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Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat

¹Pediatrics and ²Neurosciences Research Units, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Canada

Submitted 20 April 2006 ; accepted in final form 14 December 2006

	ABSTRACT

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Neonatal maternal separation (NMS) is a form of stress that exerts persistent, sex-specific effects on the hypoxic ventilatory response. Adult male rats previously subjected to NMS show a 25% increase in the response, whereas NMS females show a response 30% lower than controls (8). To assess the extent to which NMS affects ventilatory control development, we tested the hypothesis that NMS alters the ventilatory response to hypercapnia in awake, unrestrained rats. Pups subjected to NMS were placed in a temperature- and humidity-controlled incubator 3 h/day for 10 consecutive days (P3 to P12). Control pups were undisturbed. At adulthood (8 to 10 wk old), rats were placed in a plethysmography chamber for measurement of ventilatory parameters under baseline and hypercapnic conditions (inspired CO₂ fraction = 0.05). After 20 min of hypercapnia, the minute ventilation response measured in NMS males was 47% less than controls, owing to a lower tidal volume response (22%). Conversely, females previously subjected to NMS showed minute ventilation and tidal volume responses 63 and 18% larger than controls respectively. Although a lower baseline minute ventilation contributes to this effect, the higher minute ventilation/CO₂ production response observed in NMS females suggests a greater responsiveness to CO₂/H⁺ in this group. We conclude that NMS exerts sex-specific effects on the hypercapnic ventilatory response and that the neural mechanisms affected by NMS likely differ from those involved in the hypoxic chemoreflex.

control of breathing; plasticity; hypercapnia; sexual dimorphism

Detailed analysis of the time course of the hypoxic ventilatory response strongly suggests that NMS elicits sex-specific enhancement of carotid body function because the onset of the frequency response of male NMS rats (whether awake or anesthetized) was more rapid and greater than that observed in controls (8, 17). RT-PCR analysis of mRNA encoding for tyrosine hydroxylase or dopamine D₂ receptor expression indicates that NMS likely affects dopaminergic neurotransmission in the carotid body (18). However, the effects of NMS on respiratory control development are not limited to peripheral chemoreceptors because male (but not female) rats previously subjected to NMS produce greater tidal volume (VT) and phrenic responses to hypoxia than controls (8, 16).

We still have a limited understanding of the neural mechanisms underlying the effects of NMS on the respiratory control system. To better understand the extent to which NMS affects respiratory control development, the main objective of the present study was therefore to test the hypothesis that NMS disrupts the ventilatory response to moderate normoxic hypercapnia [inspired CO₂ fraction (FI_CO2) = 0.05] in a sex-specific manner in awake rats.

	METHODS

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Animals

Experiments were performed on 22 male and 30 female Sprague-Dawley rats (Charles River Canada, St. Constant, Quebec, Canada). Rats were supplied with food and water ad libitum and maintained in standard laboratory conditions (21°C, 12:12-h dark-light cycle: lights on at 0600 and off at 1800). Laval University Animal Care Committee approved the experimental procedures described in this manuscript, and the protocols used were in accordance with the guidelines detailed by the Canadian Council on Animal Care.

Mating and NMS Procedures

Virgin females were mated and delivered 10–15 pups. Two days after delivery, litters were culled to 12 pups, when necessary, with a roughly equal number of males and females. The NMS protocol, inspired from that of Wigger and Neumann (34), was identical to the one used in our previous studies (8, 17, 18). Briefly, the entire litter was separated daily from their mother for 3 h/day (0900–1200) from days 3 to 12. Separated pups were placed in a temperature (35°C)- and humidity (45%)-controlled incubator and isolated from each other by a cardboard partition. On day 21, rats were weaned and housed under standard animal care conditions until adulthood (8–10 wk old; see Table 1 for between-group comparison of age and weight data), at which time ventilatory measurements were performed.

