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. 2009 Apr;106(4):1467–1470. doi: 10.1152/japplphysiol.00057.2009

Commentaries on Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites

Luiz G S Branco 1
PMCID: PMC6842881  PMID: 19336680

CENTRAL CHEMORECEPTION IS A COMPLEX SYSTEM FUNCTION THAT INVOLVES MULTIPLE BRAIN SITES

to the editor: Amniote vertebrates adjust the acid-base status of the blood through ventilatory alterations of PaCO2 and, to some degree, by renal modulation of bicarbonate concentration. Receptor systems for the ventilatory acid-base regulation has been studied mainly in mammals, in which the ventrolateral surface of the medulla oblongata that faces the cerebrospinal fluid of the forth ventricle has been historically taken as the primary receptor site. The earliest evidence for the existence of central chemoreceptor drive to breathing in vertebrates was obtained in 1958 by Loeschcke and colleagues (4) who perfused the fourth ventricle of cats with mock cerebrospinal fluid of different pH values and measured its effect on pulmonary ventilation. Fifty years latter, Nattie and Li (5) bring us to the frontiers of respiratory physiology related to central chemoreception and shows that it involves multiple sites within the hindbrain, and different neuronal types. According to this notion, 1) glutamatergic neurons in the retrotrapezoid nucleus (3), 2) serotoninergic neurons of the medullary raphe (2), and 3) noradrenergic neurons of the locus ceruleus (1) have all been proposed as putative central chemoreceptors. The authors hypothesize that these multiple receptor sites involved in central chemoreception provide stability in a closed-loop control system. The progress related to our knowledge of this area has amazingly increased over the last 50 years but it is even more amazing how little we currently know. Further research remains urgent.

REFERENCES

  • 1.Biancardi V, Bícego KC, Almeida MC, Gargaglioni LH. Locus coeruleus noradrenergic neurons and CO2 drive to breathing. Pflugers Arch : 1119–1128, 2008. [DOI] [PubMed] [Google Scholar]
  • 2.Dias MB, Nucci TB, Margatho LO, Antunes-Rodrigues J, Gargaglioni LH, Branco LGS. Raphe magnus nucleus is involved in ventilatory but not hypothermic response to CO2. J Appl Physiol : 1780–1788, 2007. [DOI] [PubMed] [Google Scholar]
  • 3.Guyenet PG, Stornetta RL, Bayliss DA. Retrotrapezoid nucleus and central chemoreception. J Physiol : 2043–2048, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Loeschcke HH, Koepchen HP, Gertz. Über den Einfluss von Wassertoffionenkonzen-tration und CO2-Druck im Liquor cerebrospinalis auf die Atmung. Pflügers Arch : 569–585, 1958. [DOI] [PubMed] [Google Scholar]
  • 5.Nattie EE, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

Thiago S Moreira 1, Patrice G Guyenet 2

IS CENTRAL CHEMOREFLEX A WIDESPREAD PROPERTY?

to the editor: According to Dr. Nattie neurons that pass any or all the following tests qualify as putative central chemoreceptors: their destruction attenuates the central chemoreflex, they are acid-sensitive in vitro, and topical acidification of these neurons in vivo activates breathing. On that basis, Dr. Nattie proposes that central chemoreception involves elements of the central pattern generator (CPG; e.g. pre-Bötzinger complex) plus a selection of neurons that regulate the CPG (noradrenergic and serotonergic neurons, the retrotrapezoid nucleus). Many other neurons could have been added to the list (motoneurons, solitary tract nucleus, fastigial nucleus, orexinergic neurons), and the resulting picture is that chemoreception is a widespread property. The trouble is that the selected criteria are far too lax (3). Lesions do not prove that the targeted neurons detect CO2, only that their integrity is needed for the chemoreflex. The chemoreflex measured in rodents is not perfectly relevant to the homeostatic regulation of CO2 since the high CO2 levels used to trigger the reflex would be perceived as aversive in humans and therefore presumably also elicit some form of enteroceptive stress. Neurons that are highly acid sensitive in vitro may respond poorly or not at all to changes in arterial Pco2 in vivo (reviewed in 2), perhaps because they reside in regions where ISF pH is buffered against changes in arterial Pco2 by the blood brain barrier (1). If this notion is correct, topical brain acidification may be a questionable experimental paradigm if the targeted region is normally protected against blood CO2-induced acidification.

