title: Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway.
abstract: 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.
authors.affiliation: Section of Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramesh
authors.forename: Deepti
authors.initials: D
authors.lastname: Nair
authors.forename: Shelley X L
authors.initials: SX
authors.lastname: Zhang
authors.forename: Fahed
authors.initials: F
authors.lastname: Hakim
authors.forename: Navita
authors.initials: N
authors.lastname: Kaushal
authors.forename: Foaz
authors.initials: F
authors.lastname: Kayali
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Li
authors.forename: Alba
authors.initials: A
authors.lastname: Carreras
authors.forename: David
authors.initials: D
authors.lastname: Gozal
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001143:Arousal / Q000235:genetics / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D012892:Sleep Deprivation / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D012894:Sleep Stages / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha