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 Ï 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 Ï© 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...