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1 Departments of Neurology and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA 2 Veteran's Affairs Medical Center, West Haven, CT, USA 3 Neurology, LCI-712, 15 York St, PO 208018, New Haven, CT 06520-8018, USA
Abstract
To some it may seem that we now know less about respiratory chemoreception than we did 20 years ago. Back then, it was widely accepted that the central respiratory chemoreceptors (CRCs) were located exclusively on or near the surface of the ventrolateral medulla (VLMS). Now, instead, it is generally believed that there are widespread sites of chemoreception, and there is little agreement on when and how each of these sites is involved in respiratory control. However, those in the field know that this actually is progress, primarily because we have gone from simply identifying candidate regions, to identifying specific neuronal subtypes that may be the sensors. In this invited review, we have been asked to discuss some of the current controversies in the field. First, we define the minimal requirements for a cell to be a CRC, and what assumptions can not be made without more data. Then we review the evidence that two neuronal subtypes, serotonergic neurones of the midline raphé and glutamatergic neurones of the retrotrapezoid nucleus, are chemoreceptors. There is evidence supporting a role in respiratory chemoreception for both types of neurone, as well as the other candidates, but there is also information that is missing. Future work will need to focus on which of the candidates are indeed chemoreceptors, what percentage of the overall response each one contributes, and how this percentage varies under different conditions.
(Received 6 January 2005;
accepted after revision 22 February 2005; first published online 25 February 2005)
Corresponding author G. B. Richerson: Neurology, LCI-712, 15 York St, PO 208018, New Haven, CT 06520-8018, USA. Email: george.richerson{at}yale.edu
In recent years, the field of respiratory neurobiology has gone from only having a rough idea about where a subset of the central respiratory chemoreceptors (CRCs) are located (somewhere near the VLMS) to identifying numerous candidates for the specific neurones involved (most of which are not near the VLMS). These candidates include serotonergic neurones of the midline raphé (Richerson, 2004), noradrenergic neurones of the locus coeruleus (Pineda & Aghajanian, 1997; Putnam et al. 2004) and glutamatergic neurones of the retrotrapezoid nucleus (Mulkey et al. 2004). Other candidate neurones without known neurotransmitter content are located in the nucleus tractus solitarius, preBotzinger complex (PBC), hypothalamus and cerebellum (Dean et al. 1990; Richerson, 1998; Feldman et al. 2003; Putnam et al. 2004). There are also non-serotonergic neurones in the midline raphé that are inhibited by acidosis that have been proposed to disinhibit respiratory output during hypercapnia (Wang et al. 2001; Richerson, 2004).
Properties that all central respiratory chemoreceptors must possess
There are two essential criteria that all chemoreceptors must meet (Richerson, 1998; Putnam et al. 2004).
Intrinsic chemosensitivity to physiologically relevant changes in PCO2. A CRC must respond to changes in CO2 that occur under non-pathological conditions in vivo, and this response must be due to mechanisms intrinsic to that cell. To prove that the response is intrinsic, all influences from other cells must be eliminated. While theoretically straightforward, this is not so easy in practice. The only method that guarantees this is to physically separate the candidate from all other cells. Of course, this could eliminate modulatory effects that enable a CRC to express intrinsic chemosensitivity. An alternative is to combine a less complete method for physical isolation (e.g. brain slices) with pharmacological blockade of synaptic transmission. However, interconnections can remain intact in brain slices (Richerson, 1998), and none of the commonly used pharmacological methods is complete. For example, lowering calcium and increasing magnesium is not effective in blocking non-vesicular neurotransmitter release or electrical transmission via gap junctions, and the typical approach of applying glutamate and GABA receptor antagonists does not block other forms of neurotransmission.
Appropriate effects on respiratory output. A CRC must have the capability of increasing respiratory output in response to an increase in CO2. This could be accomplished if the neurone is part of the respiratory network, or if it projects to respiratory neurones and releases neurotransmitters that influence respiratory output.
