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Exchange of Views |
1 Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA
Abstract
Central chemoreception is the mechanism by which arterial blood PCO2 is detected by the CNS to regulate breathing. Two main theories have been proposed to account for the phenomenon. The distributed chemosensitivity theory argues that pH sensitivity is a widespread attribute of brainstem neurones and that central chemoreception results from the cumulative effects of pH on countless neurones. The specialized chemoreceptor theory envisions the existence of small and specialized populations of CNS cells (chemoreceptors) that are unique in their ability to detect very small pH fluctuations and, via specific connections, regulate a respiratory network that is itself unresponsive to pH. The recently identified CO2-sensitive neurones of the retrotrapezoid nucleus (RTN) seem to possess most of the attributes that one would expect of such chemoreceptors. In this review we also suggest that many fewer medullary neurones are intrinsically responsive to CO2in vivo than might have been anticipated from prior experimentation in vitro. The properties of RTN neurones provide renewed support for the specialized chemoreceptor theory of central chemoreception, proposed in the early 1960s. However, many uncertainties remain, especially as regards the molecular mechanisms of chemoreception, the type of cell that actually detects pH in vivo (neurone, glia or others) and the number and location of bona fide central chemoreceptors.
(Received 8 December 2004;
accepted after revision 22 February 2005; first published online 25 February 2005)
Corresponding author P. G. Guyenet: Department of Pharmacology, University of Virginia Health System, PO Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908-0735, USA. Email: pgg{at}virginia.edu
Central chemoreception is the mechanism by which arterial blood PCO2 is detected by the CNS in order to regulate breathing. Blood PCO2 is sensed within the lower brainstem via attending changes in brain pH and this system can produce large ventilatory changes in response to very small pH fluctuations (Nattie, 2001; Scheid et al. 2001; Rodman et al. 2001; Feldman et al. 2003; Richerson, 2004). A central chemoreceptor can be defined as a brainstem cell that possesses an intrinsic sensitivity to pH (chemosensitivity) and anatomical connections that enable it to regulate the respiratory network.
Despite decades of research neither the cell type (neurones, glial cells or vascular cells) nor the precise brainstem location of central chemoreceptors have been definitively established, the cellular and molecular mechanisms that underlie central chemoreception remain hypothetical and it is unclear whether pH is sensed intracellularly or extracellularly (Scheid, 2001; Putnam et al. 2004). There is also disagreement as to whether chemoreception is mediated by a small number of dedicated cells (hereafter called the specialized chemoreceptor theory) or whether chemoreception is a widely distributed function (hereafter called the distributed chemosensitivity theory). The specialized chemoreceptor theory envisions the existence of dedicated populations of CNS neurones that can detect small pH fluctuations either directly or via ancillary pH-sensing cells such as glia or blood vessel cells (Fig. 1). This theory considers implicitly that these specialized sensors drive a respiratory network (the central rhythm and pattern generator, CPG) that is by and large insensitive to pH fluctuations within the relevant range for blood gas homeostasis (a few tenths of a pH unit). The essential features of such a model were proposed more than 20 years ago (Loeschcke, 1982). At the other theoretical extreme, the distributed chemosensitivity theory argues that pH sensitivity is a common attribute of brainstem neurones and that central chemoreception results from the cumulative effects of pH on large numbers of CPG neurones and many of their modulatory inputs (Kawai et al. 1996).
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Distributed chemosensitivity or specialized chemoreceptors: summary of the evidence
The distributed chemosensitivity theory derives support from three types of observations. First, some degree of pH sensitivity is extremely common in brainstem neurones recorded in vitro (30–100% of randomly sampled neurones depending on the study and the recording location) (Richerson, 1995; Kawai et al. 1996; Pineda & Aghajanian, 1997; Richerson et al. 2001; Washburn et al. 2002; Putnam et al. 2004). Second, breathing can be stimulated by artificially acidifying numerous brainstem regions in vivo (Li et al. 1999; Nattie, 1999; Solomon et al. 2000; Nattie & Li, 2001; Nattie & Li, 2002; Feldman et al. 2003) and third, pH-modulated channels are widely distributed in the brainstem (e.g. Xu et al. 2000; Washburn et al. 2003).
