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

Abstract

Genest S-E, Gulemetova R, Laforest S, Drolet G, Kinkead R. Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat. J Appl Physiol 102: 1416 -1421, 2007. First published December 21, 2006; doi:10.1152/japplphysiol.00454.2006.-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 ϭ 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 ϩ 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 THE NEONATAL ENVIRONMENT is critical to proper development of neurophysiological function. The formation and fine tuning of neural circuits during early life require adequate sensory guidance, and conditions providing excessive or insufficient levels of stimulation can disrupt system development and compromise their subsequent performance throughout life. The olfactory, tactile, and auditory stimuli that the mother provides her offspring following birth are among the most potent environmental factors contributing to the "neonatal programming" of neural circuits (12,22). Although the life-long consequences of disrupting motherpup interactions have been mainly associated with behavioral and neuroendocrine dysfunction (1, 2, 20), less is known about the impact of mother-pup interaction on other homeostatic functions such as cardiorespiratory regulation. Accordingly, we showed that neonatal maternal separation (NMS) disrupts cardiorespiratory responses to moderate hypoxia in a persistent and sex-specific fashion (8,16). In addition to eliciting the well described enhancement of basal hypothalamo-pituitary-adrenal axis function in rats (34; for review see Ref. 5), we...

Neonatal stress and attenuation of the hypercapnic ventilatory response in adult male rats: the role of carotid chemoreceptors and baroreceptors

“…Neonatal maternal separation (NMS) is a well-established, clinically relevant stress model that disrupts mother-offspring interactions to reproduce environmental conditions experienced by infants deprived from adequate parental stimulation due to special medical interventions associated with prematurity or inadequate maternal care (e.g., parental neglect, mother suffering from depression, orphanage) (14,38,50). Because this stress typically occurs during a critical period of development, NMS has long-lasting consequences on CNS development and affects maturation of basic homeostatic functions, such as the neuroendocrine regulation of stress responses (18, 61) and the respiratory control system (20,21,37).With regard to respiratory regulation, several recent reviews have highlighted the profound effects of excessive stimulation of chemosensory pathways (e.g., intermittent hypoxia, chronic hypoxia) on the developmental trajectory of the neural circuits that regulate breathing (2, 7). Depending on the severity of the stimulation protocols used, these models may activate the neuroendocrine response to stress, but the contribution of these hormones to the final respiratory phenotype remains unknown.…”

“…Neonatal maternal separation (NMS) is a well-established, clinically relevant stress model that disrupts mother-offspring interactions to reproduce environmental conditions experienced by infants deprived from adequate parental stimulation due to special medical interventions associated with prematurity or inadequate maternal care (e.g., parental neglect, mother suffering from depression, orphanage) (14,38,50). Because this stress typically occurs during a critical period of development, NMS has long-lasting consequences on CNS development and affects maturation of basic homeostatic functions, such as the neuroendocrine regulation of stress responses (18, 61) and the respiratory control system (20,21,37).…”

Animal Models of Human Anxiety Disorders: Reappraisal From a Developmental Psychopathology Vantage Point

“…Some authors studied the impact of maternal separation (3 h/d for 10 consecutive days from postnatal d 1) on respiratory responses in rats. They reported the presence of respiratory alterations to both hypoxic and hypercapnic air mixtures and opposite patterns of ventilatory responses in male and female rats (79,80). Although the fact that both the response to hypoxia and hypercapnia is altered in this paradigm, and that opposite patterns of ventilatory response to hypercapnia have been observed in male and female rats, these initial data have an interest as they suggest that maternal separation per se is as an event that may induce respiratory dysregulation.…”

Long-term effects of the perinatal environment on respiratory control

“…The effect of NMS on the HCVR of male rats is equivocal: the change in minute ventilation during hypercapnia is somewhat reduced, but the change in ventilation-tometabolism ratio is not altered (i.e., the animals do not hyperventilate less than controls) (37). The enhanced HVR of male rats appears to involve both peripheral and central neural plasticity.…”

“…Consistent with the sex specificity of this plasticity, female rats also showed no change in tyrosine hydroxylase mRNA expression in the carotid body after NMS (54), further suggesting a potential link between increased tyrosine hydroxylase expression and enhanced HVR in male rats. The effects of NMS on the HCVR also differed between the sexes, with NMS females exhibiting a clear increase in the HCVR as adults (37).…”