Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse

Deepti Nair, Shelley X.L. Zhang, Vijay Ramesh, Fahed Hakim, Navita Kaushal, Yang Wang, David Gozal

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


Rationale: Sleep fragmentation (SF) is one of the major characteristics of sleep apnea, and has been implicated in its morbid consequences, which encompass excessive daytime sleepiness and neurocognitive impairments. We hypothesized that absence of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is neuroprotective in SF-induced cognitive impairments. Objectives: To examine whether increased NADPH oxidase activity may play a role in SF-induced central nervous system dysfunction. Methods: The effect of chronic SF during the sleep-predominant period on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters was assessed in mice lacking NADPH oxidase activity (gp91phox-/ Y) and wild-type littermates. Measurements and Main Results: SF for 15 days was not associated with differences in sleep duration, sleep state distribution, or sleep latency in both gp91phox-/ Y and control mice. However, on a standard place training task, gp91phox-/ Y mice displayed normal learning and were protected from the spatial learning deficits observed in wild-type littermates exposed to SF. Moreover, anxiety levels were increased inwild-type mice exposed to SF, whereas no changes emerged in gp91phox-/ Y mice. Additionally, wild-type mice, but not gp91phox-/ Ymice, had significantly elevated NADPH oxidase gene expression and activity, and in malondialdehyde and 8-oxo-2′- deoxyguanosine levels in cortical and hippocampal lysates after SF exposures. Conclusions: This work substantiates an important role for NADPH oxidase in hippocampal memory impairments induced by SF, modeling sleep apnea. Targeting NADPH oxidase, therefore, is expected to minimize hippocampal impairments from both intermittent hypoxia and SF associated with the disease.

Original languageEnglish
Pages (from-to)1305-1312
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number11
StatePublished - 1 Dec 2011
Externally publishedYes


FundersFunder number
National Heart, Lung, and Blood InstituteR01HL086662


    • NADPH oxidase
    • Neurocognitive impairments
    • Sleep fragmentation


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