Erythropoietin impacts the stress‐related respiratory dysfunction in mice: neonatal maternal separation and sex dimorphism

Abstract

Neonatal maternal separation (NMS) is an established model of early life adversity that mimics stressful conditions experienced by newborn and infants. NMS disrupts brain development and as adults, individuals show sex‐dependent abnormal neuroendocrine response, predisposing them to physiological/psychological disorders. Concerning the neural control of respiration, studies in rats revealed that NMS causes respiratory instability and increased levels of corticosterone that remained during adulthood. Moreover, increased ventilatory response to hypoxia (HVR) but decreased to hypercapnia (HcVR) was observed in male animals, while decreased HVR but increased HcVR was observed in female rats.Although it is primarily recognized for its capacity to stimulate erythrocyte production, erythropoietin (Epo) is a cytokine that is also produced in the brain (by neurons and astrocytes), and plays role in development, maintenance, protection and repair of the nervous system. Studies from our lab demonstrated that cerebral Epo is a potent and sex‐specific respiratory stimulant that enhances the ability to tolerate hypoxic conditions at neonatal and adult ages. As cerebral Epo also attenuates the activation of the hypothalamic‐pituitary‐adrenal (HPA) axis, here we hypothesized that Epo protects against the stress‐induced cardio‐respiratory dysfunction produced by NMS. To test this hypothesis, circulating corticosterone level of adult (3 months) male and female Tg21 mice, was increased by subcutaneous implantation of beeswax pellets. 14 days later basal ventilation, HVR (10%O2 in N2) and HcVR (5% CO2, 21%O2 in N2) was evaluated by whole‐body plethysmography. Our preliminary results showed that corticosterone does not alter basal ventilation nor HVR in female and male Tg21 mice. However, corticosterone decreased HcVR in female Tg21 mice, meanwhile males showed an increased HcVR. These results suggest that Epo modulates the cortiscosterone‐induced cardiorespiratory dysfunctions.Support or Funding InformationCanadian Institutes of HealthResearch (MOP 130258), the Star Foundation for Children's HealthResearch. The salary of Jorge Soliz is supported by the “Fonds de recherche du Quebec‐Santé” (FRQ‐S).