Assumptions that cannot be made about central respiratory chemoreceptors
Although assumptions are often made about the following properties of CRCs, they cannot be substantiated until the CRCs have been unequivocally identified.
Primary stimulus. It is often assumed that the primary stimulus for central chemoreception is either intracellular pH or extracellular pH, and there is good evidence for this in some CRC candidates (Wang et al. 2002; Putnam et al. 2004), but it remains possible that some CRCs respond instead to HCO3 or molecular CO2.
Type of response to acidosis. It is often assumed that the CRCs are neurones stimulated by acidosis and in turn stimulate breathing, but a CRC could also be inhibited by acidosis and then in turn release respiratory output from tonic inhibition (Wang et al. 2001). There is a precedent for such inhibitory respiratory chemoreceptors in reptiles and birds (Powell et al. 1988). It is also possible that some CRCs are glia.
Degree of chemosensitivity. At the systems level, respiratory output is extremely sensitive to changes in PCO2, so it is often assumed that each individual CRC neurone is equally sensitive. However, this is not necessary because there are many opportunities for the response to be amplified within the respiratory network. For example, many neurones contain co-localized neuropeptides that are only released after firing rate increases to higher levels, and neuropeptides can have larger effects on postsynaptic neurones than the primary neurotransmitter. There are also other mechanisms that could lead to amplification downstream, including divergence, convergence and distributed chemosensitivity (Fig. 1).
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Compartment sensed. Ventilation increases in response to acidic solutions in the cerebrospinal fluid (CSF) space, but that does not mean that the CRCs were necessarily designed specifically to sample this compartment. An alternative is that CRCs sample tissue pH near large arteries. As Virchow-Robin spaces that surround large penetrating arteries are filled with CSF, experimental changes in CSF pH would alter pH along them. This possibility is consistent with the conclusion of Pappenheimer et al. (1965) that the CRCs are located ‘two-thirds to three-fourths of the distance along the functional [gradient of pH] between CSF and blood’.
Transduction mechanism. Many ion channels are sensitive to changes in pH (Putnam et al. 2004). Although some have been linked to the response of individual CRC candidates, none have been shown to be present exclusively in CRCs, or to be critical for central respiratory chemoreception at the systems level.
Projections to specific respiratory nuclei. In principle, CRCs could target any or all respiratory nuclei. It would be possible to conclude that the respiratory pattern generator was a target of CRCs if hypercapnia consistently changed respiratory rate after the pulmonary stretch receptors were eliminated by vagotomy. However, this is usually not the case. Instead, the existing data are equally consistent with CRCs influencing respiratory output by stimulating either the respiratory pattern generator, premotor neurones, respiratory motor neurones, or all three of these cell groups.
Uniqueness of chemoreceptors to respiratory control. The term ‘central chemoreceptor’ is frequently used to describe neurones that drive respiratory output in response to hypercapnia. However, the term ‘central respiratory chemoreceptor’ has been used in this review because this is a more accurate description of these neurones. The term ‘central chemoreceptor’ should be more correctly used in a broader sense to describe any neurone that responds to changes in CO2 or pH and modulates any brain function, not just breathing. There are many non-respiratory brain functions that are sensitive to hypercapnia. As many of these have a higher threshold for activation (e.g. anxiety), it is likely that central chemoreceptors that induce these non-respiratory effects are activated at higher levels of CO2.
Evidence for central respiratory chemoreceptors in the raphé and retrotrapezoid nucleus
Serotonergic neurones of the raphé. The evidence in support of serotonergic neurones being CRCs has recently been reviewed in detail (Richerson, 2004), and is highlighted here.
