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

Abstract

-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 ...

Neonatal Maternal Separation Augments Carotid Body Response to Hypoxia in Adult Males but Not Female Rats

“…At adulthood, the hypercapnic ventilatory response of NMS females is 63% greater than controls whereas the response of NMS males is reduced by 47% (Genest et al, 2007b ). Experiments in anesthetized rats (males and females) point to central mechanisms and do not indicate that the carotid bodies play a major role in these phenotypes (Dumont and Kinkead, 2010 , 2011 ; Dumont et al, 2011 ); the data reported here support this interpretation.…”

Toward understanding the causes of blood pH irregularities and the roles of newly described binuclear neurons of carotid bodies on blood pH regulation during subarachnoid hemorrhage: Experimental study

“…The CBs are highly vascularized chemosensitive structures and play important roles in acute adaptation to hypoxia, located at the bifurcation of the common carotid artery. Mainly ECA and rarely ICA feed CBs . The CBs are the essential arterial chemoreceptors sensing arterial pCO 2 , pO 2 , blood pH, blood pressure, glucose metabolism, cerebrovascular and cardiorespiratory autoregulation .…”

“…Mainly ECA and rarely ICA feed CBs. 15,16 The CBs are the essential arterial chemoreceptors sensing arterial pCO 2 , pO 2 , blood pH, blood pressure, glucose metabolism, 10 cerebrovascular and cardiorespiratory autoregulation. 2,3 The structural unit of the CBs are glomus cells located around the capillaries and are synaptically connected to petrosal ganglion (PG) neurons.…”

Testosterone Supplementation Induces Age-Dependent Augmentation of the Hypoxic Ventilatory Response in Male Rats With Contributions From the Carotid Bodies

“…These experiments evaluated the effects of testosterone supplementation on the HVR under experimental conditions that facilitate standardization of hypoxic stimulation and quantification of arterial blood gases using standard procedures in our laboratory (Dumont and Kinkead, 2010). Anesthesia was induced by placing the rat in a closed chamber equilibrated with isoflurane (3.5%) and was then maintained via a nose cone (3%).…”