Sex, stress and their influence on respiratory regulation

Much like locomotion or micturition, respiration is a rhythmic and stereotyped motor pattern controlled mainly by non-cortical structures including a complex circuit in the brainstem. Because tight regulation of lung ventilation is essential from the beginning of life, it has been presumed that the neural system regulating breathing is fixed, following a genetically predetermined developmental pattern. Here, we review evidence indicating that early life exposure to a non-systemic stress in the form of neonatal maternal separation (NMS) is sufficient to exert sex-specific consequences on the developmental trajectory of this vital homeostatic system that persist well into full maturity. At adulthood, male rats subjected to NMS are hypertensive and show an abnormally high hypoxic chemoreflex that correlates positively with respiratory instability during sleep. The effects are not observed in females. Investigation of the mechanisms this respiratory phenotype have highlighted the importance of 1) neuroendocrine influences on respiratory regulation and 2) stress-related imbalance between inhibitory (GABAergic) and excitatory (glutamatergic) modulation of the neural elements regulating breathing. These results provide new and valuable insight into the origins of respiratory disorders related to neural control dysfunction such as sleep disordered breathing.