Recovery of the biphasic hypoxic ventilatory response in neonatal rats after chronic hyperoxia.

Newborn mammals exhibit biphasic hypoxic ventilatory responses (HVR) characterized by an initial increase in ventilation and a secondary ventilatory depression. The magnitude of the hypoxic ventilatory decline (HVD) in the late phase of the HVR normally decreases with age, but this occurs sooner in rats reared in 60% O2. We investigated whether a lower level of hyperoxia (30% O2) or a short period of recovery (1 or 3 d in 21% O2) would affect the expression of this plasticity. Similar to 60% O2, rat pups reared in 30% O2 until 3-4 days of age exhibited a less biphasic HVR to 12% O2. When pups reared in 60% O2 were returned to normoxia, the magnitude of HVD increased such that pups expressed a biphasic HVR appropriate for their chronological age. Blocking synaptic input from the carotid bodies revealed that CNS hypoxia depressed ventilation less in hyperoxia-reared rats immediately following hyperoxia and after 1 d in normoxia despite recovery of the biphasic HVR. This suggests that recovery of the biphasic HVR occurs in pathways regulating HVD that depend on carotid body activity. The early, carotid body-mediated phase of the HVR was also blunted immediately and 1 d after the hyperoxia exposure, but not after 3 d of recovery. These data confirm that short exposures to mild-to-moderate hyperoxia elicit developmental plasticity in the HVR. However, reemergence of the biphasic HVR after return to normoxia argues against a heterokairic process for the premature transition from biphasic HVR to sustained HVR in hyperoxia-reared rat pups.

Influence of chronic hypoxia on the hypoxic ventilatory response of juvenile and adult rats.

Chronic hypoxia (CH) from birth attenuates the acute hypoxic ventilatory response (HVR) in rats and other mammals, but CH is often reported to augment the HVR in adult mammals. To test the hypothesis that this transition - from blunting to augmenting the HVR - occurs in the third or fourth postnatal week in rats, juvenile and adult rats were exposed to normobaric CH (12% O2) for 7 days and the HVR was assessed by whole-body plethysmography. No transition was observed, however, and the acute HVR was reduced by 61 - 85% across all ages studied. The failure to observe an augmented HVR in adult rats could not be explained by the substrain of Sprague Dawley rats used, the duration of the CH exposure, the order in which test gases were presented, the level of hypoxia used for CH and to assess the HVR, or the effects of CH on the metabolic response to hypoxia and the hypercapnic ventilatory response. A literature survey revealed several distinct patterns of ventilatory acclimatization to hypoxia (VAH) in adult rats, with most studies (77%) revealing a decrease or no change in the acute HVR after CH. In conclusion, the effects of CH on respiratory control are qualitatively similar across age groups, at least within the populations of Sprague Dawley rats used in the present study, and there does not appear to be one "typical" pattern for VAH in adult rats.

Effects of Perinatal Hyperoxia on Breathing.

Air-breathing animals do not experience hyperoxia (inspired O2 > 21%) in nature, but preterm and full-term infants often experience hyperoxia/hyperoxemia in clinical settings. This article focuses on the effects of normobaric hyperoxia during the perinatal period on breathing in humans and other mammals, with an emphasis on the neural control of breathing during hyperoxia, after return to normoxia, and in response to subsequent hypoxic and hypercapnic challenges. Acute hyperoxia typically evokes an immediate ventilatory depression that is often, but not always, followed by hyperpnea. The hypoxic ventilatory response (HVR) is enhanced by brief periods of hyperoxia in adult mammals, but the limited data available suggest that this may not be the case for newborns. Chronic exposure to mild-to-moderate levels of hyperoxia (e.g., 30-60% O2 for several days to a few weeks) elicits several changes in breathing in nonhuman animals, some of which are unique to perinatal exposures (i.e., developmental plasticity). Examples of this developmental plasticity include hypoventilation after return to normoxia and long-lasting attenuation of the HVR. Although both peripheral and CNS mechanisms are implicated in hyperoxia-induced plasticity, it is particularly clear that perinatal hyperoxia affects carotid body development. Some of these effects may be transient (e.g., decreased O2 sensitivity of carotid body glomus cells) while others may be permanent (e.g., carotid body hypoplasia, loss of chemoafferent neurons). Whether the hyperoxic exposures routinely experienced by human infants in clinical settings are sufficient to alter respiratory control development remains an open question and requires further research. © 2020 American Physiological Society. Compr Physiol 10:597-636, 2020.