When neurones of the rat medullary raphé are isolated and grown in tissue culture, the majority of those that are serotonergic (73%) are highly chemosensitive to physiologically relevant changes in pH. Their response is maintained after blocking glutamate and GABA receptors (Wang et al. 2001). Although tissue culture potentially alters the properties of neurones, the same response also occurs in serotonergic neurones of the midline in rat medullary slices, and is maintained in both high-magnesium/low-calcium solution and in the presence of glutamate and GABA receptor antagonists (Richerson, 1995; Wang & Richerson, 1999; Bradley et al. 2002). The intrinsic response of these neurones is extremely high, with a mean increase in firing rate to 300% of control in response to a decrease in extracellular pH from 7.4 to 7.2 (Wang et al. 1998, 2001, 2002). The magnitude of this response appears to be large compared to that of the other CRC candidates (Putnam et al. 2004, 2005). In addition, this intrinsic chemosensitivity does not appear in rat raphé neurones in vitro until they are at least 12 days old (Wang & Richerson, 1999), which is the age at which the ventilatory response to hypercapnia begins to mature in the rat in vivo (Serra et al. 2001; Stunden et al. 2001), consistent with the pH response of raphé neurones contributing to the response in the intact animal.
A subset of serotonergic medullary raphé neurones (six of 27; 22%) increase their firing rate in awake, behaving cats to 160% of control in response to inhalation of 8% CO2 (Veasey et al. 1995). The response of these neurones in vivo is blunted during sleep, as is the ventilatory response of the animal. When the response of these neurones in vivo is compared to predicted changes in tissue pH (Fig. 2), there are three notable observations: (1) levels of hypercapnia sufficient to strongly stimulate ventilation in vivo (fraction of inspired CO2(FiCO2) = 0.05–0.07) induce changes in tissue pH that are small compared to those used in even the most conservative in vitro experiments (Wang et al. 2002); (2) some serotonergic neurones are sensitive to very small changes in pH in vivo; and (3) some serotonergic neurones that are sensitive to hypercapnia in cats in vivo would not have been detected if FiCO2 was limited to 0.07.
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Serotonergic neurones of the raphé project widely to medullary respiratory neurones, as well as phrenic and hypoglossal motor neurones (Richerson, 2004). These neurones release serotonin, substance P and thyrotropin-releasing hormone, all three of which stimulate breathing in vivo, promote respiratory output of the PBC in vitro, and enhance excitability of respiratory motor neurones in vitro (Richerson, 2004). Blockade of serotonin receptors also blocks respiratory bursts generated by the PBC in vitro (Richerson, 2004).
Ventilation increases when acidosis is induced selectively within the medullary raphé of rats and goats in vivo by focal application of either acetazolamide or CO2 (Feldman et al. 2003; Hodges et al. 2004b). Selective lesions of serotonergic neurones with intraventricular or focal injections of 5,7-dihydroxytryptamine, or focal injections of saporin conjugated to an antibody to the serotonin transporter, lead to a reduction of the ventilatory response to hypercapnia in vivo (Nattie et al. 2004; Richerson, 2004).
Thus, there is now compelling evidence, accumulated from a variety of both in vivo and in vitro approaches, in support of serotonergic neurones within the midline raphé being CRCs (Feldman et al. 2003; Richerson, 2004). However, there are many questions that remain, including how and when they play a role in the intact animal.
Serotonergic neurones of the ventolateral medulla (VLM). There is heterogeneity of serotonergic neurones, including differences in location, cell shape, projections and neuropeptide content. There is also heterogeneity of their intrinsic chemosensitivity, as only 73% of medullary midline (i.e. raphé) serotonergic neurones meet established criteria for intrinsic chemosensitivity (Wang et al. 2001), and among those, there is substantial variability in the degree of chemosensitivity (Wang et al. 1998, 2002). Although there is chemosensitivity in a subset of serotonergic neurones from the two regions examined to date (medullary raphé and dorsal raphé), there is no evidence that every serotonergic neurone in the CNS is a CO2/pH sensor. However, this remains a viable hypothesis.
