OBSTRUCTIVE SLEEP APNEA (OSA) WITH DAYTIME HY- PERSOMNOLENCE IS PRESENT IN AT LEAST 12 MILLION ADULTS IN THE UNITED STATES.1 TWO THIRDS of adults with OSA complain of significant sleepiness and/or fatigue

OBSTRUCTIVE SLEEP APNEA (OSA) WITH DAYTIME HYPERSOMNOLENCE IS PRESENT IN AT LEAST 12 MILLION ADULTS IN THE UNITED STATES.1 TWO THIRDS of adults with OSA complain of significant sleepiness and/or fatigue at presentation.2 Yet, therapies may not fully reverse hypersomnolence.3-6 Thus, residual sleepiness in adults treated for OSA is a significant health concern. Adult male mice exposed to hypoxia/reoxygenation patterns similar to those present in patients with severe OSA develop lasting hypersomnolence and objective sleepiness.7 These wake impairments are associated with oxidation and nitration in wakeactive regions.7-9 Both the oxidative injury and wakefulness impairments are dependent upon nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.9 Thus, the long-term intermittent hypoxia (LTIH)-induced residual wake impairments are a consequence of NADPH oxidase-dependent oxidative injury in selective brain regions. Perinatal LTIH exposure in male and female rat pups results in wake impairments lasting at least 3 weeks, associated with alterations in dopaminergic signaling.10,11 Studies have shown sex differences in dopaminergic receptor and reuptake proteins, yet show no differences of posthypoxia sleepwake architecture.10,11 Whether there are sex differences in wakeimpairment effects of LTIH in young adults is not known. Sex differences have been shown for oxidative brain injuries. In humans, female sex is associated with improved outcomes for both cerebrovascular insults and Parkinson disease.12,13 In experimentally induced oxidative brain injuries in mice, premenopausal females confer protection relative to age-matched males or ovarectomized age-matched females.14 These findings suggest that endogenous estrogen plays an important role in mechanisms of protection from brain oxidative injuries (for review, see reference 15). We hypothesized that premenopausal female mice, relative to age-matched male mice, would show protection from LTIH oxidative injury and wake impairments. The purpose of the studies presented here was to compare the effects of LTIH exposure in young adult male and female mice on wake impairments and oxidative injury to wake regions in the brain. We first determined whether hypoxia/reoxygenation events, modeling severe OSA hypoxia/reoxygenation, manifest as residual hypersomnolence and shortened sleep latencies in females, as we have found in males. In the present work, we have found that females appear to be resistant to LTIH wake impairments, both hypersomnolence and sleepiness. To gain further insight into potential mechanisms of sleepiness in women with OSA, we next measured sleep-latency responses in male and female mice exposed to short-term sleep loss. In contrast with the lack of LTIH effect on wake function in female mice, female mice showed greater sleepiness after short-term sleep loss and more robust slow-wave (delta) activity across recovery. We then Sex Differences in Susceptibility to Oxidative Injury and Sleepiness From Intermittent Hypoxia