The most extreme case of non-selective effects of pH in vitro was reported in the neonatal rat brainstem spinal cord preparation in which acidification produced large depolarizations or hyperpolarizations in essentially all brainstem respiratory neurones (Kawai et al. 1996). The relevance of these effects to central chemoreception is hard to assess given that the same acidification produced virtually no effect on the amplitude of the respiratory motor output in this preparation. The problem may be that superfused en bloc preparations have a very acidotic core (pH 6.8 within 600 µm of the surface) under resting conditions (Voipio & Ballanyi, 1997; Chesler, 2003) and further acidification may cause pH to fall into a decidedly unphysiological range with respect to central chemoreception. Though many neurones recorded in slices are also chemosensitive, their response to pH is modest and for the most part of relatively uniform magnitude (Putnam et al. 2004). This observation has been interpreted as evidence that chemosensitivity is widespread. However, another interpretation is that these mild responses are non-specific and that the real chemoreceptors, when found, would display much greater pH sensitivity. This second interpretation is supported by mounting evidence that RTN neurones are much more robustly activated by pH in vitro than neurones located elsewhere in the brainstem (Mulkey et al. 2004; Putnam et al. 2004; Fig. 2).
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The specialized chemoreceptor theory relies on three types of evidence: (1) the more recent cellular neurophysiological work on the RTN and the raphe that will be discussed later; (2) older physiological studies highlighting the importance of the ventral surface of the medulla in respiratory control (Loeschcke, 1982; Millhorn & Eldridge, 1986; Severinghaus, 1998) and; (3) the limited pattern of Fos expression in animals exposed to CO2 (e.g. Sato et al. 1992; Teppema et al. 1997). The last two lines of evidence are consistent with the notion that chemoreceptors could be located close to the ventral medullary surface but both have inherent limitations. Though ventral surface acidification activates breathing, the regional specificity of these effects was not adequately addressed by the older literature. As for the Fos methodology, it could have provided a biased representation of the anatomical distribution of central chemoreceptors given that many brain neurones do not express Fos when activated. Also, in most studies, the CO2-exposed rats had intact peripheral chemoreceptors, which raises the issue of whether central or peripheral chemoreceptor stimulation caused the pattern of Fos expression. Finally, many of the cells that express Fos after hypercapnia could be downstream from the chemosensors, and others could be a remote consequence of stress or of behaviours induced by hypercapnia.
In vivo evidence supporting the existence of central chemoreceptors within the RTN
The RTN (Cream et al. 2002; Weston et al. 2004; Mulkey et al. 2004) is located at the ventral surface of the rostrolateral medulla and was initially identified as a region that innervates the rostral ventral respiratory group (Smith et al. 1989). Injection of the GABA-mimetic muscimol into RTN depresses respiration as does focal cooling of the ventral surface that underlies the nucleus (Fukuda et al. 1993; Nattie, 2001; Feldman et al. 2003). Acidification of RTN stimulates breathing (Li & Nattie, 1997) and neurones in this region express Fos when awake rats are exposed to hypercapnia and when perfused rat brainstems are exposed to CO2in vitro (Sato et al. 1992; Okada et al. 2002). These observations are subject to all the theoretical limitations stated above and do not single out RTN as a more likely site of central chemoreception than several others (e.g. NTS or raphe) (Feldman et al. 2003). What solidifies the case of the RTN as a site of central chemoreception is the availability of strong congruent evidence obtained at the single neurone level in vivo and in vitro (Mulkey et al. 2004).
RTN contains neurones that are extremely sensitive to hypercapnia under anaesthesia in vivo (Mulkey et al. 2004) (Fig. 2A). Silent below 4% end-expiratory CO2, these neurones are activated by hypercapnia with a dynamic range of about 12 spikes s–1 for a 0.3 unit change in arterial pH. The response of RTN neurones to hypercapnia has several unique characteristics. First, RTN neurones are weakly modulated by respiration; that is, they tend to discharge throughout the central respiratory cycle, unlike CPG neurones. Second, their response to hypercapnia is unaffected by the administration of drugs that silence the CPG (morphine and kynurenic acid) (Mulkey et al. 2004). Third, their response to hypercapnia is very selective in vivo as nearby pre-sympathetic neurones and serotonergic neurones are unaffected (Mulkey et al. 2004). Of note, after blockade of lower brainstem glutamate receptors with kynurenic acid, respiratory neurones become either silent or tonic but in both cases the cells no longer respond to hypercapnia. Though this observation needs to be extended to a much greater number of respiratory neurones, it represents the first evidence that CPG neurones, unlike RTN neurones, may not be intrinsically responsive to CO2in vivo.
