Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse

Abstract

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 wildtype littermates exposed to SF. Moreover, anxiety levels were increased in wild-type mice exposed to SF, whereas no changes emerged in gp91phox-/Y mice. Additionally, wild-type mice, but not gp91phox-/Y mice, had significantly elevated NADPH oxidase gene expression and activity, and in malondialdehyde and 8-oxo-29-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. Keywords: NADPH oxidase; sleep fragmentation; neurocognitive impairmentsThe manifestations of obstructive sleep apnea (OSA) reflect the interactions of intermittent hypoxia (IH), intermittent hypercapnia, increased intrathoracic pressure swings, and sleep fragmentation (SF) as elicited by the episodic changes in upper airway resistance during sleep. SF is a common phenomenon among several clinical disorders, and can lead to impaired cognitive function via mechanisms that remain poorly understood (1). Indeed, uninterrupted sleep for a minimum length of time is required for optimal daytime vigilance and neurocognitive function (1-3). Preliminary studies in rodents using short-term SF paradigms have also confirmed the adverse effects of SF on learning and seem to be independent of adenosine-mediated synaptic inhibition (4-7).In clinical populations with severe SF (e.g., in OSA) total sleep time typically diminishes only slightly (8). The effects of experimentally induced SF on sleep patterns have not been critically characterized in rodents. It is likely that OSA-induced sleep perturbations are accompanied by obvious cognitive deficits because of increased levels of systemic markers of oxidative stress and inflammation, the latter leading to gray matter loss in neural...

Urinary Neurotransmitters Are Selectively Altered in Children With Obstructive Sleep Apnea and Predict Cognitive Morbidity

“…[29][30][31][32][33] Both intermittent hypoxia and increased oxidative stress are hallmark characteristics of OSA, 34 and the degree of oxidative stress associated with OSA has emerged as an important determinant of cognitive dysfunction in both animal models and in children. [35][36][37] A unique and intriguing observation in the present study involves the differential and predictable changes in urinary neurotransmitters in children with OSA and without evidence of neurocognitive dysfunction. In this context, the patterns of overnight changes in levels of three neurotransmitters, namely GABA, taurine, and PEA, allowed accurate prediction of cognitive defi cits in this small cohort ( Fig 2 ).…”

Human apolipoprotein E4 targeted replacement in mice reveals increased susceptibility to sleep disruption and intermittent hypoxia

“…Physiological data were continuously acquired for 24 h using Dataquest ART acquisition software (version 3.1, DSI), at a sampling rate of 500 Hz. Data were first scored automatically using SleepSign software (Kissei Comtec) (11,34,44), and records were then visually confirmed or corrected as needed by an investigator who was blinded to the experimental condition.…”

“…In this mode, the sweeper requires around 9 s to sweep the floor of the cage one way. When it reaches the end of the cage, a relay engages the timer to pause for 2 min before enabling the sweeper to move in the opposite direction (34,44). Between the two intervals, the animal remained undisturbed.…”

Reduced NADPH oxidase type 2 activity mediates sleep fragmentation-induced effects on TC1 tumors in mice

“…15,26,27 3-mo-old WT and gp91 phox-/Y mice were exposed to either SF or normal sleep conditions (SC; the SF cage was used but the sweeper remained immobile). To induce moderate to severe SF, we chose a 2-min interval between each sweep, implemented during the light period (7:00 am-7:00 pm).…”

“…14 In a series of studies exploring some of the deleterious consequences of SF, we identified the presence of increased Nox2-derived ROS and oxidative stress as major pathophysiological determinants of end-organ morbidity. [15][16][17] Based on such findings and the promoting effects of SF on tumor growth and invasion, 3 we hypothesized that genetic ablation of Nox2 would potentially elucidate the role of this important source of ROS in the oncogenic processes modulated by SF, and potentially abolish the pro-tumorigenic effects of SF.…”