The intrinsic response of serotonergic neurones in the parapyramidal region of the VLM has not yet been studied. However, as these neurones are closely associated with large arteries, and a subset of them project to respiratory neurones within the medulla, as well as phrenic motor neurones in the spinal cord (Richerson, 2004), it is possible that they are also CRCs, and that they contributed to localization of chemoreceptors to the surface of the VLM during early experiments (Loeschcke, 1982).
Recently, Guyenet and coworkers concluded that VLM serotonergic neurones are not CRCs. In this review, we have been asked to critique the evidence for that conclusion. Their assessment was based on two observations. The first was that only a small percentage of tryptophan hydroxylase-immunoreactive neurones in the marginal layer (ML) of the VLMS project to the PBC and rostral ventral respiratory group (rVRG) (Weston et al. 2004). The authors state that ‘the serotonergic neurones of the ML probably do not contribute to central [respiratory] chemoreception’, and instead ‘mediate sympathetic autonomic adjustments to [acidification of the ventral medullary surface].’ This possibility is consistent with our previous hypothesis that many CNS serotonergic neurones are central chemoreceptors that mediate non-respiratory changes in response to hypercapnia (Richerson, 2004). However, it is premature to conclude that none of the serotonergic neurones on the VLMS are CRCs for the follow reasons: (1) the subset of VLM serotonergic neurones that do project to the PBC and rVRG could be CRCs; (2) the serotonergic neurones in the ML that project to the spinal cord (Weston et al. 2004) may be CRCs that stimulate phrenic motor neurones; and (3) some ML serotonergic neurones may project to other medullary respiratory nuclei that were not assessed, such as the nucleus tractus solitarius, hypoglossal motor nucleus, and caudal VRG.
The second observation was that out of 37 recordings from serotonergic neurones in the parapyramidal region of anaesthetized rats in vivo, none increased their firing rate by more than 30% in response to an increase in end-tidal PCO2 from 5% to 10% (Mulkey et al. 2004). The conclusion, however, that none of the serotonergic neurones in the VLM are CRCs cannot be justified, in our opinion, by these data alone, for the following reasons.
(1) Anaesthesia may have suppressed the response of serotonergic neurones, as it does the ventilatory response to hypercapnia (Pavlin & Hornbein, 1986). (2) There is no evidence that all CRCs have an extremely large response to hypercapnia in vivo. Of the 37 serotonergic neurones, 19 actually did increase their firing rate above 0%, and it cannot be assumed that their response has no effect on respiratory output (see above). (3) In unanaesthetized cats, some CO2-responsive serotonergic neurones require an FiCO2 of 0.08–0.09 for activation to be detected (Fig. 2B), which roughly corresponds to an end-tidal CO2 of 10% (Fig. 2A). As rats have a much smaller hypercapnic ventilatory response than cats (Putnam et al. 2004), some chemosensitive serotonergic neurones in rats may require a larger stimulus, especially during anaesthesia. Although a high level of CO2 may be required for activation to be detected, lower levels of CO2 may increase firing in these neurones enough to have a sizeable effect on breathing if there are downstream mechanisms of amplification employed (Fig. 1). (4) It is difficult to interpret data from neurones within an intact neural network. There are extensive inhibitory connections between serotonergic neurones, and when one subset is activated by hypercapnia they may inhibit others that are less sensitive. (5) Lastly, the data were obtained from only a limited subset of VLM serotonergic neurones. All but four were from neurones deep to the surface, but there may be differences between those on the surface and those in the parenchyma, as well as those at different rostro-caudal levels of the medulla.
Mulkey et al. (2004) also made the conclusion that ‘the collective evidence does not support the view that serotonergic neurones in general, or the serotonergic cells located at the VLMS in particular, are CO2 detectors in vivo.’ This conclusion, however, is not addressed specifically by the authors' data, because observations on a small subset of VLM serotonergic neurones, which are a small minority of medullary serotonergic neurones, are not necessarily relevant to all serotonergic neurones, including those in the raphé nuclei. Recordings are needed from each of the subsets of serotonergic neurones over a larger range of CO2 levels. This protocol must also be performed in unanaesthetized animals, and in different behavioural states, particularly because sleep may shift the dominant CRC (Nattie, 1999; Mitchell, 2004). To date, this type of approach has been limited to midline serotonergic neurones, and only those in the medulla that are deep to the ventral surface (Veasey et al. 1995). Thus, there are no published data yet that directly address the possibility that the majority of serotonergic neurones are CO2 sensors in vivo.