RTN neurones are not serotonergic and have extensive dendrites within the marginal layer of the RTN (Mulkey et al. 2004) (Fig. 3). This characteristic is likely to render them sensitive to experimentally imposed changes in ventral surface pH or temperature and may account for the classic observation that ventral medullary surface acidification stimulates breathing whereas cooling has the opposite effect (Loeschcke, 1982). However there is at present no concrete evidence that the extensive superficial dendrites of RTN neurones are essential for the detection of arterial PCO2 and proximity to the ventral surface is not necessarily associated with chemosensitivity as the superficial serotonergic neurones of the parapyramidal region are unresponsive to hypercapnia in vivo (Mulkey et al. 2004). Finally, RTN neurones are glutamatergic and selectively innervate regions of the ventral respiratory column and dorsolateral pons that are involved in respiratory rhythm and pattern generation (Mulkey et al. 2004). RTN neurones are thus poised to contribute a tonic excitatory drive to the respiratory network.
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The pH sensitivity of RTN neurones in vitro appears much greater than that of other medullary neurones recorded so far. At room temperature, the dynamic range of their response to pH is clearly less than in vivo (Mulkey et al. 2004; Putnam et al. 2004) but, at 35°C, this range is dramatically increased and approaches values found in vivo (Fig. 2B). The chemosensitivity of these RTN neurones has been attributed to modulation of a background (leak) potassium current (Mulkey et al. 2004). As this background potassium conductance responds to pH in the presence of tetrodotoxin (TTX), the most parsimonious interpretation would be that the cells express pH-gated potassium channels (Fig. 1). Candidates include two-pore domain channels such as the TWIK-related acid-sensitive channels (TASK) (Bayliss et al. 2001). However, the brainstem distribution of TASK channels is wide and includes neurones that exhibit little or no sensitivity to hypercapnia in vivo (e.g. C1 neurones and serotonergic neurones) (Washburn et al. 2003; Mulkey et al. 2004). Therefore, either TASK channels are not responsible for the pH sensitivity of RTN neurones in vivo or there must be unknown compensating mechanisms in TASK-expressing non-chemoreceptor neurones to account for their lack of sensitivity to hypercapnia. However, other interpretations should also be considered. For example, acidification could release an unknown substance from neighbouring glia or blood vessels and this substance could activate receptors located on RTN neurones causing the modulation of their potassium conductance (Fig. 1). The general concept that central chemoreceptor neurones might derive their pH sensitivity from ancillary cells such as glia is not new (Loeschcke, 1982) and such a mechanism would not be affected by the presence of TTX. The possibility that glial or vascular cells are the real pH/CO2 sensors has the added attraction of providing a potential mechanism by which CNS neurones could sample arterial blood PCO2 which is the physiological variable thought to be regulated by central chemoreception as opposed to brain parenchymal PCO2. The glial or vascular cell hypothesis could also provide an explanation for why RTN neurones have such extensive dendrites within the marginal layer, a highly vascularized structure associated with a peculiar type of layered glia. Glial cells, especially those located at the brain ventral surface, can release ATP (Spyer et al. 2004) and/or glutamate (Montana et al. 2004). Although the sensitivity of RTN neurones to pH in vitro is unaffected by antagonists of ionotropic receptors to glutamate or ATP (Mulkey et al. 2004), a contribution of their cognate metabotropic receptors has not been ruled out. Clearly, the range of other potential signalling molecules is expansive.
