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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

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

Authors: Vijay Ramesh, Deepti Nair, Shelley X L Zhang, Fahed Hakim, Navita Kaushal, Foaz Kayali, Yang Wang, Richard C Li, Alba Carreras, David Gozal

Published in: Journal of Neuroinflammation | Issue 1/2012

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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.
Literature
1.
Kimoff RJ: Sleep fragmentation in obstructive sleep apnea. Sleep 1996, 19:S61-S66.PubMed
2.
Montgomery-Downs HE, Crabtree VM, Gozal D: Cognition, sleep and respiration in at-risk children treated for obstructive sleep apnoea. Eur Respir J 2005, 25:336–342.CrossRefPubMed
3.
Zorick F, Roehrs T, Wittig R, Lamphere J, Sicklesteel J, Roth T: Sleep-wake abnormalities in narcolepsy. Sleep 1986, 9:189–193.PubMed
4.
Bonnet MH: Sleep restoration as a function of periodic awakening, movement, or electroencephalographic change. Sleep 1987, 10:364–373.PubMed
5.
6.
Stepanski EJ: The effect of sleep fragmentation on daytime function. Sleep 2002, 25:268–276.PubMed
7.
8.
Benveniste EN, Benos DJ: TNF-alpha- and IFN-gamma-mediated signal transduction pathways: effects on glial cell gene expression and function. FASEB J 1995, 9:1577–1584.PubMed
9.
Weiner HL, Selkoe DJ: Inflammation and therapeutic vaccination in CNS diseases. Nature 2002, 420:879–884.CrossRefPubMed
10.
Paredes D, Acosta S, Gemma C, Bickford PC: Role of TNFalpha Induced Inflammation in Delay Eyeblink Conditioning in Young and Aged Rats. Aging Dis 2010, 1:191–198.PubMedPubMedCentral
11.
Ren WJ, Liu Y, Zhou LJ, Li W, Zhong Y, Pang RP, Xin WJ, Wei XH, Wang J, Zhu HQ, et al.: Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-alpha in rodents. Neuropsychopharmacology 2011, 36:979–992.CrossRefPubMedPubMedCentral
12.
Pickering M, Cumiskey D, O’Connor JJ: Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol 2005, 90:663–670.CrossRefPubMed
13.
Butler MP, O’Connor JJ, Moynagh PN: Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neuroscience 2004, 124:319–326.CrossRefPubMed
14.
Cunningham AJ, Murray CA, O’Neill LA, Lynch MA, O’Connor JJ: Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosci Lett 1996, 203:17–20.CrossRefPubMed
15.
Pickering M, O’Connor JJ: Pro-inflammatory cytokines and their effects in the dentate gyrus. Prog Brain Res 2007, 163:339–354.CrossRefPubMed
16.
Tancredi V, D’Arcangelo G, Grassi F, Tarroni P, Palmieri G, Santoni A, Eusebi F: Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neurosci Lett 1992, 146:176–178.CrossRefPubMed
17.
Tobinick E: Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs 2009, 23:713–725.CrossRefPubMed
18.
Maret S, Dorsaz S, Gurcel L, Pradervand S, Petit B, Pfister C, Hagenbuchle O, O’Hara BF, Franken P, Tafti M: Homer1a is a core brain molecular correlate of sleep loss. Proc Natl Acad Sci U S A 2007, 104:20090–20095.CrossRefPubMedPubMedCentral
19.
Szumlinski KK, Kalivas PW, Worley PF: Homer proteins: implications for neuropsychiatric disorders. Curr Opin Neurobiol 2006, 16:251–257.CrossRefPubMed
20.
Cirelli C, Tononi G: Gene expression in the brain across the sleep-waking cycle. Brain Res 2000, 885:303–321.CrossRefPubMed
21.
Cirelli C, Gutierrez CM, Tononi G: Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron 2004, 41:35–43.CrossRefPubMed
22.
Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, Bramham CR: Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 2002, 22:1532–1540.PubMed
23.
Silva AJ: Molecular and cellular cognitive studies of the role of synaptic plasticity in memory. J Neurobiol 2003, 54:224–237.CrossRefPubMed
24.
Wallace CS, Withers GS, Weiler IJ, George JM, Clayton DF, Greenough WT: Correspondence between sites of NGFI-A induction and sites of morphological plasticity following exposure to environmental complexity. Brain Res Mol Brain Res 1995, 32:211–220.CrossRefPubMed
25.
Frey U, Huang YY, Kandel ER: Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science 1993, 260:1661–1664.CrossRefPubMed
26.
27.
Barad M, Bourtchouladze R, Winder DG, Golan H, Kandel E: Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci U S A 1998, 95:15020–15025.CrossRefPubMedPubMedCentral
28.
Zhang HT, Crissman AM, Dorairaj NR, Chandler LJ, O’Donnell JM: Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 2000, 23:198–204.CrossRefPubMed
