Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway.

BACKGROUND: Sleepiness and cognitive dysfunction are recognized as prominent consequences of sleep deprivation. Experimentally induced short-term sleep fragmentation, even in the absence of any reductions in total sleep duration, will lead to the emergence of excessive daytime sleepiness and cognitive impairments in humans. Tumor necrosis factor (TNF)-α has important regulatory effects on sleep, and seems to play a role in the occurrence of excessive daytime sleepiness in children who have disrupted sleep as a result of obstructive sleep apnea, a condition associated with prominent sleep fragmentation. The aim of this study was to examine role of the TNF-α pathway after long-term sleep fragmentation in mice. METHODS: The effect of chronic sleep fragmentation during the sleep-predominant period on sleep architecture, sleep latency, cognitive function, behavior, and inflammatory markers was assessed in C57BL/6 J and in mice lacking the TNF-α receptor (double knockout mice). In addition, we also assessed the above parameters in C57BL/6 J mice after injection of a TNF-α neutralizing antibody. RESULTS: Mice subjected to chronic sleep fragmentation had preserved sleep duration, sleep state distribution, and cumulative delta frequency power, but also exhibited excessive sleepiness, altered cognitive abilities and mood correlates, reduced cyclic AMP response element-binding protein phosphorylation and transcriptional activity, and increased phosphodiesterase-4 expression, in the absence of AMP kinase-α phosphorylation and ATP changes. Selective increases in cortical expression of TNF-α primarily circumscribed to neurons emerged. Consequently, sleepiness and cognitive dysfunction were absent in TNF-α double receptor knockout mice subjected to sleep fragmentation, and similarly, treatment with a TNF-α neutralizing antibody abrogated sleep fragmentation-induced learning deficits and increases in sleep propensity. CONCLUSIONS: Taken together, our findings show that recurrent arousals during sleep, as happens during sleep apnea, induce excessive sleepiness via activation of inflammatory mechanisms, and more specifically TNF-α-dependent pathways, despite preserved sleep duration.

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

Intermittent hypoxia (IH) and sleep fragmentation (SF) are major manifestations of sleep apnea, a frequent condition in aging humans. Sleep perturbations are frequent in Alzheimer's disease (AD) and may underlie the progression of disease. We hypothesized that acute short-term IH, SF, and their combination (IH+SF) may reveal unique susceptibility in sleep integrity in a murine model of AD. The effects of acute IH, SF, and IH+SF on sleep architecture, delta power, sleep latency, and core body temperature were assessed in adult male human ApoE4-targeted replacement mice (hApoE4) and wild-type (WT) controls. Slow wave sleep (SWS) was significantly reduced, and rapid eye movement (REM) sleep was almost abolished during acute exposure to IH alone and IH+SF for 6 h in hApoE4, with milder effects in WT controls. Decreased delta power during SWS did not show postexposure rebound in hApoE4 unlike WT controls. IH and IH+SF induced hypothermia, which was more prominent in hApoE4 than WT controls. Mice subjected to SF also showed sleep deficits but without hypothermia. hApoE4 mice, unlike WT controls, exhibited increased sleep propensity, especially following IH and IH+SF, suggesting limited ability for sleep recovery in hApoE4 mice. These findings substantiate the potential impact of IH and SF in modulating sleep architecture and sleep homeostasis including maintenance of body temperature. Furthermore, the increased susceptibility and limited recovery ability of hApoE4 mice to sleep apnea suggests that early recognition and treatment of the latter in AD patients may restrict the progression and clinical manifestations of this frequent neurodegenerative disorder.

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

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 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-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.

TNF-α and temporal changes in sleep architecture in mice exposed to sleep fragmentation.