The molecular mechanisms that underlie chemoreception outside the RTN are even more speculative. A number of pH-sensitive ion channels have been implicated in neuronal sensitivity to pH in vitro, including inwardly rectifying (Pineda & Aghajanian, 1997; Xu et al. 2000), Ca2+-activated (Wellner-Kienitz et al. 1998), background (Bayliss et al. 2001; Washburn et al. 2002) and unidentified K+ channels (Dean et al. 1989). Even some G-protein-coupled receptors (GPCRs) have been recently proposed as capable of sensing protons around physiological pH (Ludwig et al. 2003; Wang et al. 2004). In most cases, including TASK channels, pH sensitivity was attributed to a titratable histidine located in the extracellular domain (GPCRs) or close to the selectivity pore of the channel (TASK). Any of these channels could theoretically play a role in chemoreception. However, their contribution will remain purely hypothetical until three essential pieces of evidence can be produced. First, it should be shown that these channels are present in cells that qualify as central chemoreceptors based on a comprehensive set of criteria that include their selective response to hypercapnia in vivo. Second, it should be shown that these molecules contribute significantly to the chemosensitivity of these particular neurones. Third, it should be shown that these channels contribute to central chemoreception in the whole animal. To our knowledge, no ion channel or other pH-sensitive molecule has passed any of these tests.
Are chemoreceptors located in the medullary raphe? Are raphe chemoreceptors serotonergic?
The following evidence underlies the theory that brain serotonergic neurones, regardless of location, are CO2 detectors and that those located in the medullary raphe subserve a central chemoreceptor role during sleep (Feldman et al. 2003; Mitchell, 2004; Richerson, 2004): (1) acidification of the medullary raphe stimulates breathing during sleep; (2) serotonergic neurones are physically close to the penetrating arteries; (3) midbrain and medullary serotonergic neurones in slices and/or culture discharge at a higher rate when exposed to acid; and (4) a small fraction of medullary raphe neurones are activated by CO2 in awake cats (Veasey et al. 1995). The sensitivity of dorsal raphe neurones to CO2in vitro is interpreted as a mechanism by which hypercapnia may cause arousal (Washburn et al. 2002; Richerson, 2004). This admittedly suggestive evidence is at odds with the fact that serotonergic neurones, regardless of their location, have been found largely unresponsive to hypercapnia in vivo (Veasey et al. 1995; Mulkey et al. 2004). Specifically, in anaesthetized rats the medullary serotonergic neurones are unaffected by hypercapnia as a group although a small minority was modestly activated (by a maximum of 30% from a baseline of approximately 1.5 Hz) by raising end-expiratory CO2 from 4 to 10% (Mulkey et al. 2004). In awake cats a small percentage of putative serotonergic neurones located in the midline medullary raphe was activated by hypercapnia (Veasey et al. 1995). However, the dynamic range of the responsive neurones was extremely modest and these investigators did not verify whether the few CO2-responsive neurones encountered were serotonergic (Veasey et al. 1995). Finally, the effect of CO2 on these raphe cells disappeared during sleep, which suggests that their activation by hypercapnia could have been due to behavioural changes rather than to their intrinsic ability to detect CO2 (Veasey et al. 1995).
In short, hypercapnia seems to have, at best, a marginal stimulatory effect on a small percentage of medullary raphe serotonergic neurones in vivo and these results are the main stumbling block of the theory that serotonergic neurones are CO2 detectors (Richerson, 2004). It is conceivable that the intrinsic pH sensitivity of raphe neurones could be conditional; that is, it could depend on extracellular factors (transmitters and hormones) that are not always present. However, this possibility does not adequately explain why acidification of the raphe stimulates breathing predominantly during sleep (Nattie & Li, 2001) as sleep is the very condition when putative serotonergic neurones become unresponsive to hypercapnia, in cats at least (Veasey et al. 1995). Other possibilities should therefore be considered, including the possibility that the chemoreceptors of the medullary raphe are not serotonergic.
Conclusions
The hypercapnia-sensitive neurones of RTN appear to fulfil most of the functional and anatomical criteria that one would expect from specialized central chemoreceptors (Fig. 1) (Mulkey et al. 2004). The available data are consistent with the possibility that the pH sensitivity of RTN neurones is intrinsic and mediated by a resting pH-gated potassium conductance. It appears that the proportion of medullary neurones that are intrinsically responsive to CO2in vivo may be much smaller than anticipated from prior experiments in vitro (slices, en bloc preparations and cultured neurones) (Mulkey et al. 2004) and importantly, new evidence suggests that CPG neurones may not be intrinsically responsive to CO2in vivo (Mulkey et al. 2004).
