Abstract
Premature birth is a major public health issue affecting 1 in 10 deliveries worldwide. One of the most common diagnoses in these infants is apnea of prematurity, with chronic intermittent hypoxia (CIH) as one hallmark, which includes interlacing hypoxia and normoxia episodes. The perinatal brain is vulnerable to hypoxia because it is a shifting landscape with marked growth and remodeling of the vasculature. Hypoxia provides a natural angiogenic stimulus during growth of cerebrovascular networks. However, it is unclear if exposure to CIH alters the structure and function of developing brain vascular networks. To further investigate this question, we used a neonatal mouse model that mimics the hypoxia/reoxygenation events occurring in CIH. From postnatal day P2 to P12, pups were exposed to 20.9% O 2 (normoxia) and 5.7% O 2 (hypoxia; 25-30 episodes of 5-7s per hour) for 8 hours a day during daylight hours. Our previous studies examining mouse pups (P8-P12) reared in normoxic conditions showed that ascending venules were a key locus for new vascular growth during brain capillary development. Concurrently, an initially amorphous plexus of pial venules on the cortical surface undergoes massive intussusceptive remodeling to create an optimized tree-like network for cortical blood drainage. During CIH, in vivo two-photon imaging revealed that angiogenic sprouts emerged not only from venules but also from cortical arterioles. CIH led to more active angiogenesis and increased brain capillary length and branching. In addition, arteriovenous shunts were present within the pial vasculature. Critically, we observed that mice exposure to CIH during the neonatal period presented anxiety and mood like-behaviors (interupted grooming and jump/scape behavior) at weaning age (P21). Curiously, mice exposed to CIH exhibited improved recognition memory (novel object recognition) at P30. These findings begin to clarify the vascular changes induced by CIH and their association with behavioral abnormalities after development with CIH.
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