Developmental plasticity of the hypoxic ventilatory response after perinatal hyperoxia and hypoxia

Respiratory Physiology & Neurobiology 149 (2005) 287–299

Developmental plasticity of the hypoxic ventilatory response after perinatal hyperoxia and hypoxia Ryan W. Bavis ∗ Department of Biology, Bates College, 44 Campus Ave., Carnegie Science Hall, Lewiston, ME 04240, USA Received 16 December 2004; received in revised form 31 March 2005; accepted 1 April 2005

Abstract Both genetic and environmental factors influence the normal development of the respiratory control system. This review examines the role perinatal O2 plays in the development of normoxic breathing and the hypoxic ventilatory response in mammals. Hyperoxia and hypoxia elicit plasticity in respiratory control that is unique to development and may persist weeks to years after return to normoxia. Specifically, both hyperoxia and hypoxia during early postnatal development attenuate the adult hypoxic ventilatory response, but the underlying mechanisms for this plasticity differ. Hyperoxia attenuates the hypoxic ventilatory response through potentially life-long changes in carotid body function. Neonatal hypoxia appears to have short-term effects on carotid body function, but persistent changes in the hypoxic ventilatory response may instead reflect changes in respiratory mechanics or related neural pathways. Overall, it appears that a relatively narrow range of environmental O2 is consistent with “normal” postnatal respiratory control development, predisposing animals to potentially maladaptive plasticity in the face of disease or atypical environmental conditions. © 2005 Elsevier B.V. All rights reserved. Keywords: Development; Carotid body; Plasticity; Hypoxia; Hyperoxia

1. Introduction The respiratory system experiences changing demands throughout life. Commensurate with the importance of oxygen delivery and acid–base homeostasis to survival, the respiratory control system is capable of functional changes across all major time scales: acute responses, developmental programming, phenotypic plasticity and evolutionary adaptation. ∗

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The respiratory control system is under strong genetic control, which guides the orderly development of the respiratory system and determines much of the adult respiratory phenotype (e.g., Han and Strohl, 2000; Golder et al., 2005; Borday et al., 2005). In recent years, however, it has been increasingly recognized that the environment plays a critical role in shaping respiratory control (Carroll, 2003; Mitchell and Johnson, 2003). For example, repeated or sustained exposures to low O2 and/or high CO2 alter eupneic breathing and ventilatory chemoreflexes in mammals and birds (Mitchell and Johnson, 2003). In

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adults, these forms of respiratory plasticity rarely last more than a few days after the stimulus is removed. During development, however, the same stimuli often cause long-lasting (weeks to months to years) changes in respiratory control, as well as unique forms of plasticity not elicited in adults (Carroll, 2003). Thus, developmental plasticity is fundamentally different from plasticity in adults, suggesting a greater sensitivity to internal and external conditions in the immature animal. Environmental factors may serve as normal developmental cues, but the greater capacity for respiratory plasticity will also predispose developing animals to potentially maladaptive changes in the face of disease or unpredicted environmental conditions. Oxygen levels vary considerably during the perinatal period in placental mammals, with arterial PO2 rising abruptly at birth. Individuals may also experience changes in O2 levels, or the timing of normal changes in O2 levels, as a result of premature birth, unstable breathing, cardiorespiratory disease, altitude or medical interventions (e.g., oxygen therapy). This review summarizes what is currently known about the influence of sustained alterations in O2 levels on mammalian respiratory control development, with most evidence indicating that variation in perinatal O2 levels has profound effects on respiratory control. Respiratory effects of intermittent hypoxia during development are reviewed elsewhere in this volume (Reeves and Gozal, 2005).

2. Perinatal hyperoxia 2.1. Normoxic ventilation after perinatal hyperoxia Normoxic ventilation after developmental (primarily postnatal) hyperoxia (1–4 weeks of 30–85% O2 ) has been studied in mice and rats. After being raised in 65–85% O2 for the first 4 postnatal weeks, mice (1–7 months old) exhibited a slower, deeper breathing pattern, but no change in overall resting ventilation (Warner et al., 1998; Dauger et al., 2003) or blood gases (Dauger et al., 2003). The influence of perinatal hyperoxia on normoxic ventilation of rats is less clear. Resting ventilation tended to be higher in 3–5-monthold rats exposed 60% O2 for the first postnatal month (Ling et al., 1996) but lower in rats exposed for only the

first postnatal week (Bavis et al., 2003). Whether these differences reflect the durations of perinatal hyperoxia is not known, but neither study found significant differences between treatment groups when ventilation was normalized to metabolic rate (ventilationto-metabolism ratio; V˙ E /V˙ CO2 ). In both studies, however, hyperoxia-treated rats had 3–4 mmHg lower arterial PCO2 than untreated controls and tended to have higher arterial PO2 (Ling et al., 1996; Bavis et al., 2003). Since V˙ E /V˙ CO2 did not differ from controls (Ling et al., 1996; Bavis et al., 2003), it is possible that respiratory dead space is reduced after perinatal hyperoxia. 2.2. Hypoxic ventilatory response after perinatal hyperoxia The hypoxic ventilatory response is generally weak at birth and is characterized by a larger secondary decrease in ventilation (ventilatory depression) than observed in mature mammals (Bisgard and Neubauer, 1995). It has been suggested that perinatal hyperoxia stimulates the maturational process in rats and nearterm fetal sheep (Eden and Hanson, 1986; Blanco et al., 1988), potentially mimicking the rapid rise in O2 associated with birth and hastening resetting of arterial chemoreceptors. For example, Eden and Hanson (1986) report that 5–14-day-old rats exposed to 30% O2 since birth exhibited sustained increases in ventilation typical of adult rats rather than the biphasic response observed in age-matched controls, although these data have only been published in abstract form. If these results are confirmed, the enhanced hypoxic ventilatory response after perinatal hyperoxia appears shortlived. Most studies indicate that perinatal hyperoxia ultimately results in blunted ventilatory and/or phrenic nerve responses to hypoxia (Hanson et al., 1989b; Ling et al., 1996, 1997a,b; Fuller et al., 2001, 2002; Bavis et al., 2002, 2003, 2004a). Hypoxic ventilatory responses were abolished in 12–13-day-old kittens born and raised in 30% from birth (Hanson et al., 1989b). Although the lasting effects of perinatal hyperoxia are not known for cats, several studies have examined the effects of perinatal hyperoxia on ventilatory responses of adult rats. In these studies, rats have been born and raised for the first 1–4 postnatal weeks in 30–60% O2 (Ling et al., 1996, 1997a,b; Fuller et al., 2001, 2002; Bavis et

