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J Appl Physiol 101: 1097-1103, 2006. First published June 22, 2006; doi:10.1152/japplphysiol.00378.2006
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Postnatal developmental changes in CO2 sensitivity in rats

S. E. Davis, G. Solhied, M. Castillo, M. Dwinell, D. Brozoski, and H. V. Forster

Department of Physiology, Medical College of Wisconsin and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin

Submitted 29 March 2006 ; accepted in final form 15 June 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Ventilatory sensitivity to CO2 in awake adult Brown Norway (BN) rats is 50–75% lower than in adult Sprague-Dawley (SD) and salt-sensitive Dahl S (SS) rats. The purpose of the present study was to test the hypothesis that this difference would be apparent during the development of CO2 sensitivity. Four litters of each strain were divided into four groups such that rats were exposed to 7% inspired CO2 for 5 min in a plethysmograph every third day from postnatal day (P) 0 to P21 and again on P29 and P30. From P0 to P14, CO2 exposure increased pulmonary ventilation (VE) by 25–50% in the BN and SD strains and between 25 to over 200% in the SS strain. In all strains beginning around P15, the response to CO2 increased progressively reaching a peak at P19–21 when VE during hypercapnia was 175–225% above eucapnia. There were minimal changes in CO2 sensitivity between P21 and P30, and at both ages there were minimal between-strain differences. At P30, the response to CO2 in the SS and SD strains was near the adult response, but the response in the BN rats was 100% greater at P30 than in adults. We conclude that 1) CO2-sensing mechanisms, and/or mechanisms downstream from the chemoreceptors, change dramatically at the age in rats when other physiological systems are also maturing (~P15), and 2) there is a high degree of age-dependent plasticity in CO2 sensitivity in rats, which differs between strains.

neural control of breathing; consomics; hypercapnia

THE MAJOR ROLE OF THE RESPIRATORY system is gas exchange between the environment and arterial blood to meet the metabolic demands for O2 consumption and CO2 excretion. Pulmonary ventilation (VE) regulates the exchange of O2 and CO2 between the environment and the alveoli. VE is regulated primarily by neurons in the brain stem (21, 33). CO2/H+ and O2 chemoreceptors in the brain and the periphery help regulate and contribute to maintenance of alveolar PCO2 and PO2 homeostasis by "fine tuning" VE and alveolar ventilation to metabolic rate. Accordingly, ventilatory sensitivity to changes in CO2 and O2 are important to regulation of VE.

Although considerable knowledge has been gained regarding ventilatory CO2 sensitivity, the determinants of this physiological function remain unclear (14, 32). It is known that there is considerable intra- and interindividual variation in the CO2 sensitivity of mammals. For example, the adult inbred Brown Norway (BN) rat strain has clearly a lower ventilatory sensitivity to CO2 than the outbred adult Sprague-Dawley (SD) and the inbred adult salt-sensitive Dahl S (SS) rat strains (13, 17, 19, 40).

In several mammals, CO2 sensitivity is well developed at birth with minimal change thereafter (6, 7, 23, 25, 27, 30, 35, 39, 45). Rats are an exception in that they respond to CO2 during the first few days of life, but then some studies have shown that after ~1 wk, the response is minimal (1, 3, 9, 32, 34, 41). However, the response returns sometime during the second week of life and then increases to near the apparent adult response by ~3 wk of age (32, 37, 41).

The purpose of the present study was to determine whether during the neonatal period the development of CO2 sensitivity of BN rats differed from the SD and SS rats. We reasoned that a detailed determination of CO2 sensitivity in all three strains could subsequently be exploited in studies to gain insight into determinants of CO2 sensitivity. We hypothesized that during the neonatal period, the development of CO2 sensitivity in the BN rats would be attenuated relative to the SD and SS rats.


   METHODS
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 METHODS
RESULTS
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Strains

A total of 111 male and female rats from two in-house, inbred rat strains and one outbred commercially purchased strain were studied: BN (BN/NHsdMcw, n = 32), SS (Dahl SS/JrHsdMcw, n = 38), and SD (SD/Hsd) strains (n = 41). The origins of both the BN and SS rats have been published (10). All inbred strains were housed and produced at the Medical College of Wisconsin in the Biomedical Resource Center Transgenic Barrier facility before and during the experimental protocol. The SD rats were purchased from Harlan Sprague Dawley (Indianapolis, IN).

All animals were under supervision of the Biomedical Resource Center staff, and they were provided food and water ad libitum. All protocols were reviewed and approved by the Medical College of Wisconsin Animal Care Committee.