However, many areas of uncertainties remain. First, RTN-like neurones may also be present in other regions of the ventral medullary surface (e.g. the caudal chemosensitive regions; Loeschcke, 1982) and elsewhere in the brainstem (raphe, NTS, etc.) (Nattie, 2001; Feldman et al. 2003; Richerson, 2004). These hypotheses have considerable merit but still need congruent cellular electrophysiological evidence of the type that has been collected for RTN neurones. Second, the molecular mechanisms of central chemoreception are unknown. These mechanisms are unlikely to be identified with any degree of certainty before the fundamental debate between the specialized chemoreceptor theory and the distributed chemosensitivity is settled. If the specialized chemoreceptor theory prevails, the relevant molecular mechanisms will have to be sought within the bona fide chemoreceptors, not at random in the brainstem. So far, RTN neurones appear to be very promising candidates and therefore these cells may prove to be a very important model to identify the molecular substrate of central chemoreception. However, the possibility must also be entertained that these neurones are not intrinsically pH sensitive but, instead, owe their pH response to the release of a transmitter by nearby non-neuronal cells. If the latter were to be true, the most basic molecular mechanisms of chemoreception would have to be sought within the non-neuronal cells of the ventral surface.
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Acknowledgements
This work was supported by grants HL 074011 and HL 28785 from the National Institutes of Health, Heart Lung and Blood Institute to P.G.G.
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T. S. Moreira, A. C. Takakura, E. Colombari, G. H. West, and P. G. Guyenet Inhibitory input from slowly adapting lung stretch receptors to retrotrapezoid nucleus chemoreceptors J. Physiol., April 1, 2007; 580(1): 285 - 300. [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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J. Su, L. Yang, X. Zhang, A. Rojas, Y. Shi, and C. Jiang High CO2 chemosensitivity versus wide sensing spectrum: a paradoxical problem and its solutions in cultured brainstem neurons J. Physiol., February 1, 2007; 578(3): 831 - 841. [Abstract] [Full Text] [PDF]
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E. Nattie and A. Li Neurokinin-1 receptor-expressing neurons in the ventral medulla are essential for normal central and peripheral chemoreception in the conscious rat J Appl Physiol, December 1, 2006; 101(6): 1596 - 1606. [Abstract] [Full Text] [PDF]
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N. Voituron, A. Frugiere, J. Champagnat, and L. Bodineau Hypoxia-sensing properties of the newborn rat ventral medullary surface in vitro J. Physiol., November 15, 2006; 577(1): 55 - 68. [Abstract] [Full Text] [PDF]
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A. Li, S. Zhou, and E. Nattie Simultaneous inhibition of caudal medullary raphe and retrotrapezoid nucleus decreases breathing and the CO2 response in conscious rats J. Physiol., November 15, 2006; 577(1): 307 - 318. [Abstract] [Full Text] [PDF]
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T. S. Moreira, A. C. Takakura, E. Colombari, and P. G. Guyenet Central chemoreceptors and sympathetic vasomotor outflow J. Physiol., November 15, 2006; 577(1): 369 - 386. [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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C. R. Noronha-de-Souza, K. C. Bicego, G. Michel, M. L. Glass, L. G. S. Branco, and L. H. Gargaglioni Locus coeruleus is a central chemoreceptive site in toads Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R997 - R1006. [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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A. C. T. Takakura, T. S. Moreira, E. Colombari, G. H. West, R. L. Stornetta, and P. G. Guyenet Peripheral chemoreceptor inputs to retrotrapezoid nucleus (RTN) CO2-sensitive neurons in rats J. Physiol., April 15, 2006; 572(2): 503 - 523. [Abstract] [Full Text] [PDF]
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E. E. Nattie The retrotrapezoid nucleus and the 'drive' to breathe J. Physiol., April 15, 2006; 572(2): 311 - 311. [Full Text] [PDF]
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C. A. Smith, J. R. Rodman, B. J. A. Chenuel, K. S. Henderson, and J. A. Dempsey Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors J Appl Physiol, January 1, 2006; 100(1): 13 - 19. [Abstract] [Full Text] [PDF]
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J. Duffin Role of acid-base balance in the chemoreflex control of breathing J Appl Physiol, December 1, 2005; 99(6): 2255 - 2265. [Abstract] [Full Text] [PDF]
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A. V Gourine On the peripheral and central chemoreception and control of breathing: an emerging role of ATP J. Physiol., November 1, 2005; 568(3): 715 - 724. [Abstract] [Full Text] [PDF]
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