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Fig. 1. Ventilatory and phrenic nerve responses to hypoxia in 3–6month-old male rats raised in 60% O2 for the first postnatal month (perinatal hyperoxia) or in normoxia (control). Poikilocapnic ventilatory responses were measured after 60 min of hypoxia (arterial PO2 ≈ 48 mmHg; n = 38 control, 27 perinatal hyperoxia). Isocapnic phrenic nerve responses were measured after 3–5 min of hypoxia (arterial PO2 ≈ 50 mmHg; n = 7 control, 11 perinatal hyperoxia). Note that both ventilatory and phrenic responses are attenuated in hyperoxia-treated rats. Values are means ± S.E.M. (*) P < 0.05 vs. untreated control group. Data are from Ling et al. (1996) (ventilatory responses) and Ling et al. (1997c) (phrenic nerve responses).

al., 2002, 2003, 2004a; Prieto-Lloret et al., 2004). After perinatal hyperoxia, hypoxic ventilatory responses in unanesthetized, 3–5-month-old rats are reduced by at least 20–50% after controlling for metabolic rate and arterial PO2 (Fig. 1), almost entirely through a reduced frequency response to hypoxia (Ling et al., 1996; Bavis et al., 2003); the magnitude of blunting is similar in male and female rats (R.W. Bavis and J.P. Otis, unpublished observations). Blunted hypoxic responses have been confirmed by recording phrenic nerve responses to isocapnic hypoxia in anesthetized rats (Fig. 1; Ling et al., 1997a,c; Fuller et al., 2001, 2002; Bavis et al., 2002, 2003, 2004a). The effects of perinatal hyperoxia are specific to development since 1 month of 60% O2 has no lasting effect on respiratory control if the exposure occurs in adulthood (Ling et al., 1996, 1997a). By exposing rats to 1-week durations of hyperoxia at different postnatal ages, the critical period for this plasticity was found to occur during the first 2 postnatal weeks (Bavis et al., 2002; see also Erickson et al., 1998). Experimental animals are often

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placed into hyperoxia a few days prior to delivery for these studies, but it is unclear what effect prenatal hyperoxia might have. Although prenatal hyperoxia is not required to elicit this respiratory plasticity (Bavis et al., 2002), it is not known if prenatal hyperoxia is sufficient to alter adult ventilatory responses without postnatal exposure. Despite blunted hypoxic ventilatory responses, the effects of perinatal hyperoxia on hypoxic arterial blood gases are equivocal. Hyperoxia-treated rats tend to exhibit smaller drops in arterial PCO2 relative to controls, as expected given their reduced V˙ E /V˙ CO2 during hypoxia, but this trend has not been proven statistically yet (Ling et al., 1996; Bavis et al., 2003). This may reflect difficulty in detecting the relatively small effect on arterial CO2 predicted for the observed magnitude of blunting, or changes in respiratory deadspace (Bavis et al., 2003). As described above, most studies have concluded that perinatal hyperoxia attenuates adult hypoxic ventilatory responses. Two recent studies, however, did not detect any lasting plasticity in ventilatory responses. Prieto-Lloret et al. (2004) exposed rats to 55–60% O2 for the first 4 postnatal weeks and measured their respiratory frequency responses to hypoxia as adults (3.5–4.5 months old). Although carotid chemoreceptor function was impaired in this study (see below), hypoxic frequency responses appeared normal in the intact animal. In a second study by Dauger et al. (2003), hypoxic ventilatory responses of adult mice were normal after exposure to 65% O2 for the first 4 postnatal weeks. At first glance, the Prieto-Lloret and Dauger studies seem at odds with previous studies (Hanson et al., 1989b; Ling et al., 1996, 1997a,b; Fuller et al., 2001, 2002; Bavis et al., 2002, 2003, 2004a), but the apparent inconsistencies may simply result from methodological differences. First, blood gases during hypoxic exposures were not measured in either study, so treatment groups may have received different hypoxic stimuli. Prolonged postnatal hyperoxia impairs gas exchange efficiency in rats during hypoxia as evidenced by a widening alveolar–arterial PO2 difference and, consequently, hyperoxia-treated rats are more hypoxemic at a given inspired PO2 (Ling et al., 1996); shorter hyperoxic periods (1–2 weeks) do not impair gas exchange during hypoxia (Bavis et al., 2003; R.W. Bavis and J.P. Otis, unpublished observations). Because of this