Influence of chronic hyperoxia on the developmental time course of the hypoxic ventilatory response relative to other traits in rats.

Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR) in which an initial increase in ventilation is followed by a decline back toward baseline levels. The magnitude of the secondary decline diminishes with postnatal age, but this transition occurs earlier in rat pups reared in moderate hyperoxia. This pattern is consistent with heterokairy, a form of developmental plasticity in which environmental factors alter the timing of developmental events. The present study investigated whether this plasticity is specific to the HVR or if hyperoxia instead accelerates overall development. Rat pups reared in 60 % O2 (Hyperoxia) exhibited a less biphasic ventilatory response to 12 % O2 than pups reared in 21 % O2 (Control) at 4 days of age (P4) and transitioned to a sustained HVR by P10-11; Control rats exhibited a biphasic HVR at both ages. However, the average ages at which pups attained other key developmental milestones (i.e., fur development at P5, incisor eruption at P9, and eye opening at P15) were similar between treatment groups. Moreover, growth rates and maturation of the metabolic response to cooling were not accelerated, and may have been delayed slightly, relative to Control rats. For example, the capacity for pups to increase their metabolic rate at low ambient temperatures increased with age, but this thermogenic capacity tended to be reduced in Hyperoxia pups at both P4 and P10-11 (i.e., lower CO2 production rates below the lower critical temperature). Collectively, these data support the conclusion that hyperoxia specifically advances the age at which rat pups exhibit a sustained HVR, altering the relative timing of developmental events rather than compressing the entire period of development.

Development of ventilatory chemoreflexes in Coturnix quail chicks.

Compared to mammals, little is known about the development of the respiratory control system in birds. In the present study, ventilation and metabolism were measured in Coturnix quail chicks exposed to room air, hypoxia (11 % O2), and hypercapnia (4% CO2) at 0-1, 3-4, and 6-7 days posthatching (dph). Mass-specific ventilation and metabolic rate tended to increase between 0-1 and 3-4 dph and then decrease again between 3-4 and 6-7 dph. The magnitude of the hypoxic ventilatory response (HVR) increased with age. The HVR also exhibited a biphasic shape in younger quail: after the initial increase in ventilation, ventilation declined back to (0-1 dph), or toward (4 dph), baseline. Older chicks (6-7 dph) had a "sustained HVR" in which ventilation remained high throughout the hypoxic challenge. The biphasic HVR did not appear to be caused by a decline in metabolic rate; although hypoxic hypometabolism was observed in quail chicks in all three age groups, the metabolic response appeared to occur more slowly than the biphasic HVR. The biphasic ventilatory response was also specific to hypoxia since the hypercapnic ventilatory response (HCVR) was characterized by a sustained increase in ventilation in all three age groups. The magnitude of the HCVR decreased with age. These results point to several similarities in the development of ventilatory chemorflexes between Coturnix quail and newborn mammals, including age-dependent (1) increases in the HVR, (2) transitions from a biphasic to a sustained HVR, and (3) decreases in the HCVR. Whether homologous mechanisms underlie these developmental changes remains to be determined.

Ventilatory and carotid body responses to acute hypoxia in rats exposed to chronic hypoxia during the first and second postnatal weeks.