Respiratory Measurements

Measurements of minute ventilation (E), breathing frequency (f), and VT in unrestrained rats were obtained by whole body flow-through plethysmograph (model PLY3223, Buxco Electronics, Sharon, CT) according to our method described previously (8, 15). Briefly, the system consisted of a 4.5-liter Plexiglas experimental chamber. The flow of air or hypercapnic gas mixture delivered to the chamber was kept constant and ranged between 2.0 and 2.5 l/min. Rectal temperature was measured before and after each experiment. Barometric pressure, chamber temperature, and humidity were also measured to express VT in milliliters (BTPS) per 100 g. Part of the gas mixture flowing out of the chamber was aspired by a flow-through capnograph and analyzed (Novametrix, Wallingford, CT) for subsequent calculation of CO₂ production (CO₂) with an open system (23). Based on the work of Strohl and colleagues on various rat strains, we assumed that our Sprague-Dawley rats had a respiratory quotient value of 0.74 (31).

The rat was placed in the chamber with room air flowing through. The rat was allowed to acclimatize to the chamber for roughly 1 h, and baseline (normocapnic) measurements were made when the animal was quiet but awake and the ventilatory variables were stable (8). The baseline values obtained were representative of the data recorded over the preceding 30–45 min. Then a gas mixture of 5% CO₂ in air was delivered to the chamber for 20 min, and the recording chamber was opened for a final body temperature measurement. This CO₂ level was chosen because we wanted a stimulus that was physiologically relevant. All measurements were performed between 1000 and 1200 to minimize changes in endocrine and respiratory activity associated with the circadian rhythm.

For ventilatory measurements, groups were distributed as follows: controls, 8 males and 11 females; NMS, 10 males and 16 females. Note that, for each group, rats originated from at least three different litters to ensure that treatment-related differences were not due to a litter-specific effect.

Data Analysis

Respiratory measurements.   Baseline measurements of ventilatory variables were obtained by averaging the last 10 min of stable recording, whereas a 5-min average was taken for each variable at the end of the hypercapnic exposure. Unlike the hypoxic response, the temporal dynamics of the frequency response to hypercapnia are not commonly analyzed in detail. However, a significant statistical interaction between time and separation (see RESULTS) brought us to analyze the time course of the frequency response to hypercapnia on a minute-by-minute basis and in two distinct segments (early and late phases), according to criteria similar to those established for the hypoxic response (8). Briefly, the early phase was defined as the period from the onset of hypercapnia [time (t) = 0 min] to the time at which f of NMS group reached steady state and became similar to that of controls (t = 12 min). The late phase (t > 12 min) was defined as the period during which the frequency response of both groups reached steady state until the end of the hypercapnic stimulus (t = 20 min; Fig. 1, A and B). Note that the time course of the VT (and thus E) data could not be obtained since the body temperature measurements necessary for correcting these results was not measured continuously during the experiments.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Effects of neonatal maternal separation (NMS) on the time course of the breathing frequency response to moderate hypercapnia [inspired CO2 fraction (FICO2) = 0.05] in adult female (A) and male rats (B). Graphics show breathing frequency data (in breaths/min) from controls (; males, n = 8; females, n = 11) and rats previously subjected to NMS (; males, n = 10; females, n = 16). Data are means ± SD. Statistically different from corresponding control value (P < 0.05). All values are different from baseline (P < 0.05); however, no symbols are shown for clarity.

Statistical Analysis

Respiratory data were analyzed using three-way ANOVA for repeated measures (hypercapnic stimulus x sex x separation; Statview 5.0, SAS Institute, Cary, NC). Hypercapnic ventilatory responses were analyzed using a two-way ANOVA (sex x separation). These analyses were followed by a post hoc Fisher's test when appropriate (P < 0.05). ANOVA results are typically indicated by specifying the factor(s) of interest; P values otherwise reported in the text indicate the results of the post hoc test. All data are presented as means ± SD, according to the American Physiological Society guidelines for reporting statistics (4).