Experimental Design

Protocol.   Four litters of each rat strain were utilized for this study. Each rat litter was randomly divided into four groups. Groups 1–3 were exposed to hypercapnic conditions in plethysmographs beginning on postnatal day (P) 0, P1, or P2 and repeated every third day from P0 through P21. This grouping and design enabled us to obtain data on each day from P0 to P21 without daily exposure of each rat to CO2. The fourth group served as controls, and they were studied every third day while only breathing room air but then exposed to 7% CO2 on P30. This group enabled us to determine whether the repeated exposure to CO2 in groups 1–3 influenced CO2 sensitivity (32). The animals were reacclimated to the plethysmograph on P27 and P28. All rats were then studied on P29 and P30. The plethysmographs utilized were optimal in size and temperature for studies on rats during the neonatal period. However, they were inappropriate for studies of larger and fur-covered older rats. Therefore, studies were not extended beyond P30. To avoid/minimize the potential for circadian influences on ventilatory control (30), all studies were between 8:00 AM and 2:00 PM, which was between 2 and 8 h of the 12-h light cycle. When not under study, the rats were housed with the respective dam until P21, at which point they were weaned and the sexes were separated. All rats were weighed daily throughout the extent of the protocol.

Eupneic VE and response to hypercapnia.   Eupneic breathing and ventilatory responses to hypercapnia were determined using standard plethysmographic techniques in a custom-made, 1-liter acrylic flow-through plethysmograph. Gas flow through the plethysmograph was controlled by adjusting the input airflow valve with a Dwyer Instruments (model VA10413) flowmeter in a vacuum pump-driven system. To maintain constant levels of O2 and CO2 in the plethysmograph, gas flow was adjusted during control (21% O2-0.3% CO2-balance N2) and hypercapnic (21% O2-7% CO2-balance N2) conditions. During experimentation, the rats were placed in the plethysmograph and allowed to acclimate before data collection. Once the rats were not moving and in presumably quiet wakefulness (eyes open after P12), the chamber was then sealed, and eupneic breathing was assessed between the subsequent 8 and 10 min. Immediately after this period, hypercapnic conditions were established by switching the inflow gas to 7% CO2-21% O2-balance N2. There usually was increased arousal during hypercapnia as indicated by slight body movement and general increase in alertness. Breathing was assessed between 3 and 5 min of the hypercapnic period.

Air temperature inside the plethysmograph (31.2 ± 0.1°C) and the relative humidity (46.9 ± 0.7%) were monitored using a calibrated Omega RX-93 temperature and relative humidity probe. A controlled heating element (~34°C) beneath the plethysmograph facilitated maintenance of body temperature. This temperature was chosen because it approximated the measured temperature in a group of 1- to 10-day-old rats grouped under the cover provided by the dam (37). Gases were administered (25°C) and sampled via ports in the plethysmograph, and gases were measured with calibrated O2 and CO2 gas analyzers (Applied Electrochemistry models S-3A/I and CD-3A, respectively). Rectal temperatures were obtained before and after experimentation with a calibrated thermocouple probe (Omega). VE was obtained by monitoring pressure oscillations within the chamber using a Validyne model CD-280 pressure transducer, which was calibrated using a pressure wave created with 1-ml syringe (0.3 ml) when the animal was in the chamber at the beginning of the control period.

Data Acquisition and Statistical Analysis

VE, tidal volume (VT), and breathing frequency (f) were computed using data-acquisition software (CODAS) at a sample rate of 200 samples·s–1·channel–1. The plethysmograph data were segmented and sorted into bins: minutes 8–10 of the control period, and minutes 3–5 of hypercapnia. Each segment of data used in this analysis was determined not to be sniffs or sighs to ensure accurate mean values. Raw data segments were analyzed using a software program (Windaq Playback) designed to detect peaks and valleys, and timing and integration calculations for VE. VT was calculated (and calibrated) using the methods of Drorbaugh and Fenn (12), and it was multiplied by frequency to obtain VE. Use of this method factors individual body temperatures into the VT calculations. As in our laboratory's previous studies (13, 16, 19), CO2 sensitivity was expressed as VE hypercapnia/VE eucapnia x 100.