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difference in hypoxic stimulus (and the curvilinear relationship between ventilation and arterial PO2 ), hypoxic responses measured at the same inspired PO2 may appear unchanged while actually being much reduced at equivalent arterial PO2 (Ling et al., 1996). As discussed by Prieto-Lloret et al. (2004), a second striking difference among studies is the severity of hypoxia used to assess ventilatory responsiveness after perinatal hyperoxia. Studies that detected blunted hypoxic responses utilized inspired fractional O2 concentrations greater than 12.5% (arterial PO2 > 45 mmHg) in awake rats (Ling et al., 1996; Bavis et al., 2003) or arterial PO2 ≥ 40 mmHg in anesthetized rats (Ling et al., 1997c; Fuller et al., 2001, 2002; Bavis et al., 2002, 2003, 2004a), whereas hypoxic responses were assessed at 10% O2 in the studies by Prieto-Lloret et al. (2004) and Dauger et al. (2003); 10% O2 produces arterial PO2 ∼35 mmHg in adult rats (e.g., Mortola and Saiki, 1996; Bavis et al., 2004b). Rats normally exhibit near maximal ventilatory responses at 12% O2 , with little additional increase in ventilation at lower levels of inspired O2 (e.g., Eden and Hanson, 1987). After perinatal hyperoxia, rats can still mount vigorous hypoxic responses, but lower arterial PO2 is needed to achieve a given magnitude response (i.e., the ventilatory response appears shifted toward lower PO2 ; e.g., Ling et al., 1996; Bavis et al., 2003). Thus, as arterial PO2 falls, control animals will reach their maximal ventilation and plateau whereas hyperoxia-treated rats may continue to increase ventilation and converge on a similar plateau. Accordingly, differences in ventilatory responses should be more apparent at moderate levels of hypoxia (>12% O2 ) than at severe levels (<12% O2 ). Clearly, these hypotheses need to be tested directly, but currently it does not appear that the studies to date necessarily contradict one another. Rather, most data indicate that perinatal hyperoxia causes long-lasting, if not permanent, impairment of hypoxic ventilatory responses, at least at moderate levels of hypoxia. 2.3. Localization of plasticity after perinatal hyperoxia Attenuated hypoxic ventilatory responses could reflect plasticity in one or more components of the respiratory control system, including chemoreceptors, mechanoreceptors, central neural integration of af-

ferent input or respiratory motoneurons, as well as changes in pulmonary mechanics or gas exchange. Although gas exchange is altered by longer durations (e.g., 1 month) of hyperoxia (Ling et al., 1996), the proximate cause for impaired hypoxic ventilatory responses is largely independent of changes in gas exchange and pulmonary mechanics (Ling et al., 1997a,c). Recordings made from the phrenic nerves of anesthetized, paralyzed, vagotomized and ventilated adult rats reveal that phrenic nerve activity is significantly reduced at known levels of arterial hypoxemia after perinatal hyperoxia (Fig. 1; Ling et al., 1997a,c; Fuller et al., 2001, 2002; Bavis et al., 2002, 2003, 2004a), and the magnitude of this blunting is similar to that observed in spontaneously breathing rats (Ling et al., 1996; Bavis et al., 2003). Since this experimental preparation bypasses pulmonary mechanics, the primary site of plasticity must occur upstream of the phrenic motoneuron. Furthermore, since hypoxic phrenic responses were measured under strict isocapnia (Ling et al., 1997a,c; Fuller et al., 2001, 2002; Bavis et al., 2002, 2003, 2004a), and since spontaneously breathing rats exhibit normal hypercapnic ventilatory responses after perinatal hyperoxia (Ling et al., 1996; Prieto-Lloret et al., 2004), blunted hypoxic responses appear to be the direct result of plasticity in neural systems associated with hypoxic responses versus indirect effects of altered CO2 sensitivity. Hyperoxia-induced plasticity most likely occurs at either O2 -sensitive chemoreceptors or central neural integration of chemoafferent inputs. However, there currently is no evidence of compromised central neural integration. Input–output relationships, studied by electrically stimulating the carotid sinus nerve (CSN) and recording changes in phrenic nerve activity, are normal after perinatal hyperoxia (Ling et al., 1997b; Fuller et al., 2002), suggesting that central integration of afferent impulses from peripheral chemoreceptors is not impaired. In contrast, there is now considerable evidence that perinatal hyperoxia impairs carotid body function (Eden and Hanson, 1986; Hanson et al., 1989b; Ling et al., 1997a; Fuller et al., 2002; Bisgard et al., 2003, 2005; Kim et al., 2003; Prieto-Lloret et al., 2004; Donnelly et al., in press). In rats, for example, acute responses to hypoxia, asphyxia and/or cyanide of whole CSN preparations are dramatically reduced immediately after (Eden and Hanson, 1986) and several months after 1–4 weeks of postnatal hyperoxia

