-Neonatal maternal separation (NMS) is a form of stress that disrupts respiratory control development. Awake adult male rats previously subjected to NMS show a ventilatory response to hypercapnia (HCVR; FICO 2 ϭ 0.05) 47% lower than controls; however, the underlying mechanisms are unknown. To address this issue, we first tested the hypothesis that carotid bodies contribute to NMS-related attenuation of the HCVR by using carotid sinus nerve section or FIO 2 manipulation to maintain PaO 2 constant (iso-oxic) during hypercapnic hyperpnea. We then determined whether NMS-related augmentation of baroreflex sensitivity contributes to the reduced HCVR in NMS rats. Nitroprusside and phenylephrine injections were used to manipulate arterial blood pressure in both groups of rats. Pups subjected to NMS were separated from their mother 3 h/day from postnatal days 3 to 12. Control rats were undisturbed. At adulthood, rats were anesthetized [urethane (1g/kg) ϩ isoflurane (0.5%)], and diaphragmatic electromyogram (dEMG) was measured under baseline and hypercapnic conditions (PaCO 2 : 10 Torr above baseline). The relative minute activity response to hypercapnia of anesthetized NMS rats was 34% lower than controls. Maintaining PaO 2 constant during hypercapnia reversed this phenotype; the HCVR of NMS rats was 45% greater than controls. Although the decrease in breathing frequency during baroreflex activation was greater in NMS rats, the change observed within the range of pressure change observed during hypercapnia was minimal. We conclude that NMS-related changes in carotid body sensitivity to chemical stimuli and/or its central integration is a key mechanism in the attenuation of HCVR by NMS. control of breathing; development; stress; central integration IN HUMANS, RATS, AND NONHUMAN primates, the tactile, olfactory, and auditory stimuli provided by the mother to her offspring have a strong influence on central nervous system (CNS) development (17,18,38,40,50,56). 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 ...