Between-strain and postnatal day differences were assessed with a two-way ANOVA followed with a Bonferroni post hoc test. Linear regression analysis was utilized to determine the relationship between CO2 sensitivity and body temperature. All statistical analyses were limited to a 95% confidence interval to test for significant differences between sexes and strains.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
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Growth of Rats

An age-dependent curvilinear increase in animal weight was apparent during postnatal developmental (Fig. 1). The average weight at birth was 6.23 g (strains and sexes combined). The SD rats weighed significantly (P < 0.05) more than the BN and SS rats starting on P7 and P16, respectively, and continuing throughout the remainder of the study. The SS rats weighed significantly (P < 0.05) more than the BN rats between P11 through P30. By P30 the BN rats weighed an average of 12 and 18 g less than the SS and SD rats, respectively. Male SD rats weighed significantly (P < 0.001) more than female SD rats, but there were no significant sex differences in the weight of the SS and BN rats. For each strain, the number of rats in each of the four litters varied and the growth of the rats was inversely related to litter size. On P30, there was no significant difference in body weight between the rats exposed every third day to CO2 and those exposed only on P30.


Figure 1
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  		Fig. 1. Body weight increased continually from postnatal day [P (PN day)] 0 to P30 in all rat strains. Values are averages ± SE for male and female rats combined. SS, salt-sensitive Dahl S; BN; Brown Norway; SD, Sprague-Dawley. In only the SD rats was there a significant (P < 0.05) sex difference with the females lower than males.

 
Body temperature, eupneic breathing, and ventilatory sensitivity to CO2 changed in distinct phases over the first 21 days of life.

Phase 1: Early Development, P0 to P10

Body temperature (34–35°C) did not change significantly within or between the strains from P0 to P10 (Fig. 2). The body temperature during the first 10 days (phase 1) is 1° over the temperature of the environment under the dam (38), and this body temperature is less than other mammals at this age (Dwinell MR, Hogan GE, Sirlin E, Mayhew DL, and Forster HV, unpublished observations). Although the absolute VE and VT increased progressively with growth, throughout phase 1, there was an overall decrease in eupneic VE and VT normalized to body weight for all strains (Fig. 3, A and B), which is typical of other mammals (Dwinell MR, Hogan GE, Sirlin E, Mayhew DL, and Forster HV, unpublished observations; Refs. 28, 29). During phase 1, eupneic breathing frequency increased (P < 0.05) in the BN rats. In contrast, the SS and SD rats, eupneic breathing frequency decreased (P < 0.05) during this phase.


Figure 2
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  		Fig. 2. Body temperature in rats significantly (P < 0.05) increased after ~14 days of age. Values are averages ± SE for male and female rats combined (for P0–P21, n = 9; for P29–P30, n = 26). There were no significant sex differences.

 

Figure 3
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  		Fig. 3. In all rat strains there was a significant (P < 0.05) decrease in eupneic pulmonary ventilation (VE; A) and tidal volume (VT; B) normalized to body mass from P0 to P30, but breathing frequency (freq; C) changed minimally. Values are averages ± SE for male and female rats combined. There were no significant sex differences.

 
There were significant (P < 0.05) differences between strains in CO2 sensitivity during phase 1 (Fig. 4). Throughout this phase, in both the BN and the SD rats, VE and VT only increased by 25–50% during CO2 inhalation. In contrast, the response in the SS rats was generally 50–100% greater than the BN and SD rats. The differences in hypercapnic response were primarily a result of changes in VT.


Figure 4
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  		Fig. 4. Ventilatory sensitivity to CO2 (VE hypercapnia/VE eucapnia x 100) changed dramatically from P0 to P30 in all rat strains. Values are averages ± SE for male and female rats combined. A: VE. B: VT. C: freq. There were no significant sex differences.

 
For eupneic breathing and while inhaling 7% CO2, VE and VT were more variable between rats and between days in the SS rats than in the BN and SD rats.

Phase 2: Transitional Period, P11 to P14

In all strains, there was a significant (P < 0.05) increase in body temperature of ~1°C at about P12 to P14 (Fig. 2). There were significant strain differences and an overall increase in weight normalized eupneic VE and VT (Fig. 3, A and B) in all three strains, during this transitional phase. Eupneic frequency also increased (P < 0.05) in all three strains (Fig. 3C).

There were significant (P < 0.05) strain differences in CO2 sensitivity during phase two (Fig. 4, A–C). Throughout this phase, in both the BN and the SD rats, VE and VT only increased by 25–75% during CO2 inhalation. In contrast, the response in the SS rats reached a peak increase of over 200% on P12, but then it decreased significantly (P < 0.05) to the same level as in the BN and SD strains. The differences in hypercapnic response were again primarily a result of changes in VT. As in phase 1, VE and VT during both eucapnia and hypercapnia were more variable in the SS rats than in the BN and SD rats.