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(Ling et al., 1997a; Fuller et al., 2002; Bisgard et al., 2003, 2005; Prieto-Lloret et al., 2004). Attenuated CSN responses could result from fewer O2 -sensitive cells and afferent neurons, the inability of the remaining cells to respond to hypoxic stimuli or a combination of these factors. For example, after 1–4 weeks of 30–60% O2 during postnatal development, carotid body volume is only 25–60% of control values, with a proportionate reduction in the volume occupied by glomus cells (Erickson et al., 1998; Fuller et al., 2001, 2002; Bisgard et al., 2003; Prieto-Lloret et al., 2004). In addition, Erickson et al. (1998) observed a 41% decrease in unmyelinated axons after 4 weeks of postnatal hyperoxia and a 32% decrease in tyrosine hydroxylase-positive (TH-positive) neurons in the pertrosal ganglion after only 1 week of postnatal hyperoxia; these changes are specific to the carotid chemoafferent pathway as numbers of TH-positive cells were unchanged in the nearby no dose ganglion. Thus, hyperoxia-treated rats exhibit substantial reduction in numbers of O2 -sensitive cells in the carotid body as well as loss of neurons that carry sensory feedback from the carotid body to the CNS. Fewer numbers of otherwise functional glomus cells and associated afferent neurons may reduce the population-level response to hypoxia measured in whole nerve preparations. However, phrenic responses to electrical CSN stimulation are normal after perinatal hyperoxia (Ling et al., 1997b; Fuller et al., 2002), suggesting that the CNS may compensate to some degree for fewer afferent neurons. Consistent with this hypothesis, normal hypoxic ventilatory response can be achieved with only one functional carotid sinus nerve (Cragg and Khrisanapant, 1994). If the CNS compensates for input from fewer afferent neurons, the reduced hypoxic ventilatory response may instead reflect reduced sensitivity of the remaining chemoreceptors. In other words, perinatal hyperoxia may alter hypoxic responses by directly impairing hypoxic chemotransduction of carotid body glomus cells and/or transmission of this information by chemoafferent neurons. There is growing evidence to support this hypothesis. In cats, hypoxic responses in single-fiber and few-fiber recordings from the CSN are greatly diminished by development in 30% O2 for the first 12–23 postnatal days (Hanson et al., 1989b), consistent with reduced hypoxic responsiveness of individual receptor cells. This result was recently replicated in rats using in

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vitro recordings of single-unit petrosal ganglion neurons arising from the carotid body of ∼2-week-old rats raised from birth in 60% O2 (Donnelly et al., in press). Further, isolated glomus cells from the carotid bodies of rats reared under these conditions often exhibited smaller membrane depolarization and smaller increases in intracellular Ca2+ in response to hypoxic and anoxic stimuli, yet these cells were capable of normal responses to high extracellular K+ (Kim et al., 2003; J.L. Carroll, personal communication). Thus, in at least some surviving glomus cells, the cellular mechanism underlying hypoxia-induced depolarization is impaired immediately after developmental hyperoxia; this conclusion does not exclude additional impairment at the level of synaptic transmission between glomus cells and chemoafferent neurons. In adult rats, Prieto-Lloret et al. (2004) suggest that there is a bimodal distribution for hypoxic responses of surviving O2 -sensitive cells. They report that ∼75% of CSN fibers and carotid bodies appear incapable of responding to low O2 by increasing discharge or releasing catecholamines (but respond normally to K+ ), whereas the responses of the remaining fibers and carotid bodies are statistically unchanged relative to controls (despite a trend toward reduced responsiveness), at least in response to severe hypoxia (Prieto-Lloret et al., 2004); it is possible that responsive cells would exhibit attenuated responses to moderate levels of hypoxia. Similarly, fewer glomus cells that were isolated from the carotid bodies of adult, hyperoxia-treated rats were responsive to hypoxia, but the intracellular Ca2+ response to hypoxia of these cells, while sluggish, had a similar magnitude to controls overall (Prieto-Lloret et al., 2004). In summary, the current weight of evidence suggests that, in addition to fewer chemoreceptor cells in the carotid body after perinatal hyperoxia, only a fraction of the remaining chemoreceptor cells retain the capacity to respond normally to hypoxic stimuli. Whether this impairment is all-or-none, as implied by PrietoLloret et al. (2004), or graded is yet to be determined definitively. Immediately after hyperoxia, young rats and cats have some chemoreceptor units capable of responding only weakly (Hanson et al., 1989b; Kim et al., 2003; Donnelly et al., in press; J.L. Carroll, personal communication). It is possible that those retaining partial function recover fully by adulthood, explaining the bimodal distribution in adult animals (see Section 2.5 below).

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2.4. Influence of hyperoxia on carotid body development While there has been considerable progress toward understanding the role of carotid body function in respiratory plasticity after perinatal hyperoxia, the link between high O2 and altered carotid body function is just beginning to be studied. Three key, non-mutually exclusive hypotheses include: oxygen toxicity, inhibition of carotid body activity and altered expression of genes regulated by O2 and/or reactive oxygen species. During hyperoxic exposures, the rate of reactive oxygen species (ROS) production outpaces the body’s antioxidant defense system. This increase in ROS has a variety of effects including disruption of cell membranes, inactivation of enzymes and inhibition of protein and nucleotide biosynthesis (Frank, 1991). Although the lung is considered to be the primary site of oxygen toxicity in normobaric hypoxia (Frank, 1991; Turrens, 2003), high arterial O2 partial pressures are also hypothesized to promote ROS-mediated cellular damage in systemic tissues, particularly in tissues such as the carotid body that exhibit high blood flow relative to metabolic rate (Mokashi and Lahiri, 1991; Di Giulio et al., 1998). Thus, local ROS-mediated toxicity could contribute to the loss and/or impaired function of glomus cells and chemoafferent neurons, and ultimately to impaired hypoxic responses, in hyperoxia-treated rats. Indeed, it has been suggested that oxygen toxicity causes impaired carotid body function in adult cats after severe hyperoxia (100% O2 for 60 h) (Lahiri et al., 1987; Mokashi and Lahiri, 1991). However, perinatal exposure to as little as 30% O2 for 1 week blunts hypoxic phrenic responses in rats (Bavis et al., 2003), and most studies utilize varying durations of only 30–60% O2 to elicit developmental plasticity. It is not clear that such mild hyperoxic exposures will cause oxygen toxicity at normobaric pressures. For example, exposing adult rats to 1 month of 60% O2 does not attenuate their hypoxic responses (Ling et al., 1996, 1997a,b), and neonates often exhibit greater tolerance to hyperoxic exposures than adults (Frank, 1991). In addition, the effects of perinatal hyperoxia are generally confined to the carotid chemoafferent pathway, with no morphological changes in other neural pathways (Erickson et al., 1998; Prieto-Lloret et al., 2004) or functional changes in the hypercapnic ventilatory response or CNS integration of chemoafferent input (Ling et al.,

