Central chemoreception is a complex system function that involves multiple brain stem sites.

CENTRAL CHEMORECEPTION refers to detection of CO2/pH within the brain and the subsequent reflex effects on breathing. It involves multiple sites within the hindbrain (9, 12, 19) as focal acidification in vivo uniquely at these sites stimulates breathing, indicating detection and chemoreflex initiation. This Viewpoint is not all inclusive but focuses on recent reports of substantial decreases in the CO2 response arising from disruption in each of three central chemoreceptor sites (1, 2, 6) as well as in a broad distribution of neurokinin-1 receptor immunoreactive (NK1R-ir) neurons and processes (21). These latter results are significant as two of the chemoreceptor sites of present interest express NK1Rs and the other contains substance P, the natural ligand for the NK1R. At issue is how the central chemoreceptor system is organized if disruption in many locations causes substantial loss of chemosensitivity in vivo. The emphasis is on data obtained in conscious animals as anesthesia substantially reduces the CO2 response (1). Glutamatergic neurons in the retrotrapezoid nucleus (RTN) that express the transcription factor Phox2b have been proposed as putative central chemoreceptors (11, 28) and suggested to be of predominant importance (11). The RTN in the rodent lies between the ventral medullary surface and facial nucleus and extends a few hundred micrometers caudal to it (5, 11, 28). It appears to overlap with or lie adjacent to the parafacial respiratory group (pFRG) thought to be involved in rhythm generation in neonatal rats (24). The exact relationship between the RTN and the pFRG is unclear. Very small lesions of the RTN can cause apnea in the anesthetized animal (see Ref. 1). In unilateral studies of the RTN in the conscious rat, 1) 44% loss of NK1R-ir neurons and processes reduced the CO2 response by 30% (22), 2) inhibition by muscimol decreased the CO2 response by 22% (20), and 3) excitotoxin lesions with 35% loss of neurons decreased the CO2 response by 39% (1). These are moderate effects on the CO2 response produced by moderately sized lesions. The overall importance of the RTN in the conscious adult animal remains uncertain. The Phox2b cells in the RTN are certainly of import in early life as their loss by genetic manipulation in mice is associated with absent chemoreception, unstable breathing, and death within hours of birth (7), although there may be additional functional abnormalities, e.g., in the carotid body. That patients with Central Congenital Hypoventilation Syndrome (CCHS) have Phox2b abnormalities and markedly diminished CO2 responses suggests an important role for Phox2b RTN cells, although again these patients can have multiple abnormalities of the autonomic nervous system including brain noradrenergic neurons (27). Serotonergic (5-HT) neurons of the medullary raphe have been proposed as putative central chemoreceptors due to their chemosensitivity in vitro and to their proximate location to cerebral blood vessels (26). If all 5-HT neurons are absent from early prenatal life, as in the floxed Lmx1b/Pet-1 Cre mouse, the CO2 response is reduced by 50% (13). This could reflect loss of 5-HT effects on 1) neuronal development, 2) chemosensitivity, and/or 3) excitatory modulation of chemoreceptor and respiratory neurons (see below). Adult rat lesion data also implicate 5-HT neurons in chemoreception. A 28% loss of 5-HT neurons distributed over the medullary raphe reduced the CO2 response by up to 18% (23). More focal and effective killing, via injection of the cell specific toxin anti-SERTsaporin, of 5-HT neurons in raphe magnus (50% loss) reduced the CO2 response by up to 62%, a very substantial effect (6). Removal of the 5-HT transport protein (5-HTT) by genetic knockout in mice also results in a substantially reduced response to CO2 that is more pronounced in males ( 68%) than females ( 22%), a result attributed to a medullary 5-HT system that is “downregulated” by the constant excess of extracellular 5-HT (15). Acute inhibition of raphe magnus 5-HT neurons by microdialyis of the 5-HT1A receptor agonist 8-OH-DPAT decreased the CO2 response by up to 30% (29) and focal acidic stimulation of raphe magnus increased ventilation (12, see 9, 19). More caudally, inhibition of medullary raphe 5-HT neurons had no effect on the CO2 response (16) and enhanced the inhibition of the CO2 response at the RTN produced by simultaneous application of muscimol (16). The rostral medullary raphe (raphe magnus and pallidus) may be a site of chemosensitivity that directly affects respiratory neurons while the caudal medullary raphe (raphe obscurus) acts as a modulator of other chemoreceptor sites, e.g., the RTN. Phox2b positive RTN neurons that are putative chemoreceptors possess 5-HT receptors and can be excited by local 5-HT application (18). The overall importance of 5-HT neurons in the medullary raphe in the conscious adult animal in chemoreception remains uncertain. The medullary raphe 5-HT cells are certainly of import in the development of breathing control in early life as their loss produced by a mutation of the transcription factor pet-1 is associated with unstable breathing and death of some pups in some conditions (8). Noradrenergic neurons of the locus ceruleus have been proposed as putative central chemoreceptors due to their che-