view of the world. Several years ago, a consensus was emerging that respiratory rhythm in mammals arose from a single medullary site. Then suddenly several observations suggested that a second site was also involved (Janczewski et al. 2002; Mellen et al. 2003; Onimaru and Homma 2003). In this issue of the Journal of Neurophysiology (p. 55–61), a cleverly designed and well-executed study by Onimaru et al. (2006b) adds critical observations to the developing idea that two distinct oscillators in the medulla, the pre-Bötzinger Complex (pre-BötC) and the more rostral parafacial respiratory group (pFRG), contribute to respiratory rhythm generation in mammals (Feldman and Del Negro 2006; Feldman et al. 2003; Janczewski and Feldman 2006; Janczewski et al. 2002; Mellen et al. 2003; Onimaru and Homma 2003; Tanabe et al. 2005).In in vitro brain stem (en bloc) preparations from neonatal rats that generate respiratory motor nerve activity, the authors recorded rhythmic respiratory activity from the C4 spinal root (which innervates the diaphragm, the principal inspiratory muscle in mammals), the facial nerve (VIIn; which innervates the “alae nasi” muscles affecting resistance to airflow), and pFRG preinspiratory (preI) neurons, which are active before and after but are inhibited during inspiratory activity (Brockhaus and Ballanyi 1998; Onimaru et al. 1997). In intact mammals, the phrenic nerve is active during inspiration and silent during active expiration, whereas the VIIn has both inspiratory and expiratory activity. In en bloc preparations, inspiratory bursts in the C4 root and VIIn can skip one or more respiratory cycles, i.e., quantal breathing (Mellen et al. 2003). During these skipped cycles, the expiratory, i.e., peri-inspiratory, bursts of VIIn activity lose their inspiratory pause, merging into a single rhythmic burst just like concurrently recorded preI neurons.The first modern studies of the effects of brain stem transections on breathing were performed ∼200 yr ago (Le Gallois 1813). More recently, studies performed both in vitro (Smith et al. 1991) and in vivo (Janczewski and Feldman 2006) show that serial transverse medullary transections, progressing rostral to caudal, do not abolish rhythm in the C4 inspiratory output until the pre-BötC is reached. A unique and valuable component of the present study is that the rhythm both rostral and caudal to the transection was analyzed. When the authors transected their preparation just rostral to the pre-BötC, rhythmic output was observable in both the C4 root of the caudal block (containing the pre-BötC) (Smith et al. 1991) and the VIIn of the rostral block (containing the pFRG and the retrotrapezoid nucleus—RTN) but under different conditions. The inspiratory-modulated rhythm in the C4 root stopped briefly after transection but then resumed. This rhythm was suppressed by opioids (DAMGO) and subsequently restored when the bath K+ concentration was increased from 5 to ∼10 mM. The respiratory rhythm in the VIIn initially disappeared, but could be restarted by DAMGO; this induced rhythm lacked inspiratory-modulated activity, so that the activity patterns of VIIn and preI neurons resembled those seen previously in the intact brain stem during skipped breaths characteristic of quantal breathing.These findings provide strong support for the hypothesis that two distinct and independent respiratory oscillators are present in the medulla (Feldman and Del Negro 2006; Feldman et al. 2003; Janczewski and Feldman 2006; Janczewski et al. 2002; Mellen et al. 2003; Onimaru and Homma 2003; Tanabe et al. 2005) with the rhythm generator for inspiratory activity in the caudal block, whereas that generating rhythmic VIIn expiratory activity was in the rostral block.Taking these and other observations into account, the authors view the (RTN/)pFRG as the master generator of the respiratory rhythm in mammals (Onimaru and Homma 2003). We have recently debated this issue with the authors in a sister journal (Onimaru et al. 2006a) as we interpret the data differently (Feldman and Del Negro 2006; Janczewski and Feldman 2006): under normal conditions at rest in intact mammals, when there is minimal active expiratory activity, the respiratory rhythm is driven by the pre-BötC. In this scheme, the RTN/pFRG, in addition to its likely role in chemoreception (Guyenet et al. 2005; Li and Nattie 2002; Mulkey et al. 2004; Takakura et al. 2006), contributes as a second oscillator under conditions where active expiratory activity is generated, such as during exercise or elevated blood CO2. Regardless of the differing visions of the role of the pFRG, the data and insights provided by Onimaru, Kumagawa, and Homma represent an important contribution to our understanding of generation of the respiratory rhythm and challenge those interested in this fundamental problem to undertake more detailed studies of the role and interactions between rhythm generators in the pre-BötC and in the RTN/pFRG.REFERENCESBrockhaus and Ballanyi 1998 Brockhaus J and Ballanyi K. Synaptic inhibition in the isolated respiratory network of neonatal rats. Eur J Neurosci 10: 3823–3839, 1998.Crossref | PubMed | ISI | Google ScholarFeldman and Del 2006 Feldman JL and Del Negro CA. Looking for inspiration: new perspectives on respiratory rhythm. Nat Rev Neurosci 7: 232–242, 2006.Crossref | PubMed | ISI | Google ScholarFeldman et al. 2003 Feldman JL, Mitchell GS, and Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. 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