J Appl Physiol 103: 721-722, 2007;
doi:10.1152/japplphysiol.00003.2007b
8750-7587/07 $8.00
POINT-COUNTERPOINT
Rebuttal from Ramirez
Our in vitro experiments indicate the following.
Network reconfiguration underlies eupnea, sighs, and gasping (3).
Pacemaker activity reconfigures during eupnea and gasping (5).
Two to six years later, Paton et al. (4) reproduce similar results in vivo and in situ. It is thus surprising that the debate continues.
One source for continued confusion is a wrong understanding of rhythmogenesis. Many regions contribute to eupneic rhythm and pattern without actually generating the rhythm. The pons, for example, tonically modulates rhythmogenesis, and motor nuclei shape the motor pattern. But neither modulation nor pattern formation constitute rhythmogenesis. The term "neurogenesis" used by Paton and St. John is unspecific and potentially confusing. It could imply that the authors mean "rhythmogenesis," when, in fact, "neurogenesis" includes any neuronal process underlying eupnea, which involves neuronal processes originating in pons, medulla, spinal cord, cerebellum, and neocortex. Characterizing motor outflow may be optimal to assign behavioral terms to a respiratory motor pattern, but its characterization can not go much beyond the description of a motor pattern. Motor outflow is the result of rhythmogenesis, pattern formation, and modulation, and its characterization allows no differentiation between these processes.
Synaptic inhibition is essential for eupneic rhythmogenesis in vivo, in situ and in vitro (Fig. 1, A and B). It is incorrect to state that in vitro rhythms are little altered by the blockade of synaptic inhibition. Synaptic inhibition establishes different phases of eupnea and regulates excitability (3, 8). Blocking synaptic inhibition promotes pacemaker bursting, synchronizes post-I activity with inspiration, and eliminates expiration (3, 7). Although rhythmicity persists in vitro and in situ (1, 3), everybody agrees that the persisting rhythm is not eupnea, as critical features are abolished.
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Fig. 1. Reconfiguration of respiratory network in vitro. Different colors symbolize different network configuration. A: In normoxia, inhibition defines expiratory activity (top trace). In hypoxia, the same neuron discharges in phase with inspiration (blue top trace). Activity is lost during prolonged hypoxia (red top trace). Note, concurrent change in integrated activity (bottom traces; Ref. 10). B: pacemaker activity (black) is suppressed in presence of synaptic inhibition (red), but bursting is not suppressed in all pacemakers (4). C: norepinephrine (NE) enhances augmenting burst in presence of INaP and ICAN (black, blue top trace), but causes decrementing burst following blockade of ICAN (red top trace). Respiratory rhythm persists following blockade of INaP (black bottom trace), but is abolished by NE (red bottom trace; Ref. 7).
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In normoxia, rhythmicity persists in vivo, in situ and in vitro following blockade of INaP (current responsible for bursting in cadmium-insensitive pacemakers). St. John and Paton conclude that INap is not essential for "eupnea." However, the persisting network responds differently to neuromodulators (Fig. 2C; Ref. 10), and rhythmogenesis becomes dependent on ICAN. Because rhythmogenesis is fundamentally altered we conclude that INaP is essential for generating eupnea."
In normoxia, respiratory rhythmogenesis is abolished following blockade of INaP and ICAN [eliminating bursting in both pacemaker types (2, 9)]. In a small percentage of preparations, substance P temporarily restores network (2, 9), but also pacemaker, activity (9). We thus propose that pacemakers are essential for rhythmogenesis in normoxia.
In conclusion, we propose that eupnea results from rhythm-generating mechanisms that include inhibition, excitation, and pacemaker activity. Each mechanism conveys properties essential for eupnea. Abolishing any of these mechanisms alters rhythmogenesis that forms the basis of eupneic activity.
REFERENCES
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- Lieske SP, Thoby-Brisson M, Telgkamp P, Ramirez JM. Reconfiguration of the neural network controlling multiple breathing patterns: Eupnea, sighs and gasps. Nat Neurosci 3: 600–607, 2000.[CrossRef][Web of Science][Medline]
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Copyright © 2007 by the American Physiological Society.