Glutamate neurones of the retrotrapezoid nucleus. The retrotrapezoid nucleus (RTN) was first recognized as potentially being involved in control of breathing because it projects extensively to respiratory nuclei (Smith et al. 1989). Later, Nattie et al. (1993) demonstrated that a large percentage of neurones in the RTN are stimulated by hypercapnia in decerebrate cats. When Li & Nattie (1997) then demonstrated that ventilation was increased in response to CO2 dialysis in the RTN of rats in vivo it became clear that the RTN might contain CRCs.
In this review, we have been asked to examine recent evidence, provided by Mulkey et al. (2004), for the possibility that the RTN contains glutamatergic CRCs. They recorded from the RTN in anaesthetized rats in vivo, and confirmed the work of Nattie et al. (1993) that there is a subset of neurones that increases their firing rate in response to hypercapnia. They then showed that these neurones continue to have a robust response to hypercapnia after application of kynurenic acid (a glutamate receptor antagonist) to the ventricular and subarachnoid spaces, or after intravenous injection of morphine. It was reasoned that kynurenic acid or morphine ‘blocked the respiratory pattern generator’, and it was implied that this very large response in vivo was due to intrinsic chemosensitivity of RTN neurones. Although this is an exciting possibility, the data do not yet support this conclusion, because the methods used by the investigators would not be expected to block all synaptic input into RTN neurones (Mitchell, 2004). Kynurenic acid would only block glutamatergic neurotransmission, and even this may have been incomplete due to lack of penetration into the brain parenchyma. Morphine would have a general inhibitory effect on neuronal activity, but would not specifically affect synaptic transmission. Thus, the majority of synaptic inputs into RTN neurones would be unaffected, including serotonin, noradrenaline (norepinephrine), glycine, GABA, neuropeptides, purines, NO and gap junctions. Thus, there are insufficient data to determine whether the response to hypercapnia was intrinsic or due to synaptic input from CRCs elsewhere (Fig. 3).
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The new finding of this study (Mulkey et al. 2004) came from juxtacellular labelling combined with immunohistochemistry. Using this approach, the authors demonstrated that CO2-activated neurones of the RTN are glutamatergic. This is an important result, because it now defines a specific phenotype for a putative CRC in the RTN. Mulkey et al. (2004) found that RTN neurones have processes in the ML of the VLM. They concluded that glutamatergic neurones of the RTN are ‘the long sought-after VLMS chemoreceptors.’ This conclusion is based primarily on the belief that CRCs are located in the ML, where they could sense CSF pH. However, as discussed above there is no definitive evidence that there are CRCs in the ML, or that CRCs are designed specifically to sense CSF pH. Therefore, the significance of this anatomical observation remains unclear. In addition, neurones of the VRG (Pilowsky et al. 1993; Kawai et al. 1996), and serotonergic neurones of the parapyramidal region (Bradley et al. 2002) also have processes in the ML, so this finding is not specific to glutamatergic RTN neurones.
In summary, the evidence for chemoreception by glutamatergic neurones of the RTN is provocative and important, but requires further analysis. A key piece of missing information is whether these neurones meet one of the basic requirements of a chemoreceptor – intrinsic chemosensitivity – or whether they simply transmit the response of other neurones that are the actual sensors. If they do possess intrinsic chemosensitivity, the magnitude of their response is not unusually large. As discussed above, this does not rule out a major contribution to respiratory chemoreception, but the existing data do not support a conclusion that these neurones are uniquely important. In fact, the finding that the ventilatory response induced by focal acidosis in the RTN is roughly equal to that of other chemoreceptor regions (Li & Nattie, 1997; Feldman et al. 2003) suggests otherwise. There is also not yet evidence that specific lesions of just the glutamate neurones in the RTN leads to a decreased CO2 response at the systems level. However, it is exciting that we have identified the phenotype of a neurone in the RTN that may be a CRC. It will now be important to determine whether these specific neurones meet the criteria for a CRC, and whether they play a role under physiological or pathological conditions.
