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

Journal of Neuroinflammation

David Gozal¹  Alba Carreras²  Richard C Li²  Yang Wang²  Foaz Kayali²  Navita Kaushal²  Fahed Hakim²  Shelley X L Zhang²  Deepti Nair²  Vijay Ramesh² 

[1] Department of Pediatrics, The University of Chicago, 5721S. Maryland Avenue, MC 8000, Suite K-160, Chicago, IL, 60637, USA;Section of Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA

关键词: ATP;    Sleep apnea;    Neurocognitive impairments;    Sleep fragmentation;    TNF-α;   

Others  :  1212623
DOI  :  10.1186/1742-2094-9-91

 received in 2011-11-21, accepted in 2012-05-11,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

   
2012 Ramesh et al.; licensee BioMed Central Ltd.

【 图 表 】

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