Chronic hypoxia (CH) during postnatal development causes a blunted hypoxic ventilatory response (HVR) in neonatal mammals. The magnitude of the HVR generally increases with age, so CH could blunt the HVR by delaying this process. Accordingly, we predicted that CH would have different effects on the respiratory control of neonatal rats if initiated at birth versus initiated later in postnatal development (i.e., after the HVR has had time to mature). Rats had blunted ventilatory and carotid body responses to hypoxia whether CH (12 % O2) occurred for the first postnatal week (P0 to P7) or second postnatal week (P7 to P14). However, if initiated at P0, CH also caused the HVR to retain the "biphasic" shape characteristic of newborn mammals; CH during the second postnatal week did not result in a biphasic HVR. CH from birth delayed the transition from a biphasic HVR to a sustained HVR until at least P9-11, but the HVR attained a sustained (albeit blunted) phenotype by P13-15. Since delayed maturation of the HVR did not completely explain the blunted HVR, we tested the alternative hypothesis that the blunted HVR was caused by an inflammatory response to CH. Daily administration of the anti-inflammatory drug ibuprofen (4 mg kg-1, i.p.) did not alter the effects of CH on the HVR. Collectively, these data suggest that CH blunts the HVR in neonatal rats by impairing carotid body responses to hypoxia and by delaying (but not preventing) postnatal maturation of the biphasic HVR. The mechanisms underlying this plasticity require further investigation.

Combined effects of intermittent hyperoxia and intermittent hypercapnic hypoxia on respiratory control in neonatal rats.

Chronic exposure to intermittent hyperoxia causes abnormal carotid body development and attenuates the hypoxic ventilatory response (HVR) in neonatal rats. We hypothesized that concurrent exposure to intermittent hypercapnic hypoxia would influence this plasticity. Newborn rats were exposed to alternating bouts of hypercapnic hypoxia (10% O2/6% CO2) and hyperoxia (30-40% O2) (5 cycles h-1, 24 h d-1) through 13-14 days of age; the experiment was run twice, once in a background of 21% O2 and once in a background of 30% O2 (i.e., "relative hyperoxia"). Hyperoxia had only small effects on carotid body development when combined with intermittent hypercapnic hypoxia: the carotid chemoafferent response to hypoxia was reduced, but this did not affect the HVR. In contrast, sustained exposure to 30% O2 reduced carotid chemoafferent activity and carotid body size which resulted in a blunted HVR. When given alone, chronic intermittent hypercapnic hypoxia increased carotid body size and reduced the hypercapnic ventilatory response but did not affect the HVR. Overall, it appears that intermittent hypercapnic hypoxia counteracted the effects of hyperoxia on the carotid body and prevented developmental plasticity of the HVR.

Long-term effects of the perinatal environment on respiratory control.

The respiratory control system exhibits considerable plasticity, similar to other regions of the nervous system. Plasticity is a persistent change in system behavior triggered by experiences such as changes in neural activity, hypoxia, and/or disease/injury. Although plasticity is observed in animals of all ages, some forms of plasticity appear to be unique to development (i.e., "developmental plasticity"). Developmental plasticity is an alteration in respiratory control induced by experiences during "critical" developmental periods; similar experiences outside the critical period will have little or no lasting effect. Thus complementary experiments on both mature and developing animals are generally needed to verify that the observed plasticity is unique to development. Frequently studied models of developmental plasticity in respiratory control include developmental manipulations of respiratory gas concentrations (O(2) and CO(2)). Environmental factors not specifically associated with breathing may also trigger developmental plasticity, however, including psychological stress or chemicals associated with maternal habits (e.g., nicotine, cocaine). Despite rapid advances in describing models of developmental plasticity in breathing, our understanding of fundamental mechanisms giving rise to such plasticity is poor; mechanistic studies of developmental plasticity are of considerable importance. Developmental plasticity may enable organisms to "fine tune" their phenotype to optimize the performance of this critical homeostatic regulatory system. On the other hand, developmental plasticity could also increase the risk of disease later in life. Future directions for studies concerning the mechanisms and functional implications of developmental plasticity in respiratory motor control are discussed.

