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Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10- and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits.

Obstructive sleep apnea (OSA) is a frequent medical condition and is associated with cognitive impairments in adults and with hyperactivity and decreased school performance in children. In an adult rodent model, intermittent hypoxia (IH), such as occurs in OSA, is associated with neurodegenerative changes in the hippocampus and cortex and with spatial learning deficits. Because a unique developmental window of neural vulnerability to IH is present, we hypothesized that exposure to IH throughout the vulnerable ages would result in increased behavioral impairments in the juvenile rat. Rat pups were therefore exposed to either room air or IH beginning at postnatal (PN) d 10 until PN d 30. Learning and memory were assessed via a standard place-training version of the Morris water maze beginning at PN d 25. Locomotor activity was assessed on PN d 29 and 30. Pups exposed to IH displayed significant spatial learning impairments, and exposed male rats but not female rats displayed increased locomotor activity in the open field. Collectively, these findings indicate that exposure to IH at an age that corresponds to the peak incidence of OSA in children induces substantial learning impairment and gender-dependent behavioral hyperactivity in the juvenile rat. We postulate that this novel experimental model may allow for future exploration of mechanisms underlying the neurobehavioral deficits of children with OSA.