Phase 3: Increase in CO2 Sensitivity, P15 to P21

In all strains there was a further significant (P < 0.05) increase in body temperature of ~1°C by P21 (Fig. 2). There was an overall decrease in weight normalized eupneic VE and VT (Fig. 3, A and B) and a significant (P < 0.05) strain difference on P15, during this phase. Eupneic frequency also decreased in all three strains (Fig. 3C).

There were no significant (P < 0.05) strain differences in CO2 sensitivity during phase 3 (Fig. 4, A–C). Beginning around P15, ventilatory sensitivity to CO2 increased dramatically in all three strains. In both the BN and the SD rats, VE and VT increased by ~100–200% during CO2 inhalation throughout this phase. The response in the SS rats reached a peak increase of nearly 250% on P17 and P19 to P21. The variations in hypercapnic response were again primarily a result of differences in VT.

Adultlike Period, P29 and P30

Body temperature significantly (P < 0.05) increased (~1.5°C) from P21 to P29 in the BN and SD rats (Fig. 2). There were no significant within-strain changes in weight-normalized eupneic VE or VT (Fig. 3, A and B) between P21 and P29 or P30. However, the SS rats weight normalized eupneic VE was significantly higher than both the BN and SD rats on P30, which was a result of a significantly (P < 0.05) higher eupneic frequency.

There were no significant strain differences in CO2 sensitivity on P29 and P30. There was a significant (P < 0.05) decrease in the hypercapnic response of the SS rats between P21 and P29, which was due to a significant (P < 0.05) decrease in VT.

VE During Hypercapnia Normalized to Body Weight

When VE during hypercapnia was normalized to body weight, the response decreased from P0 to P13 nearly in parallel with the decrease in VE during room air breathing normalized to body weight (Fig. 5A). This decrease contrasts to the relatively stable or increasing index of CO2 sensitivity over this time period when sensitivity was expressed as VE during hypercapnia divided by VE during room air multiplied by 100 (Fig. 5B). Both methods of expressing CO2 sensitivity indicate an increasing response between P15 and P21, but the weight-normalized index was at or below P0 at P19–P21 and P29–P30, whereas on these days the percent above control index was ~150% above P0.


Figure 5
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  		Fig. 5. Normalizing VE during hypercapnia to body weight is not an appropriate expression of CO2 sensitivity. Values are averages ± SE for male and female SD rats combined. Note that VE normalized to body weight (A) decreased and was nearly parallel for eucapnic and hypercapnic conditions from P0 to P14, whereas VE during hypercapnia (B), expressed as a percentage of eucapnia, was relatively stable from P0 to P14.

 
Relationship of CO2 Sensitivity to Body Temperature

Because others have shown that changes in temperature can affect respiratory control (26, 31, 35), and because both body temperature and CO2 sensitivity increased during the neonatal period, we determined the relationship between these variables. There were no significant (P > 0.10) sex differences in these relationships within any strain, and there were no significant (P > 0.05) differences in the regression slopes between the three strains (Table 1). The relationship between temperature and CO2 sensitivity was not strong because, judging from the r2 values in Table 1, the variation in temperature could account for at best only 33% (BN strain) of the variation in CO2 sensitivity.


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  		Table 1. Relationship between CO2 sensitivity and body temperature during neonatal period (male and female rats combined)

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The major findings of this study were the between-strain variation in CO2 sensitivity of rats between P0 and P14 and the dramatic increase in CO2 sensitivity in all rat strains between P15 and P21.

General Development of Rats

Rats are an immature species at birth. They have yet to develop hair/fur, and their eyelids and external ear ducts are still sealed shut with periderm. This period is over the first approximate 10 days and corresponds to phase 1, described earlier when the rats are dependent on the dam for survival. Phase 2 in rats, aptly described as a transition period (betweenP11 and P14), is when the eyes and ears open, the hair/fur develops, adult sleep patterns begin to develop, and the rats are more mobile and independent of the cover provided by the dam. Phase 3 (between P15 and P24) in rat neonatal development begins approximately at the completion of some of these changes ~P15, and it is a period when CO2 sensitivity is progressively increasing.

