Mild Neonatal Hypoxia Modifies the Reactivity of the Glucocorticoid System in Adult Rats, Promoting Improved Learning and Spatial Memory Under Stressful Conditions.

Mild neonatal hypoxia (NH) can serve as a conditioning stimulus that persistently modulates stress systems. We tested whether brief neonatal hypobaric hypoxia induces long-term changes hypothalamic-pituitary-adrenal (HPA) regulation and adult behavior. Male Wistar rats received three 2 h hypobaric sessions on postnatal days 8-10. At 3 months, behavior was assessed. Biochemical measures included plasma/adrenal corticosterone (CORT), plasma ACTH, brain CORT, CRH/POMC/GR/11β-HSD2 protein, and HPA/steroidogenic gene expression. NH yielded a calmer, context-beneficial phenotype: startle latency increased, Morris water maze memory improved, whereas Barnes, recognition memory, and forced swim measures were unchanged. Hypothalamic CRH protein and pituitary/plasma ACTH were reduced, despite unchanged crh and Pomc mRNA, suggesting post-transcriptional control. Basal CORT in plasma and adrenals remained unchanged, but the CORT response to mild stress was larger and more sustained. In the adrenal glands, Cyp11b1 was selectively downregulated, whereas Mc2r, Cyp11a1, Hsd3b2, Cyp21a1 were unaffected. GR and 11β-HSD2 protein did not differ across tissues. In the brain, CORT decreased selectively in the amygdala. NH appears to act as developmental preconditioning, leading to persistent behavioral adaptations and altered HPA regulation in adulthood, characterized by reduced central drive at rest, preserved basal output, and efficient mobilization under challenge.