REFERENCES

  • 1.Arita H, Ichikawa K, Kuwana S, Kogo N. Possible locations of pH-dependent central chemoreceptors: intramedullary regions with acidic shift of extracellular fluid pH during hypercapnia. Brain Res : 285–293, 1989. [DOI] [PubMed] [Google Scholar]
  • 2.Guyenet PG. The 2008 Carl Ludwig Lecture: Retrotrapezoid nucleus, CO2 homeostasis, and breathing automaticity. J Appl Physiol : 404–416, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Guyenet PG, Stornetta RL, Bayliss DA. Retrotrapezoid nucleus and central chemoreception. J Physiol : 2043–2048, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Nattie EE, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

Peter M Lalley 1

to the editor: The Viewpoint (3) that there are multiple brain stem locations where CO2/pH-sensitive chemoreceptors adjust ventilation to meet metabolic demand is consistent with the results of in vivo (1–3) as well as in vitro (5) studies. The three sites Nattie and Li (3) single out for discussion (see their Viewpoint Refs. 1, 2, 6) each express CO2/pH-sensitive neurons that, presumably, evoke distinctive downstream respiratory motor effects through different neurotransmitter and neuromodulator substances. In the retrotrapezoid nucleus (RTN), the chemoreceptor neurons are glutamatergic (2), and their destruction (1) reduces tidal volume (VT). Lesions of noradrenergic neurons in locus ceruleus (LC) and serotonergic neurons in raphe magnus (RM) also depress VT (1,3), whereas a nonselective lesion in RM depresses both VT and breathing frequency (3). Breathing frequency increases when chemoreceptor neurons in the medullary raphe are activated by CO2 during microdialysis but only during sleep; there is no ventilatory effect during wakefulness (5). In the RTN, CO2 elevation increases VT during wakefulness but not sleep. Collectively, these results suggest a high degree of neurotransmitter- and state-dependent plasticity in central chemoreceptor control of ventilation, which remains to be explained in neuroanatomical and neurochemical terms. State-dependant modulation by LC and raphe regions might be anticipated on the basis of studies of other types of motor behavior that they influence, but the wiring of chemoreceptor neurons into the respiratory network and the neurochemical mechanisms through which they differentially affect VT and breathing frequency are surprising and should be particularly interesting topics for future research.

REFERENCES

  • 1.Akilesh MR, Kamper M, Li A, Nattie EE. Effects of unilateral lesions of retrotrapezoid nucleus on breathing in awake rats. J Appl Physiol : 469–479, 1997. [DOI] [PubMed] [Google Scholar]
  • 2.Guyenet PG. The 2008 Carl Ludwig Lecture: Retrotrapezoid nucleus, CO2 homeostasis and breathing automaticity. J Appl Physiol : 404–416, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Nattie EE, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
  • 4.Nattie EE, Li A. CO2 dialysis in the medullary raphe of the rat increases ventilation in sleep. J Appl Physiol : 1247–1257, 2001. [DOI] [PubMed] [Google Scholar]
  • 5.Putnam RW. Intracellular pH regulation of neurons in chemosensitive and nonchemosensitive areas of brain slices. Respir Physiol : 37–56, 2001. [DOI] [PubMed] [Google Scholar]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