Developmental hyperoxia attenuates the hypoxic ventilatory response in Japanese quail (Coturnix japonica).

Early life experiences can influence development of the respiratory control system. We hypothesized that chronic hyperoxia (60% O(2)) during development would attenuate the hypoxic ventilatory response (HVR) of Japanese quail (Coturnix japonica), similar to the effects of developmental hyperoxia in mammals. Quail were exposed to hyperoxia during prenatal development, during postnatal development, or during both prenatal and postnatal development (for approximately 2 or 4 weeks). HVR (11% O(2)) was subsequently assessed in adults (>6 weeks old) via barometric plethysmography and compared to quail raised in normoxia (i.e., control). The HVR of quail exposed to hyperoxia both prenatally and postnatally was reduced 50-60% compared to control quail whereas postnatally exposed quail exhibited normal HVR. The effects of prenatal hyperoxia on HVR were equivocal and depended on how HVR was expressed. We conclude that developmental exposure to 60% O(2) attenuates the HVR in quail and that the critical period for this plasticity encompasses the late prenatal and early postnatal periods.

Respiratory plasticity after perinatal hyperoxia is not prevented by antioxidant supplementation.

Perinatal hyperoxia attenuates the hypoxic ventilatory response in rats by altering development of the carotid body and its chemoafferent neurons. In this study, we tested the hypothesis that hyperoxia elicits this plasticity through the increased production of reactive oxygen species (ROS). Rats were born and raised in 60% O(2) for the first two postnatal weeks while treated with one of two antioxidants: vitamin E (via milk from mothers whose diet was enriched with 1000 IU vitamin E kg(-1)) or a superoxide dismutase mimetic, manganese(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; via daily intraperitoneal injection of 5-10 mg kg(-1)); rats were subsequently raised in room air until studied as adults. Peripheral chemoreflexes, assessed by carotid sinus nerve responses to cyanide, asphyxia, anoxia and isocapnic hypoxia (vitamin E experiments) or by hypoxic ventilatory responses (MnTMPyP experiments), were reduced after perinatal hyperoxia compared to those of normoxia-reared controls (all P<0.01); antioxidant treatment had no effect on these responses. Similarly, the carotid bodies of hyperoxia-reared rats were only one-third the volume of carotid bodies from normoxia-reared controls (P <0.001), regardless of antioxidant treatment. Protein carbonyl concentrations in the blood plasma, measured as an indicator of oxidative stress, were not increased in neonatal rats (2 and 8 days of age) exposed to 60% O(2) from birth. Collectively, these data do not support the hypothesis that perinatal hyperoxia impairs peripheral chemoreceptor development through ROS-mediated oxygen toxicity.

Thermoregulatory and metabolic responses of Japanese quail to hypoxia.

Common responses to hypoxia include decreased body temperature (Tb) and decreased energy metabolism. In this study, the effects of hypoxia and hypercapnia on Tb and metabolic oxygen consumption (VO2) were investigated in Japanese quail (Coturnix japonica). When exposed to hypoxia (15, 13, 11 and 9% O2), Tb decreased only at 11% and 9% O2 compared to normoxia; quail were better able to maintain Tb during acute hypoxia after a one-week acclimation to 10% O2. VO2 also decreased during hypoxia, but at 9% O2 this was partially offset by increased anaerobic metabolism. Tb and VO2 responses to 9% O2 were exaggerated at lower ambient temperature (Ta), reflecting a decreased lower critical temperature during hypoxia. Conversely, hypoxia had little effect on T(b) or VO2 at higher Ta (36 degrees C). We conclude that Japanese quail respond to hypoxia in much the same way as mammals, by reducing both Tb and VO2. No relationship was found between the magnitudes of decreases in Tb and VO2 during 9% O2, however. Since metabolism is the source of heat generation, this suggests that Japanese quail increase thermolysis to reduce Tb. During hypercapnia (3, 6 and 9% CO2), Tb was reduced only at 9% CO2 while VO2 was unchanged.