1997b; Fuller et al., 2002; Prieto-Lloret et al., 2004) that might be expected in oxygen toxicity. Furthermore, hyperoxia impairs carotid body growth by preventing cellular proliferation during postnatal development with no evidence of apoptosis or necrosis of existing cells (Wang and Bisgard, 2005). Finally, dietary supplementation (via maternal milk) with the antioxidant Vitamin E did not ameliorate the effects of perinatal hyperoxia on CSN responses to cyanide or asphyxia or on carotid body volume in rats (Wenninger et al., 2004). If it is confirmed that this treatment enhanced antioxidant defenses of the rat pups, these preliminary data do not support a role for ROS in this plasticity. Hyperoxia may also alter the normal postnatal development of the carotid chemoafferent pathway by inhibiting depolarization of the carotid body chemosensory cells. For example, afferent neurons within the CSN require trophic support from the carotid body during the early postnatal period (Hertzberg et al., 1994), and carotid body glomus cells express both brainderived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF), as well as the receptors for BDNF, in neonatal rats (Wang and Bisgard, 2005). The release of BDNF has been linked to membrane depolarization in some cell types, including sensory neurons from the petrosal ganglion (Balkowiec and Katz, 2000). High O2 levels minimize carotid body activity at rest and should reduce the occurrence of hypoxic bouts capable of stimulating carotid chemoreceptors. If glomus cells also release trophic factors in an activity-dependent manner, inadequate release of trophic factors during perinatal hyperoxia could result in abnormal development and loss of carotid body cells and/or chemoafferent neurons. Importantly, carotid chemoafferent neurons no longer require trophic support by the third postnatal week (Hertzberg et al., 1994), consistent with the critical period for hyperoxia-induced changes in carotid body morphology (Erickson et al., 1998) and hypoxic phrenic responses (Bavis et al., 2002). Hyperoxic inhibition of glomus cell depolarization will also reduce synaptic activation of chemoafferent neurons. Perinatal activity is known to regulate the expression of tyrosine hydroxylase in these dopaminergic cells (Hertzberg et al., 1995; Brosenitsch and Katz, 2002), and other developmentally important genes similarly could be regulated by activity-dependent processes.

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Activity-independent regulation of carotid body gene expression in hyperoxia is an important topic that has received little attention. Many genes are regulated by O2 or related changes in ROS (D’Angio and Finkelstein, 2000; Paulding et al., 2002; Land and Wilson, 2005), and some of these genes could directly or indirectly influence O2 sensing (e.g., ion channels) or neurotransmitter release in the carotid body. For example, vascular endothelial growth factor (VEGF), which is expressed in the carotid body, promotes growth and maintenance of immature blood vessels (Dor et al., 2001; Tipoe and Fung, 2003). If hyperoxia downregulates VEGF production in the carotid body, as it does elsewhere in the body (Dor et al., 2001), perinatal hyperoxia could lead to poor carotid body vascularization. Loss of vasculature could alter O2 profiles within the carotid body, and therefore O2 sensitivity, or could attenuate proliferation of glomus tissue (and thus limit trophic support for developing chemoafferent neurons). 2.5. Recovery of hypoxic responses after perinatal hyperoxia Phrenic nerve and CSN responses to hypoxia are still attenuated in 14–15-month-old rats exposed to 60% O2 for the first month of life (Fuller et al., 2002), suggesting that perinatal hyperoxia causes life-long impairment of respiratory control. Further, there is no evidence for spontaneous recovery between 3 and 15 month of age in these rats (Bavis et al., 2003). After only 1 week of 60% O2 , however, there is a progressive, spontaneous recovery of hypoxic phrenic responses between 3 and 12 month of age (Bavis et al., 2003); this recovery is nearly complete in some individuals but appears to be absent in others. Although hypoxic phrenic responses are attenuated equally after 1 week and 1 month of 60% O2 (Bavis et al., 2002), shorter durations of hyperoxia may have smaller effects on some aspects of carotid body function (Bisgard et al., 2003, 2005). Whole CSN responses to acute isocapnic hypoxia (arterial PO2 ∼ 45 mmHg) are reduced to similar extents in rats exposed to 60% O2 for the first 1, 2 or 4 postnatal weeks, but CSN responses to asphyxia and cyanide are impaired to a far greater extent by the longer hyperoxic exposures (Bisgard et al., 2003, 2005). Differences in residual functional capacity may explain varying degrees of spontaneous recovery in rats. Future