	RESULTS

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Sex, NMS, and Basal E

Baseline (normocapnic) ventilatory measurements of control animals were comparable to those reported in other studies using male and female Sprague-Dawley rats under similar conditions (Figs. 1 and 2) (3, 6–8, 14, 24, 26, 27, 30). Females subjected to NMS showed a lower resting E compared with controls (treatment effect: P = 0.04; Fig. 2A), owing to a lower VT (treatment effect: P = 0.003; Fig. 2C). These results contrast with those reported for males in which baseline E was the same for NMS and controls (Fig. 2B) and from our previous study in which NMS females had a higher baseline E than controls (8). During normoxia, neither body temperature nor CO₂ (Table 1) were affected by NMS. Overall, CO₂ was higher in females than in males (sex effect: P = 0.03). Despite suggestive trends, sex-related differences in body temperature were not statistically significant (sex effect: P = 0.12; Table 1).

View larger version (20K): [in this window] [in a new window]   Fig. 2. Effects of NMS on minute ventilation (E; A and B), tidal volume measurements (VT; C and D), and CO2-related convective requirement [minute ventilation/CO2 production (E/CO2); E and F] obtained under baseline (normoxic normocapnic) conditions and after 20 min of moderate hypercapnic exposure (FICO2 = 0.05). For each group, measurements were performed in female and male rats, and data are compared between controls (; males, n = 8; females, n = 11) and rats previously subjected to NMS (; males, n = 10; females, n = 16). These data show that NMS reduced the E response to hypercapnia in males (B) but not females (A) (stimulus x treatment: P = 0.008 and P = 0.7 for males and females, respectively). However, NMS augments the E/CO2 response to hypercapnia in females (E) but not in males (stimulus x treatment: P = 0.07 and P = 0.7 for males and females, respectively). Values are expressed as means ± SD. *Statistically different from baseline (P < 0.05). Statistically different from corresponding control value (P < 0.05). Statistically different from corresponding control value (P < 0.1).

Temporal analysis of the frequency response to hypercapnia showed that the initial phase (0–12 min) varied according to sex and separation (bifactorial interaction: P = 0.07). In females, there is no between-group difference during the hypercapnic ventilatory response (P = 0.6; Fig. 1A). At the onset of hypercapnia, male rats subjected to NMS showed a stronger increase in f than controls (P = 0.01; Fig. 1B), which then decreased slightly to reach steady state at a rate similar to that of the control group at 12 min. During the late phase of the response (13–20 min), there was no between-group difference, either in females (Fig. 1A) or in males (Fig. 1B).

Sex, NMS, and Hypercapnic Ventilatory Response

E increased during hypercapnia (stimulus effect: P < 0.0001), but the response measured at the end of hypercapnic exposure was higher in females than in males (stimulus x sex: P = 0.014; Fig. 2, A and B). NMS reduced the magnitude of the response in males but had no significant effect in females (stimulus x treatment: P = 0.008 and P = 0.7 for males and females, respectively; Fig. 2, A and B). These treatment-related differences in the response were mainly related to differences in the VT increase (stimulus x treatment: P = 0.008 and P = 0.8 for males and females, respectively; Fig. 2, C and D). Expressing these data as a percent change from baseline values yielded similar results for most variables, except E in females. Statistical analysis of the responses (% change from baseline) showed a significant interaction between sex and separation for E, VT, inspiratory flow, and the convective requirement for CO₂ (E/CO₂) (P = 0.003, P = 0.0007, P = 0.02, and P = 0.04, respectively; Fig. 2). Compared with controls, the E response of NMS adult female rats was increased by 63% due to the augmentation of VT response (18%; Fig. 2A). For females, the difference between absolute and normalized results is related to the lower baseline values. The inspiratory flow and E/CO₂ responses were greater than controls also (by 61 and 117%, respectively). These results contrast with those of NMS males in which E and VT responses were decreased by 27 and 32%, respectively (Fig. 2B). Furthermore, the inspiratory flow and E/CO₂ responses of males were not affected by NMS. The f response was unchanged by NMS in both sexes. Hypercapnia had a significant effect on the variables reported in Table 1 with the exception of CO₂ in females. After 20 min of hypercapnia, body temperature decreased in all groups (stimulus effect: P < 0.0001; Table 1).