Development of CO2 Sensitivity in Rats

In several mammals, ventilatory CO2 sensitivity is well developed at birth with minimal changes in the neonatal period (6, 7, 23, 25, 27, 30, 35, 41, 45). Rats are exceptional and in some respects are comparable to preterm infants (23, 34) in that CO2 sensitivity undergoes major changes during the neonatal period (1, 3, 9, 32, 34, 41). In the present study, the CO2 sensitivity of all three rat strains differed from some (32, 37, 41), previous studies that reported a ventilatory response to CO2 at P0 and P1 that then declined and/or was absent at P5 to P7. In past studies, the magnitude of the initial response and the subsequent decline were greatest in those studies in which the response was normalized to body weight (32, 41). In contrast, when the response was expressed as the percent increase above the room air breathing, then both the response on P1 and P2 and the subsequent decline were small (37).

In the present study, the weight-normalized VE response to CO2 also decreased between P0 and P14 (Fig. 5), nearly in parallel with the decrease in eupneic breathing normalized to body weight. This similarity indicates that the decline in the weight-normalized CO2 response does not reflect an actual decrease in CO2 sensitivity and that expressing the CO2 response in this manner provides an erroneous index of CO2 sensitivity. In other words, an increase in body size and therefore an increase in metabolic rate will increase VE during both eucapnia and hypercapnia, but this increase does not mean metabolic rate has affected CO2 sensitivity. Indeed it has been shown that differences/changes in body size and metabolic rate do not per se affect CO2/H+ chemosensitivity during the neonatal period (27, 28, 36). Moreover, it has also been shown that an exercise-induced increase in metabolic rate does not alter CO2 sensitivity (2, 8, 11). Accordingly, there is no rationale for expressing CO2 sensitivity as normalized to body weight. We therefore believe it appropriate and correct to express the CO2 response as the percent increase in VE between eucapnia and hypercapnia. Indeed, expressed in this manner, we found a rather stable sensitivity to CO2 in two strains and an age-dependent increase in the third strain between P0 and P10.

The fact that we did not find the decrease in the CO2 response on P6 and P7 in this study, as our laboratory did in a previous study, could be due to differences in procedures (such as maintaining body temperature in this but not in our laboratory's previous study) (37). Indeed, Saiki and Mortola (35) found in P6 SD rats that the response to CO2 was affected by environmental temperature. Combining data in our laboratory's previous study and the present study, we conclude that CO2 sensitivity from P0 to P14 in rats is low or else highly variable, or highly plastic, and can be altered or can differ with differences in genetic background or environmental influences.

The present findings are consistent with previous studies on rats in showing that CO2 sensitivity begins to increase at about P15 (32, 37, 41). In all three strains, CO2 sensitivity increased progressively nearly threefold between P15 and P19 to P21. This increase is the dominant change in CO2 sensitivity that occurs during the neonatal period and seems to have greater significance than the small decrease that has been documented at P6 and P7.

In only the SS strain was there a significant change in CO2 sensitivity between P21 and P30. At P29 and P30, there were no between strain differences in CO2 sensitivity. Moreover, at this age, for all three strains there were no differences in CO2 sensitivity between rats who had not been previously exposed to CO2 and those rats that had been exposed every third day to CO2 from P0 to P21. In other words, as our laboratory also recently found in piglets (Dwinell MR, Hogan GE, Sirlin E, Mayhew DL, and Forster HV, unpublished observations), brief exposure to CO2 every third day during the neonatal period does not have a chronic effect on CO2 sensitivity.

Our hypothesis was that development of CO2 sensitivity in the BN rat would be attenuated relative to the SS and SD rats. The data do not support this hypothesis. The CO2 sensitivity in BN rats parallels CO2 sensitivity in SD rats from P0 to P30 and nearly parallels CO2 sensitivity in the SS rats from P15 to P30. The SS strain was unique during the neonatal period with periods of CO2 sensitivity equal to or greater than the other strains and, in addition, with greater within-strain and between-day variability.

Our laboratory (13, 16, 19) and others (40) have previously found that adult (>P70) BN rats are significantly less sensitive to CO2 than adult SD and SS rats and that these latter strains do not differ in CO2 sensitivity. At P30, CO2 sensitivity in the SD and SS rats is near that of adult rats. In contrast, CO2 sensitivity in the BN strain is threefold greater at P30 than at P70 (14, 17, 19). In other words, between P30 and P70, it appears that the BN strain must lose the CO2 sensitivity gained between P15 and P21. An alternative explanation is that the daily stimulation from studies during the neonatal period resulted in plasticity and thus comparable CO2 sensitivity in all strains at P30.