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experiments are needed to address (1) the mechanism of spontaneous recovery and (2) whether rats exhibit any recovery between the end of hyperoxic exposures and maturity (i.e., between 2–4 weeks and 3 months of age). In addition to any spontaneous recovery, it may be possible to actively restore hypoxic responses after perinatal hyperoxia. Fuller et al. (2001) treated adult rats that had been exposed to 60% O2 for the first postnatal month with 1 week of sustained or intermittent hypoxia (12% O2 ). Both treatments enhanced hypoxic phrenic responses to near control values. Partial recovery persisted for 1 week after intermittent hypoxia but the effect appeared to be fading (Fuller et al., 2001); persistence of recovery was not studied after sustained hypoxia in this study, but sustained hypoxia immediately after developmental hyperoxia does not cause measurable recovery 2–3 months later (Bavis et al., 2004a). It is likely that both models of chronic hypoxia enhanced the residual hypoxic response rather than reversing the original impairment (i.e., metaplasticity; Mitchell and Johnson, 2003). For example, Bisgard et al. (2005) recently studied the effects of chronic sustained hypoxia on CSN responses in rats treated with 1, 2 or 4 week of perinatal hyperoxia. Sustained hypoxia enhanced CSN responses to acute hypoxia in 1-week hyperoxia-treated rats, but had minimal effects on rats exposed to longer durations of hyperoxia. Since Fuller et al. (2001) studied rats after 4 weeks of hyperoxia, the “recovery” of phrenic responses they observed likely resulted from enhanced central neural integration of chemoafferent inputs (Powell et al., 2000) or other central neural mechanisms rather than recovery of lost carotid body function; enhanced central neural integration could also explain increased hypoxic phrenic responses after intermittent hypoxia (e.g., Ling et al., 2001). Rats exposed to shorter periods of hyperoxia appear to retain greater functional capacity in their carotid bodies (Bisgard et al., 2003, 2005), and the enhanced CSN responses of these rats after sustained hypoxia may reflect normal acclimatization in residual tissue (Bisgard and Neubauer, 1995; Bisgard et al., 2005). 3. Neonatal hypoxia 3.1. Normoxic ventilation after neonatal hypoxia Rats raised in hypoxia (10% O2 ) for the first postnatal week hyperventilate when transferred to room air

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(Mortola et al., 1986) and Okubo and Mortola (1988, 1990) reported that rats continue to hyperventilate 6–7 weeks after return to normoxia; similar hypoxic exposures in adult rats did not alter their normoxic ventilation. Persistent hyperventilation has also been observed up to 3 weeks after prenatal hyperoxia in rats, but normoxic ventilation returns to normal by 9 weeks (Peyronnet et al., 2000). In contrast, a more recent study failed to detect lasting changes in normoxic ventilation in rats at 6–8 week after neonatal hypoxia (Bavis et al., 2004b). Given the nearly identical protocols used in the studies by Bavis et al. (2004b) and Okubo and Mortola (1988, 1990), it is not clear why these studies obtained different results. However, neonatal hypoxia does not alter normoxic ventilation in sheep (Sladek et al., 1993). Without more data, therefore, the effects of perinatal hypoxia on resting ventilation remain equivocal. 3.2. Hypoxic ventilatory response after neonatal hypoxia Humans born and raised at high altitude often exhibit blunted hypoxic ventilatory responses relative to sea level natives, even after moving to lower altitudes (e.g., Moore, 2000; Gamboa et al., 2003). This blunting may be acquired, at least partially, during prolonged exposure to altitude, particularly if the exposure occurs during early life (Lahiri et al., 1976, 1978; Lahiri, 1981; Moore, 2000). Blunted hypoxic chemoreflexes are also observed after congenital cyanotic heart disease (Sørensen and Severinghaus, 1968; Edelman et al., 1970; Blesa et al., 1977); this blunting is longlasting, and may even persist into adulthood, but does not appear to be permanent (Edelman et al., 1970; Blesa et al., 1977). A factor shared by people in these cases is chronic hypoxia during much of their postnatal development. Several studies have manipulated perinatal O2 levels to test directly the influence of hypoxia on the development of ventilatory control. Hypoxic ventilatory responses are consistently absent or severely attenuated in young rats, cats and sheep maintained in hypoxia (10–15% O2 ) from birth until 0–24 h prior to study (5 day to 10 week of age) (Eden and Hanson, 1987; Hanson et al., 1989a,b; Sladek et al., 1993; Wyatt et al., 1995; Mortola and Saiki, 1996); hypoxic responses after prenatal hypoxia are more complex (see Section 3.4, below). When rats or sheep are returned

to normoxia after 1–2 week neonatal hypoxia, hypoxic ventilatory responses remain blunted for at least 5–8 week (Okubo and Mortola, 1990; Sladek et al., 1993; Bavis et al., 2004b), primarily through a reduced respiratory frequency response (Sladek et al., 1993; Bavis et al., 2004b). In rats, however, the persistent blunting of the hypoxic ventilatory response occurs in males only, with females exhibiting normal hypoxic responses at 7–9 week of age (Bavis et al., 2004b). The influence of sex was not investigated in any other study of respiratory control after neonatal hypoxia, so it is not yet known whether females are less susceptible to environmental hypoxia during development (i.e., less plastic) or simply recover faster upon return to normoxia. The effects of 1–2 week exposures to chronic neonatal hypoxia are quite different than expected in adult animals after similar hypoxic exposures. Adult hypoxic ventilatory responses generally increase during chronic hypoxia (i.e., ventilatory acclimatization) through a combination of central and peripheral effects (Bisgard and Neubauer, 1995; Powell et al., 2000), and these effects generally fade within a week or two once normoxia is restored. Indeed, hypoxic ventilatory responses return to normal within a week when adult rats are exposed to 1 week at 10% O2 (Okubo and Mortola, 1990). Plasticity elicited by neonatal hypoxia is therefore specific to development, but the critical period has not yet been defined beyond postnatal week 1. Despite persistent attenuation of their hypoxic ventilatory responses, sheep (Sladek et al., 1993) and rats (Bavis et al., 2004b) exhibit hypoxic blood gases that are indistinguishable from those of control animals breathing similar gas mixtures. Assuming metabolic responses to hypoxia are normal after neonatal hypoxia, which they are in rats (Bavis et al., 2004b), one would predict smaller changes in arterial PCO2 during poikilocapnic hypoxia in spontaneously breathing rats. A similar situation has been reported for rats after perinatal hyperoxia (Ling et al., 1996; Bavis et al., 2003), as described above (see Section 2.1), but the observed blood gases approximate the values predicted for hyperoxia-treated rats (Bavis et al., 2003); this is not the case following neonatal hypoxia. As in sheep (Sladek et al., 1993), blunting was greatest in the initial moments of acute hypoxia in neonatal hypoxia-treated rats (Bavis et al., 2004b). Since blood gases were sampled at the end of hypoxic exposures, it may simply be that influences on blood gases were missed. Alterna-