A Kawai 1

to the editor: We agree with the argument for a complex organization of neurons and sites that participate in central chemoreception (4). Although such neurons that are described in the Viewpoint are surely involved in the mechanisms of central chemoreception, respiratory modulated neurons in the pFRG and in other sites have also been shown to function as central chemosensors of respiration. Our recent data have demonstrated that pre-inspiratory neurons in the pFRG, which are putative respiratory rhythm generators (6), are both intrinsically and synaptically chemosensitive to CO2/pH (3). The chemosensitivity may be of importance in adaptation of the respiratory rhythm to adequate level in response to CO2/pH change. Our past experiment showed some inspiratory neurons are also chemosensitive (2). These neurons may affect the respiratory tidal volume in response to CO2/pH change. Thus both respiratory rhythm generators and pattern generators might be involved in central chemoreception. In addition to the Viewpoint, some neurons and structures that are chemosensitive have been reported. Some small cholinergic neurons that are located just beneath the surface of the ventral medulla are also chemosensitive (5) and might stimulate the respiratory neuronal network. Release of ATP from the classical brain stem chemosensitive structures might also participate to mediate the effect of CO2 on breathing (1), although the cellular sources and mechanisms underlying release of ATP have not been elucidated. We suggest that central chemoreception might be properly provided by the interaction of multiple chemoreceptor sites and structures, including the respiratory modulated neurons and other many neurons.

REFERENCES

  • 1.Gourine AV, Llaudet E, Dale N, Spyer KM. ATP is a mediator of chemosensory transduction in the central nervous system. Nature : 108–111, 2005. [DOI] [PubMed] [Google Scholar]
  • 2.Kawai A, Ballantyne D, Muekenhoff K, Scheid P. Chemosensitive medullary neurons in the brainstem-spinal cord preparation of the neonatal rat. J Physiol : 277–292, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Kawai A, Onimaru H, Homma I. Mechanisms of CO2/H+ chemoreception by respiratory rhythm generator neurons in the medulla from newborn rats in vitro. J Physiol : 525–537, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Nattie E, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
  • 5.Okada Y, Chen Z, Jiang W, Kuwana S, Eldridge FL. Anatomical arrangement of hypercapnia-activated cells in the superficial ventral medulla of rats. J Appl Physiol : 427–439, 2002. [DOI] [PubMed] [Google Scholar]
  • 6.Onimaru H, Homma I. Point:Counterpoint: The parafacial respiratory group(pFRG)/pre-Botzinger complex(preBoetC) is the primary site of respiratory rhythm generation in the mammal. J Appl Physiol : 2094–2098, 2006. [DOI] [PubMed] [Google Scholar]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

Robert W Putnam 1

CHEMORECEPTION LIKELY INVOLVES A COMPLEX DISTRIBUTED NETWORK THROUGHOUT DEVELOPMENT

to the editor: The recent Viewpoint article by Nattie and Li (3) is a welcome addition to the debate about whether central chemoreception arises from a complex distributed network of sensory elements or is restricted to a single region containing specialized neurons (1). Nattie and Li (3) properly focus the debate on defining chemoreceptive regions based on data derived from conscious animals (focal acidosis and lesioning studies) and not on defining chemoreceptive neurons based largely on their response to acidosis (1). Evidence for the involvement of glutamatergic neurons from the retrotrapezoid nucleus, serotonergic neurons from the medullary raphe, and noradrenergic neurons from the locus ceruleus (LC) in central chemoreception is reviewed as support for a distributed chemosensitive network. Work from my laboratory suggests that there is also a neonatal form of chemoreception that transitions to an adult form during development (4). We recently found that a high percentage of LC neurons from neonatal rats younger than day 10 are intrinsically chemosensitive (respond to CO2 with electrical and chemical synapses blocked) and exhibit a large firing rate increase in response to hypercapnia. Interestingly, rat adrenal chromaffin cells have likewise been shown to be CO2 sensors up to neonatal day 10, releasing catecholamines in response to peripheral hypercapnia (2). These findings suggest that neonatal chemoreception is strongly dependent on CO2-induced release of catecholamines, both peripherally and centrally. If true, this would indicate that chemoreception is even more complex, involving peripheral sites as well as central sites and varying with development.