The cause(s) of the differences/changes in CO2 sensitivity are unknown. Wang et al. (42, 43) have shown in in vitro studies that CO2 sensitivity of neurons from the raphe nucleus is minimal until about P14 when the response begins to substantially increase. These findings suggest that changes in a CO2 sensing or signaling mechanism may underlie the in vivo changes we presently found. In contrast, others have found in in vitro studies that the firing rate of neurons in several medullary nuclei in response to hypercapnia did not change over the neonatal period (9, 32, 42). Others used c-Fos labeling to identify CO2-activated neurons and found that activation was independent of age (4, 44). These findings may suggest that our in vivo findings might be due to changes that occur in the respiratory network downstream from the chemoreceptors. Alternatively, if indeed intracranial CO2 sensitivity does not change over the neonatal period, the increased response beginning at P15 could be due to an enhanced contribution of the carotid chemoreceptors. At least for hypoxia, the carotid chemoreceptors seem to mature near the end of the second postnatal week (22), and these chemoreceptors, at least in adults, account for about one-third of CO2 sensitivity (16). It is alsopossible that the increase in body temperature could have contributed to the increase in CO2 sensitivity beginning at P15 (27, 31), but the data in Table 1 suggest that changes in body temperature over the neonatal period are not a major consistent contributor to the change in CO2 sensitivity. Finally, because changes occur in the dynamics of sleep-wake cyclicity in rats beginning at P14 (5), these changes must be considered as contributing factors to the observed changes in CO2 sensitivity beginning at about this age. However, as indicated by open eyes throughout the eucapnic and hypercapnic periods, our rats were not cycling between state at the ages when CO2 sensitivity was increasing dramatically.

Irrespective of whether the in vivo changes reflect changes in chemoreceptor neurons or neurons downstream from chemoreceptors, it seems highly relevant that the beginning of the major in vivo changes in CO2 sensitivity occur 3 days after transient changes in the neurochemistry of medullary respiratory nuclei of SD rats (47). Specifically, there is a transient reduction in cytochrome oxidase activity [presumed marker of neuronal activity (46)] of medullary respiratory nuclei in rats at P12, and there are transient changes in numbers of excitatory and inhibitory neuronal receptors, favoring overall an increase in inhibition (47). In contrast, our findings and the conclusion of others (32) suggest that there is a decrease in overall inhibition beginning at about this age. The data presently are too limited to determine whether there is any relationship between these neurochemical and physiological changes, but the close correspondence is provocative and warrants further studies. Indeed, it seems that further in vivo and in vitro studies between P15 and P21 would provide insight into mechanisms of CO2 sensitivity and control of breathing in rats.

There must also be consequences of the differences/changes in CO2 sensitivity during the developmental period. Similar to piglets (25), in rats arterial PCO2 likely is low during the neonatal period, as it is only 25 Torr by P23, after which it increases to ~35 Torr by P40 (37). Thus with a low PCO2 and low or highly variable CO2 sensitivity from P0 to P14, it seems that CO2 is a relatively unimportant and/or not a critical stimulus for breathing. There are multiple other examples of a dissociation between eupneic arterial PCO2 and CO2 sensitivity, including the clinical condition known as congenital central alveolar hypoventilation (38) and after experimental lesions in the brain stem of mammals (15, 20). Conceivably, a high degree of plasticity in the ventilatory control system enables the respiratory control system to function properly despite a low or highly variable excitatory input from CO2/H+ chemoreceptors.

The present findings are significant because they provide a focus for studies (P14 to P21 in rats) that have a high potential for gaining insight into key aspects of ventilatory control. What cellular and molecular mechanisms underlie the change in CO2 sensitivity between P15 and P21 in all strains and between P30 and P70 in the BN strains? What changes occur in other aspects of control in the in vivo state such as during exercise or changes between wakefulness and non-rapid eye movement and rapid eye movement sleep? Elucidating these insights in rats will further understanding of ventilatory control in humans, even though neonatal CO2 sensitivity development in rats differs greatly from humans.


   GRANTS
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 ABSTRACT
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 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
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This study was supported by the Children's Research Institute of Wisconsin; by National Heart, Lung, and Blood Institute Grant HL-25739; and by the Department of Veterans Affairs


   ACKNOWLEDGMENTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
The authors are grateful for the contributions to this work of Dr. Matthew Hodges, Dr. Thom Feroah, Katie Krause, Josh Bonis, Paul Martino, and Zack Viegut.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. V. Forster, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: bforster{at}mcw.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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