Ventilatory and metabolic responses of burrowing owls, Athene cunicularia, to moderate and extreme hypoxia: analysis of the hypoxic ventilatory threshold vs. hemoglobin oxygen affinity relationship in birds.

We measured ventilation, oxygen consumption and blood gases in burrowing owls (Athene cunicularia) breathing moderate and extreme hypoxic gas mixtures to determine their hypoxic ventilatory threshold (HVT) and to assess if they, like other birds and mammals, exhibit a relationship between HVT and hemoglobin O2 affinity (P(50)) of their blood. An earlier report of an attenuated ventilatory responsiveness of this species to hypoxia was enigmatic given the low O2 affinity (high P(50)) of burrowing owl hemoglobin. In the current study, burrowing owls breathing 11% and 9% O2 showed a significantly elevated total ventilation. The arterial partial pressure of oxygen (PaO2) at which ventilation is elevated above normoxic values in burrowing owls was 58 mm Hg. This threshold value conforms well to expectations based on the high P(50) of their hemoglobin and the HVT vs. P(50) relationship for birds developed in this study. Correcting for phylogenetic relatedness in the multi-species analysis had no effect on the HVT vs. P(50) relationship. Also, because burrowing owls in this study did not show a hypometabolic response at any level of hypoxia (even at 9% O2); HVT described in terms of percent change in oxygen convection requirement is identical to that based on ventilation alone.

BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia.

Intermittent hypoxia causes a form of serotonin-dependent synaptic plasticity in the spinal cord known as phrenic long-term facilitation (pLTF). Here we show that increased synthesis of brain-derived neurotrophic factor (BDNF) in the spinal cord is necessary and sufficient for pLTF in adult rats. We found that intermittent hypoxia elicited serotonin-dependent increases in BDNF synthesis in ventral spinal segments containing the phrenic nucleus, and the magnitude of these BDNF increases correlated with pLTF magnitude. We used RNA interference (RNAi) to interfere with BDNF expression, and tyrosine kinase receptor inhibition to block BDNF signaling. These disruptions blocked pLTF, whereas intrathecal injection of BDNF elicited an effect similar to pLTF. Our findings demonstrate new roles and regulatory mechanisms for BDNF in the spinal cord and suggest new therapeutic strategies for treating breathing disorders such as respiratory insufficiency after spinal injury. These experiments also illustrate the potential use of RNAi to investigate functional consequences of gene expression in the mammalian nervous system in vivo.

Hypoxic ventilatory responses in rats after hypercapnic hyperoxia and intermittent hyperoxia.

Perinatal hyperoxia attenuates the adult hypoxic ventilatory response in rats. Hyperoxia might elicit this plasticity by inhibiting chemoreceptor activity during early life. Thus, we hypothesized that stimulating chemoreceptors with CO(2) during hyperoxia or interrupting hyperoxia with periods of normoxia would reduce the effects of hyperoxia on the hypoxic ventilatory response. Rats were born and raised in 60% O(2) for the first two postnatal weeks. Two groups were simultaneously exposed to either sustained hypercapnia (5% CO(2)) or intermittent hypercapnia (alternating 1-h exposures to 0 and 7.5% CO(2)) while another group was exposed to only intermittent hyperoxia (alternating 1-h exposures to 21 and 60% O(2)). Hypoxic ventilatory responses were assessed at 6-10 weeks of age by whole-body plethysmography. Rats exposed to intermittent hypercapnia during hyperoxia or to intermittent hyperoxia exhibited greater increases in ventilation-to-metabolism ratio ( VE/VO2 ) in response to 12.5% O(2) than rats exposed to hyperoxia alone (both P<0.05), although responses were generally less than those of normoxia-reared controls; a similar trend was observed for rats exposed to sustained hypercapnia during hyperoxia (P=0.053). These data suggest that activity-dependent mechanisms contribute to hyperoxia-induced developmental plasticity, although contributions from additional mechanisms cannot be excluded.

