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INVITED EDITORIAL
Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine
Northwestern University
Chicago, IL 60611-3008
E-mail: dm{at}northwestern.edu
A CENTRAL QUESTION in the control of breathing is how and where the brain generates respiratory rhythm. No single approach is likely to provide a definitive answer to this question; however, a pair of papers in the present volume of this journal by Wenninger et al. (18, 19) confront this problem and, in the process, illuminate a number of the issues surrounding this question. Their data indicate a necessary role of pre-Bötzinger complex (pre-BötzC) neurons in the generation of a normal relaxed respiratory rhythm (eupnea). The pre-BötzC is a discrete region located ventral to the caudal end of the compact part of nucleus ambiguus, within the ventral respiratory column of the ventrolateral medulla (1). In the neonatal rat brain stem in vitro, Smith et al. (14) demonstrated that this small region is both essential and sufficient for the maintenance of periodic activity approximating the respiratory rhythm, when measured on respiratory-related cranial nerves. A variety of in vivo and in vitro studies have subsequently reinforced the concept that the pre-BötzC is important in the generation of a normal breathing rhythm. Blockade of synaptic transmission in the pre-BötzC in rats or cats abolishes respiratory rhythm (3), whereas discrete microinjection of an excitatory amino acid in the same region results in tachypnea and contrasts with respiratory slowing after similar injections immediately rostral or caudal to this structure (11, 17).
There is also morphological support for the concept of the pre-BötzC as a unique ventral respiratory column compartment. Gray et al. (5) observed that neurons expressing substance P receptors [i.e., neurokinin-1 receptor (NK1R)] occur in greater numbers in the pre-BötzC and demonstrated physiologically that they identify a subset of pre-BötzC neurons. In unanesthetized adult rats, selective lesions of these neurons using the metabolic toxin saporin conjugated to substance P (SP-SAP) result in ataxic breathing (4). In the mouse, a genetic knockout of the transcription factor MafB produces animals incapable of adequate breathing that die shortly after birth (2). MafB is expressed in a subset of NK1R-positive neurons located within the pre-BötzC, and these neurons appear to be selectively lost in the knockout mice. Complementing the observations on the rat and mouse, Wenninger et al. (18) observed that SP-SAP injections in the pre-BötzC region of goats produced a 29% loss of pre-BötzC NK1R neurons and disrupted the normal breathing patterns.
The ventral medulla is not the only site at which lesions or pharmacological manipulations alter respiratory rhythm. Pontine portions of the rhombencephalon also contribute importantly to respiratory rhythm and pattern, demonstrated by the fact that lesions, neurotoxins, neurochemical stimulation, and blockade all modify respiration (15, 16). In now classic studies, Lumsden (8) showed that a normal relaxed respiratory pattern may be sustained by the rhombencephalon in the absence of the forebrain. Moreover, he argued that separation of the pons from the medulla precluded normal respiration, leaving only gasping originating in the medulla.
This stance, contradicting the view that the isolated medulla (containing the pre-BötzC) may be sufficient for sustaining normal respiratory rhythm, remains an active perspective in respiratory research. St. John and Paton (15, 16), for example, posit that generation of the normal free-easy breathing pattern requires an intact pontomedullary network, and they argue, as did Lumsden (8), that the rhythm sustained by the isolated medulla is gasping rather than eupnea. They note that in vitro medullary preparations generate a slow rhythm with inspiratory bursts exhibiting abrupt onsets with decrementing patterns of activity that do resemble gasping in vivo. However, the activity measured from the in vitro slice or medulla may not be the same as gasping. Richter (13) points out that, in vitro, given the loss of both central and peripheral afferents and the loss of interactions within the respiratory circuit, it should not be surprising that the pattern of motor activity exhibited by reduced preparations differs substantially from the normal pattern of the intact animal. Moreover, the respiratory pattern of in vitro preparations is altered in response to lowering tissue oxygen tension (7) and responds to pulmonary mechanoreceptor input if the lung is left attached to the medulla via the vagus nerve (9). Consequently, these preparations maintain responses to stimuli that affect the intact respiratory network in vivo, but which are not generally thought to alter gasping. In the end, as suggested by Richter (13), it may be inappropriate to refer to in vitro rhythms of the pre-BötzC as either eupnea or gasping even if, as shown by Wenninger et al. (18, 19) and others (2, 4, 11, 17), this structure normally supports eupnea in vivo.
Wenninger et al. (19) report an additive disruption of normal respiration when SP-SAP injections, which selectively destroy NK1R neurons, are followed 7–10 days later by the neurotoxin ibotenic acid. This toxin kills many of the remaining pre-BötzC neurons, including the non-NK1R neurons that constitute the majority of pre-BötzC cells. Following failure of respiration in these animals, Wenninger et al. (19) were still able to record phasic expiratory activity in abdominal muscles. This persistence of an expiratory rhythm in the absence of active inspiration is potentially related to recent arguments (based on in vitro experiments) for the existence of an expiratory rhythm generator independent of the pre-BötzC (6, 10, 12). These expiratory neurons located ventral to the facial nucleus together with inspiratory pre-BötzC neurons are postulated to function as coupled oscillators in generating respiratory rhythm (10). Wenninger et al. (19) provide the only evidence so far for the existence of this expiratory oscillator in the unanesthetized adult mammal.
In summary, Wenninger et al. (18, 19) demonstrate, in their difficult series of studies in unanesthetized adult animals, the importance of the pre-BötzC to the generation of the normal breathing rhythm. Along the way, their experiments touch on many of the current issues in respiratory control, including the special significance of NK1R pre-BötzC neurons, but also the importance of the entire population of pre-BötzC neurons (including non-NK1R neurons) and the potential existence of an expiratory rhythm generator in an adult animal.
REFERENCES
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