REFERENCES

  • 1.Guyenet PG, Stornetta RL, Bayliss DA. Retrotrapezoid nucleus and central chemoreception. J Physiol : 2043–2048, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Muñoz-Cabello AM, Toledo-Aral JJ, López-Barneo J, Echevarria M. Rat adrenal chromaffin cells are neonatal CO2 sensors. J Neurosci : 6631–6640, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Nattie E, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
  • 4.Stunden CE, Filosa JA, Garcia AJ, Dean JB, Putnam RW. Development of in vivo ventilatory and single chemosensitive neuron responses to hypercapnia in rats. Resp Physiol : 135–155, 2001. [DOI] [PubMed] [Google Scholar]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

Nancy L Chamberlin 1, Clifford B Saper 1

to the editor: Drs. Nattie and Li (2) address a fundamental issue in how the central chemoreceptor system is organized: does the control of respiratory chemoreflexes lie with modulatory neurons that reside at a single site in the brain or at multiple sites? They marshal evidence supporting a distributed chemoreceptor network involving the retrotrapezoid nucleus (RTN), raphe nuclei, locus ceruleus, and possibly others, whereas Guyenet and colleagues have similarly argued in favor of the RTN being the principal site of central chemoreception (1). This disagreement may be more apparent than real, if different populations of chemosensitive neurons are recruited by varying levels of hypoxia or hypercarbia, and under specific physiological conditions (e.g., with exercise, hyperthermia, etc). Part of the reason for the disagreement is the lack of critical experiments that will test each hypothesis. For example, if the RTN is necessary and sufficient for accomplishing central chemoreception, disabling these glutamatergic, PHOX2b positive neurons should cause severe, and probably lethal respiratory deficits in unanesthetized animals. This experiment has never been done. The distributed theory could be tested by examining the effects of molecular lesions (for example, focal interference with TASK channels) of specific populations of neurons in the network on chemoreflexes under selected physiological conditions. These experiments might not be easy to do, but until rigorous experiments are done that can actually disprove one of the hypotheses, the controversy will live on.

REFERENCES

  • 1.Guyenet PG, Stornetta DA, Bayliss RL. Retrotrapezoid nucleus and central chemoreception. J Physiol : 2043–2048, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Nattie E, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

Alexander V Gourine 1

to the editor: Nattie and Li review data suggesting that the central respiratory chemosensitivity is a complex system function that involves multiple brain stem sites. This idea is supported by the evidence that in conscious states lesions of glutamatergic neurons in the retrotrapezoid nucleus, serotonergic neurons in the medullary raphe, locus ceruleus NA neurons, or NK-1 receptor expressing cells in the ventral medulla reduce (albeit to a different degree) the ventilatory responses to CO2. The existence of functional respiratory chemosensors in several brain stem sites makes a lot of sense to ensure redundancy and stability within this “high-gain” system (1 mmHg increase in arterial Pco2 may lead to a 2 l/min increase in lung ventilation). This, however, greatly complicates studies of the underlying cellular mechanisms as these could be quite distinct in chemosensory neurons at different locations. We found that on the ventral surface of the medulla CO2 chemosensory transduction involves release of ATP, which is acting at downstream neurons to increase respiratory activity (2, 3). ATP may also play a role at other sites as all of them are equipped with ATP receptors, which are expressed by brain stem catecholaminergic neurons among other cell types (4). Finally, we should not forget about the peripheral chemoreceptors (in the carotid and aortic bodies), which contribute about 1/3 of the overall response to CO2 and play a predominant role in controlling arterial Pco2 during eupnic breathing (1). This is particularly important considering that most of the studies discussed by Nattie and Li were performed in animals with intact peripheral chemoreceptors.