Developmental plasticity in the neural control of breathing.

The respiratory control system undergoes a diversity of morphological and physiological transformational stages during intrauterine development as it prepares to transition into an air-breathing lifestyle. Following birth, the respiratory system continues to develop and may pass through critical periods of heightened vulnerability to acute environmental stressors. Over a similar time course, however, the developing respiratory control system exhibits substantial capacity to undergo plasticity in response to chronic or repeated environmental stimuli. A hallmark of developmental plasticity is that it requires an interaction between a stimulus (e.g., hypoxia, hyperoxia, or psychosocial stress) and a unique window of development; the same stimulus experienced beyond the boundaries of this critical window of plasticity (e.g., at maturity), therefore, will have little if any appreciable effect on the phenotype. However, there are major gaps in our understanding of the mechanistic basis of developmental plasticity. Filling these gaps in our knowledge may be crucial to advancing our understanding of the developmental origin of adult health and disease. In this review, we: i) begin by clarifying some ambiguities in the definitions of plasticity and related terms that have arisen in recent years; ii) describe various levels of the respiratory control system where plasticity can (or has been identified to) occur; iii) emphasize the importance of understanding the mechanistic basis of developmental plasticity; iv) consider factors that influence whether developmental plasticity is permanent or whether function can be restored; v) discuss genetic and sex-based variation in the expression of developmental plasticity; and vi) provide a translational perspective to developmental plasticity.

Ventilatory and chemoreceptor responses to hypercapnia in neonatal rats chronically exposed to moderate hyperoxia.

Rats reared in hyperoxia hypoventilate in normoxia and exhibit progressive blunting of the hypoxic ventilatory response, changes which are at least partially attributed to abnormal carotid body development. Since the carotid body also responds to changes in arterial CO2/pH, we tested the hypothesis that developmental hyperoxia would attenuate the hypercapnic ventilatory response (HCVR) of neonatal rats by blunting peripheral and/or central chemoreceptor responses to hypercapnic challenges. Rats were reared in 21% O2 (Control) or 60% O2 (Hyperoxia) until studied at 4, 6-7, or 13-14days of age. Hyperoxia rats had significantly reduced single-unit carotid chemoafferent responses to 15% CO2 at all ages; CO2 sensitivity recovered within 7days after return to room air. Hypercapnic responses of CO2-sensitive neurons of the caudal nucleus tractus solitarius (cNTS) were unaffected by chronic hyperoxia, but there was evidence for a small decrease in neuronal excitability. There was also evidence for augmented excitatory synaptic input to cNTS neurons within brainstem slices. Steady-state ventilatory responses to 4% and 8% CO2 were unaffected by developmental hyperoxia in all three age groups, but ventilation increased more slowly during the normocapnia-to-hypercapnia transition in 4-day-old Hyperoxia rats. We conclude that developmental hyperoxia impairs carotid body chemosensitivity to hypercapnia, and this may compromise protective ventilatory reflexes during dynamic respiratory challenges in newborn rats. Impaired carotid body function has less of an impact on the HCVR in older rats, potentially reflecting compensatory plasticity within the CNS.

Respiratory plasticity after perinatal hypercapnia in rats.