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tively, gas exchange may be relatively more efficient during hypoxia in hypoxia-treated rats by improved regulation of physiological deadspace. For example, perinatal hypoxia may reduce hypoxic vasoconstriction in pulmonary vessels, thereby enhancing gas exchange (Jones et al., 2004). If improved gas exchange efficiency is confirmed, the mechanism and time course of this compensatory plasticity represents an important area for future research. Hypercapnic ventilatory responses are not altered by neonatal hypoxia (Okubo and Mortola, 1990; Hanson and Kumar, 1994). 3.3. Localization of plasticity after neonatal hypoxia Neonatal hypoxia delays the normal postnatal resetting of carotid body responses to hypoxia (Hanson et al., 1989a,b; Wyatt et al., 1995; Sterni et al., 1999) or combined hypoxia and hypercapnia (Landauer et al., 1995). These changes undoubtedly contribute to blunted hypoxic ventilatory responses in neonates that are hypoxic from birth. However, long-lasting changes in the hypoxic ventilatory response (i.e., at least 5–8 weeks after normoxia is restored) do not appear to reflect altered function of peripheral chemoreceptors. For example, Eden and Hanson (1987) observed that whole CSN responses to acute isocapnic hypoxia were normal in 5–10-week-old rats maintained in hypoxia (13–15% O2 ) from birth, even though these rats exhibited blunted ventilatory responses. Sterni et al. (1999) found that intracellular Ca2+ responses to hypoxia where absent in glomus cells isolated from carotid bodies of chronically hypoxic rats, but responsiveness was largely restored in cells isolated from rats that had been returned to normoxia for 1 week. Similarly, sheep have impaired ventilatory responses to hyperoxia (Dejours’ test) immediately after neonatal hypoxia, suggesting abnormal peripheral chemoreceptor function, but these responses recover within 4 days after return to normoxia (Sladek et al., 1993). Thus, changes in carotid body function are transient after neonatal hypoxia and cannot contribute to impaired hypoxic ventilatory responses several weeks after return to normoxia. In addition to postnatal maturation in carotid body function, there may also be central inhibitory mechanisms present at birth, which are slowly overcome during normal development of the hypoxic ventilatory

Fig. 2. Ventilatory and phrenic nerve responses to hypoxia in 7–9week-old male rats raised in 10% O2 for the first postnatal week (neonatal hypoxia) or in normoxia (control). Poikilocapnic ventilatory responses were measured after 10–20 min of hypoxia (arterial PO2 ≈ 43 mmHg; n = 11 control, 11 neonatal hypoxia). Isocapnic phrenic nerve responses were measured after 5 min of hypoxia (arterial PO2 ≈ 40 mmHg; n = 11 control, 11 neonatal hypoxia). Note that only ventilatory responses are attenuated in hypoxia-treated rats. Values are means ± S.E.M. (*) P < 0.05 vs. untreated control group. Data are from Bavis et al. (2004b).

response, and this inhibition could be prolonged by neonatal hypoxia (Eden and Hanson, 1987; Sladek et al., 1993). However, phrenic nerve responses to isocapnic hypoxia are normal in anesthetized, male rats (2 months of age) after neonatal hypoxia (Bavis et al., 2002). This result does not support a central neural mechanism for the blunted hypoxic ventilatory response, at least in rats. Indeed, the combination of normal phrenic nerve responses and blunted ventilatory responses (Fig. 2) strongly suggests that blunting arises downstream of the phrenic motoneuron, at the level of the neuromuscular junction, respiratory muscles or respiratory mechanics (and related neural pathways). Hypoxic ventilatory responses were measured under poikilocapnic conditions so altered CO2 sensitivity could confound this analysis, but neonatal hypoxia does not alter hypercapnic ventilatory responses in rats (Okubo and Mortola, 1990). Neonatal hypoxia delays maturation of the neuromuscular transmission at the diaphragm and reduces the specific force of diaphragm contraction, although neuromuscular transmission normalizes by approximately 3 weeks of age even in continual hypoxia (Kass