What information is still needed?
Now that so many CRC candidates have been identified, the field can focus on the relative importance and role(s) of each one. It is possible that they are all redundant, that some are only important under certain conditions (Nattie, 1999), or that some are not CRCs at all. Nevertheless, none of the current candidates can be excluded as actual chemoreceptors because there is still incomplete information. It is unlikely that there is a single experimental approach or preparation that will unequivocally answer this question, but instead a combination of in vivo and in vitro approaches will be needed. In interpreting new data, it will be important to apply rigorous criteria that do not rely on assumptions that have not been validated, including the belief that originated more than 20 years ago that the VLMS is the sole site of CRCs. Given the modern tools in neuroscience, the next 20 years should be exciting in establishing which neurones mediate the respiratory and non-respiratory responses to hypercapnia, and how dysfunction of these chemoreceptors contributes to human disease.
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Acknowledgements
We wish to thank Robert Putnam, Hannah Kinney and Eugene Nattie for critical review of the manuscript. This work was supported by NHLBI HL52539, NICHD HD36379 and the VAMC.
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D. K. Mulkey, D. L. Rosin, G. West, A. C. Takakura, T. S. Moreira, D. A. Bayliss, and P. G. Guyenet Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism J. Neurosci., December 19, 2007; 27(51): 14128 - 14138. [Abstract] [Full Text] [PDF]
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T. A. Day and R. J. A. Wilson Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation J. Physiol., February 1, 2007; 578(3): 843 - 857. [Abstract] [Full Text] [PDF]
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R. L. Stornetta, T. S. Moreira, A. C. Takakura, B. J. Kang, D. A. Chang, G. H. West, J. F. Brunet, D. K. Mulkey, D. A. Bayliss, and P. G. Guyenet Expression of Phox2b by Brainstem Neurons Involved in Chemosensory Integration in the Adult Rat J. Neurosci., October 4, 2006; 26(40): 10305 - 10314. [Abstract] [Full Text] [PDF]
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P. F. Martino, M. R. Hodges, S. Davis, C. Opansky, L. G. Pan, K. Krause, B. Qian, and H. V. Forster CO2/H+ chemoreceptors in the cerebellar fastigial nucleus do not uniformly affect breathing of awake goats J Appl Physiol, July 1, 2006; 101(1): 241 - 248. [Abstract] [Full Text] [PDF]
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S. Sood, E. Raddatz, X. Liu, H. Liu, and R. L. Horner Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats J Appl Physiol, June 1, 2006; 100(6): 1807 - 1821. [Abstract] [Full Text] [PDF]
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N. S. Cherniack and G. S. Longobardo Mathematical models of periodic breathing and their usefulness in understanding cardiovascular and respiratory disorders Exp Physiol, March 1, 2006; 91(2): 295 - 305. [Abstract] [Full Text] [PDF]
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P. G. Guyenet, D. K. Mulkey, R. L. Stornetta, and D. A. Bayliss Regulation of Ventral Surface Chemoreceptors by the Central Respiratory Pattern Generator J. Neurosci., September 28, 2005; 25(39): 8938 - 8947. [Abstract] [Full Text] [PDF]
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N. C Taylor, A. Li, and E. E Nattie Medullary serotonergic neurones modulate the ventilatory response to hypercapnia, but not hypoxia in conscious rats J. Physiol., July 15, 2005; 566(2): 543 - 557. [Abstract] [Full Text] [PDF]
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