Environmental conditions during early life may have profound effects on respiratory control development. We hypothesized that perinatal hypercapnia would exert lasting effects on the mammalian hypercapnic ventilatory response, but that these effects would differ between males and females. Rats were exposed to 5% CO2 from 1 to 3 days before birth through postnatal week 2 and ventilation was subsequently measured by whole-body plethysmography. In both male and female rats exposed to perinatal hypercapnia, a rapid, shallow breathing pattern was observed for the first 2 weeks after return to normocapnia, but ventilation was unchanged. Acute hypercapnic ventilatory responses (3% and 5% CO2) were reduced 27% immediately following perinatal hypercapnia, but these responses were normal after 2 weeks of recovery in both sexes and remained normal as adults. Collectively, these data suggest that perinatal hypercapnia elicits only transient respiratory plasticity in both male and female rats. This plasticity appears similar to that observed after chronic hypercapnia in adult animals and, therefore, is not unique to development.

Chronic intermittent hyperoxia alters the development of the hypoxic ventilatory response in neonatal rats.

Chronic exposure to sustained hyperoxia alters the development of the respiratory control system, but the respiratory effects of chronic intermittent hyperoxia have rarely been investigated. We exposed newborn rats to short, repeated bouts of 30% O2 or 60% O2 (5 bouts h(-1)) for 4-15 days and then assessed their hypoxic ventilatory response (HVR; 10 min at 12% O2) by plethysmography. The HVR tended to be enhanced by intermittent hyperoxia at P4 (early phase of the HVR), but it was significantly reduced at P14-15 (primarily late phase of the HVR) compared to age-matched controls; the HVR recovered when individuals were returned to room air and re-studied as adults. To investigate the role of carotid body function in this plasticity, single-unit carotid chemoafferent activity was recorded in vitro. Intermittent hyperoxia tended to decrease spontaneous action potential frequency under normoxic conditions but, contrary to expectations, hypoxic responses were only reduced at P4 (not at P14) and only in rats exposed to higher O2 levels (i.e., intermittent 60% O2). Rats exposed to intermittent hyperoxia had smaller carotid bodies, and this morphological change may contribute to the blunted HVR. In contrast to rats exposed to intermittent hyperoxia beginning at birth, two weeks of intermittent 60% O2 had no effect on the HVR or carotid body size of rats exposed beginning at P28; therefore, intermittent hyperoxia-induced respiratory plasticity appears to be unique to development. Although both intermittent and sustained hyperoxia alter carotid body development and the HVR of rats, the specific effects and time course of this plasticity differs.

Differences in time-dependent hypoxic phrenic responses among inbred rat strains.

Hypoxic ventilatory responses differ between rodent strains, suggesting a genetic contribution to interindividual variability. However, hypoxic ventilatory responses consist of multiple time-dependent mechanisms that can be observed in different respiratory motor outputs. We hypothesized that strain differences would exist in discrete time-dependent mechanisms of the hypoxic response and, furthermore, that there may be differences between hypoglossal and phrenic nerve responses to hypoxia. Hypoglossal and phrenic nerve responses were assessed during and after a 5-min hypoxic episode in anesthetized, vagotomized, and ventilated rats from four inbred strains: Brown Norway (BN), Fischer 344 (FS), Lewis (LW), and Piebald-viral-Glaxo (PVG). During baseline, burst frequency was higher in PVG than LW rats (P < 0.05), phrenic burst amplitude was higher in PVG vs. other strains (P < 0.05), and hypoglossal burst amplitude was higher in PVG and BN vs. FS and LW (P < 0.05). During hypoxia, burst frequency did not change in BN or LW rats, but it increased in PVG and FS rats. The phrenic amplitude response was smallest in PVG vs. other strains (P < 0.05), and the hypoglossal response was similar among strains. Short-term potentiation posthypoxia was slowest in FS and fastest in LW rats (P < 0.05). Posthypoxia frequency decline was absent in PVG, but it was observed in all other strains. Augmented breaths were observed during hypoxia in FS rats only. Thus genetic differences exist in the time domains of the hypoxic response, and these are differentially expressed in hypoglossal and phrenic nerves. Furthermore, genetic diversity observed in hypoxic ventilatory responses in unanesthetized rats may arise from multiple neural mechanisms.

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

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.