TNF-α plays critical roles in host-defense, sleep-wake regulation, and the pathogenesis of various disorders. Increases in the concentration of circulating TNF-α after either sleep deprivation or sleep fragmentation (SF) appear to underlie excessive daytime sleepiness in patients with sleep apnea (OSA). Following baseline recordings, mice were subjected to 15 days of SF (daily for 12 h/day from 07.00 h to 19.00 h), and sleep parameters were recorded on days1, 7 and 15. Sleep architecture and sleep propensity were assessed in both C57BL/6J and in TNF-α double receptor KO mice (TNFR KO). To further confirm the role of TNF-α, we also assessed the effect of treatment with a TNF- α neutralizing antibody in C57BL/6J mice. SF was not associated with major changes in global sleep architecture in C57BL/6J and TNFR KO mice. TNFR KO mice showed higher baseline SWS delta power. Further, following 15 days of SF, mice injected with TNF-α neutralizing antibody and TNFR KO mice showed increased EEG SWS activity. However, SWS latency, indicative of increased propensity to sleep, was only decreased in C57BL/6J, and was unaffected in TNFR KO mice as well as in C57BL/6J mice exposed to SF but treated with TNF-α neutralizing antibody. Taken together, our findings show that the excessive sleepiness incurred by recurrent arousals during sleep may be due to activation of TNF-alpha-dependent inflammatory pathways, despite the presence of preserved sleep duration and global sleep architecture.

Socially isolated mice exhibit a blunted homeostatic sleep response to acute sleep deprivation compared to socially paired mice.

Sleep is an important physiological process underlying maintenance of physical, mental and emotional health. Consequently, sleep deprivation (SD) is associated with adverse consequences and increases the risk for anxiety, immune, and cognitive disorders. SD is characterized by increased energy expenditure responses and sleep rebound upon recovery that are regulated by homeostatic processes, which in turn are influenced by stress. Since all previous studies on SD were conducted in a setting of social isolation, the impact of the social contextual setting is unknown. Therefore, we used a relatively stress-free SD paradigm in mice to assess the impact of social isolation on sleep, wakefulness and delta electroencephalogram (EEG) power during non-rapid eye movement (NREM) sleep. Paired or isolated C57BL/6J adult chronically-implanted male mice were exposed to SD for 6h and telemetric polygraphic recordings were conducted, including 18 h recovery. Recovery from SD in the paired group showed a significant decrease in wake and significant increase in NREM sleep and rapid eye movement (REM), and a similar, albeit less robust response occurred in the isolated mice. Delta power during NREM sleep was increased in both groups immediately following SD, but paired mice exhibited significantly higher delta power throughout the dark period. The increase in body temperature and gross motor activity observed during the SD procedure was decreased during the dark period. In both open field and elevated plus maze tests, socially isolated mice showed significantly higher anxiety than paired mice. The homeostatic processes altered by SD are differentially affected in paired and isolated mice, suggesting that the social context of isolation stress may adversely affect the quantity and quality of sleep in mice.

Intermittent hypoxia activates temporally coordinated transcriptional programs in visceral adipose tissue.

Obstructive sleep apnea (OSA) is a prevalent disorder characterized by intermittent hypoxia (IH) during sleep. OSA is strongly associated with obesity and dysregulation of metabolism-yet the molecular pathways linking the effects of IH on adipocyte biology remain unknown. We hypothesized that exposure to IH would activate distinct, time-dependent transcriptional programs in visceral adipose tissue of mice. We exposed 36 mice to IH or normoxia for up to 13 days. We transcriptionally profiled visceral fat tissue harvested from the animals and performed functional enrichment and network analysis on differentially expressed genes. We identified over 3,000 genes with significant expression patterns during the time course of IH exposure. The most enriched pathways mapped to metabolic processes, mitochondrion, and oxidative stress responses. We confirmed the pathophysiological relevance of these findings by demonstrating that mice exposed to chronic IH developed dyslipidemia and underwent significant lipid and protein oxidation within their visceral adipose depots. We applied gene-gene interaction network analysis to identify critical controllers of IH-induced transcriptional programs in adipocytes-these network hubs represent putative targets to modulate the effects of chronic IH on adipose tissue. Our approach to integrate computational methods with gene expression profiling of visceral fat tissue during IH exposure shows promise in helping unravel the mechanistic links between OSA and adipocyte biology.