	DISCUSSION

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This study expands on our previous findings by showing that NMS alters development of the hypercapnic ventilatory response in a persistent and sex-specific fashion. Male NMS rats initially showed a greater frequency increase at the onset of hypercapnia compared with controls, a result consistent with the hypothesis that NMS augments overall carotid body function in male rats (Ref. 18, present data). However, this response was not sustained, and the E response measured at the end of hypercapnia was lower than controls. These results contrast with those obtained in female rats in which NMS increased the E response measured at the end of the hypercapnic exposure, suggesting a greater responsiveness to CO₂/H⁺. These results, combined with our previous work (8), show that NMS affects both the hypercapnic and hypoxic chemoreflexes in a distinct and sex-specific manner.

NMS and Sex-Specific Plasticity of the Hypercapnic Ventilatory Response

The time domains of the hypoxic ventilatory response are well described, and the rapid increase in f at the onset of hypoxia is commonly attributed to carotid body activation (29). Although carotid bodies have been shown to contribute to the rapid response to CO₂ in dogs (25), the mechanisms underlying the temporal dynamics of the hypercapnic ventilatory response have received little attention. Short-term depression of f is a phenomenon that characterizes the hypoxic ventilatory response since it does not normally occur during hypercapnic challenge. Adenosine, cellular acidification, a change in the balance between excitatory (glutamate) and inhibitory (GABA) inputs, and activation of the platelet derived growth factor -receptor at the level of the NTS are mechanisms that likely contribute to the frequency "roll-off" during hypoxia (11). Since this is the first time that an experimental treatment appears to elicit f depression during a hypercapnic challenge, it is difficult to explain why, unlike all other groups, NMS males did not maintain a constant f throughout the hypercapnic period. Although it is possible that NMS affects one or several of the aforementioned neural mechanisms, the larger increase in f at the onset of hypercapnia could be linked to carotid body responsiveness and/or a higher state of vigilance in this group.

At the end of the hypercapnic stimulus, the E response of male NMS rats was lower than controls, owing to an attenuation of the VT response. This effect differs from the enhancement of VT and inspiratory efforts observed in male NMS rats during an acute hypoxic challenge or carotid sinus nerve stimulation (8, 17). The mechanisms underlying the effects of NMS on the hypercapnic chemoreflex in males are unclear but are similar to the attenuation of the hypercapnic (but not hypoxic) ventilatory response observed in rats previously subjected to one or two daily sessions of immobilization stress (15). Since activation of the hypothalamo-pituitary axis is a common feature of both experimental procedures (NMS and immobilization stress), these data suggest that changes in neuroendocrine function, such as elevation of corticosteroid levels, disrupt the hypercapnic chemoreflex at sites that remain to be determined.

The fact that neither NMS nor immobilization stress affects arterial blood gases, either at rest or during exposure to a ventilatory challenge (8, 15), indicates that between-group differences in the level of chemical stimulation unlikely account for the NMS-related differences in hypercapnic ventilatory responses. Because NMS had no effect on the E/CO₂ response measured at the end of hypercapnic stimulation, it would appear that the long-term effects of this form of early life stress on the responsiveness to CO₂/H⁺ in male rats is marginal. Since the hyperventilation that occurs during acute exposure to 5% CO₂ typically augments arterial PO₂ (Pa_{O2) from 105 to 125 Torr (15), we propose that the lower E observed in male NMS rats is related to their higher sensibility and responsiveness to changes in PaO2 than controls (8, 17). This increase in PaO2 may not be sufficient to reduce carotid body discharge frequency under normocapnic conditions (33) but could reduce carotid body activity during hypercapnia (especially in NMS rats) since O2 and CO2 levels interact in a multiplicative fashion to determine the overall level of carotid body activity (9). Accordingly, we propose that the PaO2 increase observed during hypercapnia attenuates carotid body-mediated respiratory drive in this group. Although this hypothesis remains to be addressed with a more direct (electrophysiological) approach, the fact that there is no evidence suggesting that NMS alters carotid body function in females is consistent with this interpretation.}