REFERENCES

  • 1.Forster HV, Martino P, Hodges M, Krause K, Bonis J, Davis S, Pan L. The carotid chemoreceptors are a major determinant of ventilatory CO2 sensitivity and of PaCO2 during eupneic breathing. Adv Exp Med Biol : 322–326, 2008. [DOI] [PubMed] [Google Scholar]
  • 2.Gourine AV, Atkinson L, Deuchars J, Spyer KM. Purinergic signalling in the medullary mechanisms of respiratory control in the rat: respiratory neurones express the P2X2 receptor subunit. J Physiol : 197–211, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Gourine AV, Llaudet E, Dale N, Spyer KM. ATP is a mediator of chemosensory transduction in the central nervous system. Nature : 108–111, 2005. [DOI] [PubMed] [Google Scholar]
  • 4.Nattie EE, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
  • 5.Yao ST, Barden JA, Finkelstein DI, Bennett MR, Lawrence AJ. Comparative study on the distribution patterns of P2X1-P2X6 receptor immunoreactivity in the brainstem of the rat and the common marmoset (Callithrix jacchus): association with catecholamine cell groups. J Comp Neurol : 485–507, 2000. [PubMed] [Google Scholar]
J Appl Physiol. 2009 Apr;106(4):1467–1470.

Article

Mitsuko Kanamaru 1, Ikuo Homma 2

to the editor: The importance of raphe 5-HT neurons for chemoreception is discussed (4). We propose pathways and receptor type mediating raphe 5-HT neuron activity to clarify a role for the neurons. Serotonin release in the dorsomedial medulla oblongata (DMM), including the solitary tract nucleus (nTS) and the hypoglossal nucleus (nXII), is increased by hypercapnia. The 5-HT release acting on 5-HT2 receptors induces an upward shift in hypercapnic ventilatory response (HVR) because of an increase in tidal volume with basal airway opening; however, it does not affect CO2 sensitivity in adult mice (2). Serotonergic neurons that project to the nTS, a site of the dorsal respiratory group, partially originate from the raphe nuclei and paraolivary nucleus, of which half comes from the raphe magnus nucleus (nRM) (5). Serotonergic neurons in the nRM increase HVR by increasing tidal volume (1), which corresponds to the responses mediated via 5-HT2 receptors in the DMM. Those in the caudal raphe pallidus and obscurus nuclei mainly project to the nXII (3). Collectively, these facts suggest that the excitations of 5-HT neurons in the nRM and caudal raphe nuclei at least augment respiratory afferent inputs and hypoglossal motor outputs, respectively, through 5-HT2 receptors in the DMM; thus indicating a modulatory role in chemoreception. However, the activity mediated via 5-HT2 receptors in the DMM interacts with CO2 drive; periodically elicits hyperventilation with airway opening and hypoventilation with airway narrowing; hence it may play important roles in physiological respiratory and airway control, periodic breathing, and obstructive sleep apnea.

REFERENCES

  • 1.Dias MB, Nucci TB, Margatho LO, Antunes-Rodrigues J, Gargaglioni LH, Branco LG. Raphe magnus nucleus is involved in ventilatory but not hypothermic response to CO2 J Appl Physiol : 1780–1788, 2007. [DOI] [PubMed] [Google Scholar]
  • 2.Kanamaru M, Homma I. Compensatory airway dilation and additive ventilatory augmentation mediated by dorsomedial medullary 5- hydroxytryptamine 2 receptor activity and hypercapnia. Am J Physiol Regul Integr Comp Physiol : R854–R860, 2007. [DOI] [PubMed] [Google Scholar]
  • 3.Manaker S, Tischler LJ. Origin of serotoninergic afferents to the hypoglossal nucleus in the rat. J Comp Neurol : 466–476, 1993. [DOI] [PubMed] [Google Scholar]
  • 4.Nattie EE, Li A. Viewpoint: Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol; doi: 10.1152/japplphysiol.00112.2008. [DOI] [PMC free article] [PubMed]
  • 5.Thor KB, Helke CJ. Serotonin- and substance P-containing projections to the nucleus tractus solitarii of the rat. J Comp Neurol : 275–293, 1987. [DOI] [PubMed] [Google Scholar]

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