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and Bazzy, 2001). Since neonatal hypoxia attenuates respiratory frequency responses to hypoxia versus tidal volume (Sladek et al., 1993; Bavis et al., 2004b), and since hypercapnic ventilatory responses are unaltered (Okubo and Mortola, 1990), changes in diaphragm force production do not explain changes in the hypoxic ventilatory response either. By process of elimination, therefore, the most likely cause for blunted ventilatory response is a change in respiratory mechanics or afferent feedback from mechanoreceptors. Neonatal hypoxia alters respiratory system compliance and pulmonary resistance in rats (Okubo and Mortola, 1988, 1989), but has relatively small effects in sheep (Sladek et al., 1993). Importantly, these changes in respiratory mechanics, measured under normoxic conditions, do not seem to impair the hypercapnic ventilatory response (Okubo and Mortola, 1990). It has therefore been proposed that neonatal hypoxia alters physiological changes in respiratory mechanics that occur specifically during hypoxic breathing (e.g., changes in airway resistance), thereby altering respiratory rates (Bavis et al., 2004b); this hypothesis has not yet been tested directly. 3.4. Prenatal hypoxia Prenatal exposure to hypoxia has complex, timedependent effects on the hypoxic ventilatory response in rats. Peyronnet et al. (2000) exposed pregnant rats continuously to 10% O2 for embryonic days 5–20. Hypoxic ventilatory responses appeared to be enhanced at 1 and 3 weeks of age after prenatal hypoxia (compared to blunted hypoxic responses after chronic neonatal hypoxia; see Section 3.2, above). Hypoxia-treated rats tended to have a sustained increase in ventilation during hypoxia versus the normal biphasic response at 1 week as well as having an overall greater hypoxic response at 3 weeks of age (Peyronnet et al., 2000); metabolic rates were higher during hypoxia in hypoxia-treated rats, but the increase in V˙ E /V˙ CO2 (estimated from their Table 4) still appears to be increased at 3 weeks of age after prenatal hypoxia. Peyronnet et al. report that prenatal hypoxia reduces postnatal expression of dopamine in the carotid body and reduces noradrenergic turnover in the brainstem, which may contribute to enhanced ventilatory responses. Moreover, carotid body glomus cells isolated from rats following prenatal hypoxia (second day of gestation through postnatal

days 5–8) exhibit membrane current properties consistent with increased excitability (Hempleman, 1995, 1996). Although rats experienced both prenatal and postnatal hypoxia, these observations suggest another potential mechanism for enhanced hypoxic responses following prenatal hypoxia. Interestingly, Peyronnet et al. (2000) found that prenatal hypoxia-treated rats had blunted hypoxic ventilatory responses when studied at 9 weeks of age, indicating that enhanced responses are transient. The mechanism of blunting at 9 weeks of age is not known, although some of the effects on noradrenergic brainstem cells that were observed at 3 weeks of age were no longer evident (Peyronnet et al., 2000).

4. Summary and conclusions It appears that a relatively narrow range of environmental O2 levels results in normal postnatal development of respiratory control. Long-lasting changes have been observed after relatively mild exposures to both hypoxia (15% O2 ; Eden and Hanson, 1987) and hyperoxia (30% O2 ; Bavis et al., 2003), and milder deviations in environmental O2 have not yet been investigated. The mechanisms of plasticity are not fully understood for any model of O2 -induced developmental plasticity (hyperoxia, neonatal (postnatal) hypoxia or prenatal hypoxia), but progress continues to be made. For now, a few generalizations seem reasonable. First, perinatal hypoxia and hyperoxia both elicit long-lasting, if not permanent, plasticity in the hypoxic ventilatory response that is unique to development. Second, the hypercapnic ventilatory response does not appear to be durably altered by variation in perinatal O2 levels (Okubo and Mortola, 1990; Ling et al., 1996; Sterni et al., 1999). Third, there seems to be a fundamental difference between exposures to varying O2 levels in the prenatal versus postnatal period, at least in response to hypoxia; prenatal effects of hyperoxia have received little attention. Prenatal hypoxia tends to enhance hypoxic ventilatory responses (Peyronnet et al., 2000), whereas postnatal hypoxia blunts the hypoxic response (Okubo and Mortola, 1990; Sladek et al., 1993; Bavis et al., 2004b). This could reflect a difference in the hypoxic stimulus (i.e., being buffered by the mother) or a difference in developmental stage during exposure. Finally, hypoxia and hyperoxia do not necessarily have opposite effects on respiratory control development.

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tions to prevent, manage or even reverse maladaptive respiratory plasticity when it occurs. Acknowledgement I would like to thank Dr. David D. Fuller and an anonymous reviewer for helpful suggestions on Fig. 3. References

Fig. 3. Simplified diagram of potential sites for developmental plasticity of the adult hypoxic ventilatory response. In rats, perinatal hyperoxia (1–4 weeks) attenuates the hypoxic ventilatory response through morphological and functional changes to the carotid body and chemoafferent neurons; longer durations of hyperoxia (4 weeks) also impair gas exchange. Although neonatal hypoxia (approximately 1 week) has transient effects at the carotid body and diaphragm, persistent attenuation of the hypoxic ventilatory response appears to occur between respiratory muscle contraction and pulmonary ventilation, perhaps through changes in respiratory mechanics. See text for details.

At first it may seem paradoxical that both low and high levels of O2 during early postnatal development result in the same adult phenotype, an attenuated hypoxic ventilatory response. However, the solution rests in what appears to be a very different mechanism of plasticity—whereas hyperoxia impairs the function of the carotid body, hypoxia appears to exert its lasting effects through changes in respiratory mechanics (Fig. 3). Given the changes in O2 levels that accompany birth, as well as those that might arise through disease, injury, altitude or medical intervention (O2 therapy), O2 induced developmental plasticity may be a critical factor in both normal and pathological development of respiratory control. Understanding the mechanisms underlying this plasticity may enable therapeutic interven-

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