These data contrast remarkably with those observed in females in which proportional enhancement of the VT response accounts for the larger increase in E. However, these data must be interpreted carefully because treatment-related differences in baseline VT (and thus E) contribute the enhancement of the response seen with normalized data (see Fig. 3). Moreover, despite rigorously controlled experimental conditions, NMS affected baseline E in females in a way that was opposite from that reported in our previous study (8). The factors underlying this puzzling difference between the two studies are still unclear to us, but since baseline ventilatory data obtained in males were nearly identical between these two studies, such effect could be related to differences in the predominant stage of the oestrus cycle during which experiments were performed. Nonetheless, the higher E/CO₂ response observed in NMS females is consistent with the enhanced responsiveness to CO₂/H⁺. This observation, combined with the lack of evidence suggesting that NMS affects carotid body function in females, suggests that NMS increases central chemosensitivity in a sex-specific fashion. However, a more direct experimental approach is necessary to test this hypothesis adequately, especially since NMS rats showed no CO₂ increase during hypercapnic exposure, thereby suggesting that regulation of metabolism may contribute also. But in the present context, it is interesting to note that these results contrast substantially with the effects of NMS on the hypoxic chemoreflex in which females showed a depression of the f response to hypoxia (8). In light of the present data, the decrease in arterial PCO₂ during hypoxia combined with the higher CO₂/H⁺ responsiveness in NMS females may explain why these animals showed a lower response during hypoxia.

View larger version (17K): [in this window] [in a new window]   Fig. 3. Effects of NMS on hypercapnic ventilatory response of adult female (A) and male (B) rats. For each group, selected ventilatory variables (E, VT, breathing frequency, inspiratory flow, and E/CO2) were measured after 20 min of exposure to moderate hypercapnia (FICO2 = 0.05) and expressed as a percentage change from normoxic baseline values. Data are compared between controls (filled bars); males: n = 8 and females: n = 11) and rats previously subjected to NMS (open bars); males, n = 10; females, n = 16). Values are expressed as means ± SD. Statistically different from corresponding control value (P < 0.05). Statistically different from corresponding control value (P < 0.1). #Statistically different from corresponding female value (P < 0.05).

Together, these data reinforce the notion that adverse early life experiences that do not pose a direct threat to respiratory homeostasis have long-lasting consequences on respiratory control development (16). The mechanisms at the basis of these alterations in neonatal programming are still unclear, but the sex-specific nature of this manifestation of respiratory plasticity suggest that gonadal hormones contribute to the expression of the effect of NMS. Moreover, these results indicate that ovarian hormones do not necessarily protect against the effects of early life stress on respiratory control development. In light of the present data, we propose that, with such enhancement of the CO₂ chemoreflex, NMS rats may be more susceptible to develop respiratory disorders associated with neural control dysfunction such as respiratory instability during sleep or panic attacks (10, 13, 19, 28, 32). Should data support this hypothesis, NMS may be a valuable model to understand these pathologies.

	GRANTS

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This research was supported by the Hospital for Sick Children Foundation, la Fondation de la Recherche sur les Maladies Infantiles, and the Canadian Institutes of Health Research. R. Kinkead is the chairholder of the Canada Research Chair in Respiratory Neurobiology. S.-E. Genest and G. Drolet held scholarships from Le Fonds en Recherche en Santé du Québec.

	ACKNOWLEDGMENTS

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The authors thank Dominique Boivin and Evelyne Vachon for technical help.

	FOOTNOTES

 

Address for reprint requests and other correspondence: R. Kinkead, Centre de Recherche (D0-711), Hôpital St-François d'Assise, 10 rue de l'Espinay, Québec, QC, Canada G1L 3L5 (e-mail: Richard.Kinkead{at}crsfa.ulaval.ca)

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.

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