29.
Cheng YF, Wang C, Lin HB, Li YF, Huang Y, Xu JP, Zhang HT: Inhibition of phosphodiesterase-4 reverses memory deficits produced by Abeta25–35 or Abeta1–40 peptide in rats. Psychopharmacology (Berl) 2010, 212:181–191.CrossRef
30.
Sjostrom PJ, Turrigiano GG, Nelson SB: Rate, timing, and cooperativity jointly determine cortical synaptic plasticity. Neuron 2001, 32:1149–1164.CrossRefPubMed
31.
Huber R, Tononi G, Cirelli C: Exploratory behavior, cortical BDNF expression, and sleep homeostasis. Sleep 2007, 30:129–139.PubMed
32.
Cirelli C, Tononi G: Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system. J Neurosci 2000, 20:9187–9194.PubMed
33.
Braun AR, Balkin TJ, Wesenten NJ, Carson RE, Varga M, Baldwin P, Selbie S, Belenky G, Herscovitch P: Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study. Brain 1997,120(Pt 7):1173–1197.CrossRefPubMed
34.
Vyazovskiy VV, Achermann P, Borbely AA, Tobler I: The dynamics of spindles and EEG slow-wave activity in NREM sleep in mice. Arch Ital Biol 2004, 142:511–523.PubMed
35.
Vyazovskiy V, Borbely AA, Tobler I: Unilateral vibrissae stimulation during waking induces interhemispheric EEG asymmetry during subsequent sleep in the rat. J Sleep Res 2000, 9:367–371.CrossRefPubMed
36.
Huber R, Deboer T, Tobler I: Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations. Brain Res 2000, 857:8–19.CrossRefPubMed
37.
Lydic R, Baghdoyan HA: Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology 2005, 103:1268–1295.CrossRefPubMed
38.
Ramesh V, Thatte HS, McCarley RW, Basheer R: Adenosine and sleep deprivation promote NF-kappaB nuclear translocation in cholinergic basal forebrain. J Neurochem 2007, 100:1351–1363.CrossRefPubMed
39.
McKenna JT, Tartar JL, Ward CP, Thakkar MM, Cordeira JW, McCarley RW, Strecker RE: Sleep fragmentation elevates behavioral, electrographic and neurochemical measures of sleepiness. Neuroscience 2007, 146:1462–1473.CrossRefPubMedPubMedCentral
40.
Sinton CM, Kovakkattu D, Friese RS: Validation of a novel method to interrupt sleep in the mouse. J Neurosci Methods 2009, 184:71–78.CrossRefPubMed
41.
Tartar JL, Ward CP, McKenna JT, Thakkar M, Arrigoni E, McCarley RW, Brown RE, Strecker RE: Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation. Eur J Neurosci 2006, 23:2739–2748.CrossRefPubMedPubMedCentral
42.
Ward CP, McCoy JG, McKenna JT, Connolly NP, McCarley RW, Strecker RE: Spatial learning and memory deficits following exposure to 24 h of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea. Brain Res 2009, 1294:128–137.CrossRefPubMedPubMedCentral
43.
Ramesh V, Kaushal N, Gozal D: Sleep fragmentation modifies EEG delta power during slow wave sleep in socially isolated and paired mice. Sleep Science 2009, 2:64–75.
44.
Espana RA, McCormack SL, Mochizuki T, Scammell TE: Running promotes wakefulness and increases cataplexy in orexin knockout mice. Sleep 2007, 30:1417–1425.PubMedPubMedCentral
45.
Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M: Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci U S A 2010, 107:20518–20522.CrossRefPubMedPubMedCentral
46.
Morris R: Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 1984, 11:47–60.CrossRefPubMed
47.
Gerlai R, Clayton NS: Analysing hippocampal function in transgenic mice: an ethological perspective. Trends Neurosci 1999, 22:47–51.CrossRefPubMed
48.
Nair D, Zhang SX, Ramesh V, Hakim F, Kaushal N, Wang Y, Gozal D: Sleep fragmentation induces cognitive deficits via nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways in mouse. Am J Respir Crit Care Med 2011, 184:1305–1312.CrossRefPubMedPubMedCentral
49.
Nair D, Dayyat EA, Zhang SX, Wang Y, Gozal D: Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS One 2011, 6:e19847.CrossRefPubMedPubMedCentral
50.
Eckeli AL, Dach F, Rodrigues AL: Acute treatments with GMP produce antidepressant-like effects in mice. Neuroreport 2000, 11:1839–1843.CrossRefPubMed
51.
Dias Elpo Zomkowski A, Oscar Rosa A, Lin J, Santos AR, Calixto JB, Lucia Severo Rodrigues A: Evidence for serotonin receptor subtypes involvement in agmatine antidepressant like-effect in the mouse forced swimming test. Brain Res 2004, 1023:253–263.CrossRefPubMed
52.
O’Callaghan JP SK: Focused microwave irradiation of the brain preserves in vivo protein phosphorylation: comparison with other methods of sacrifice and analysis of multiple phosphoproteins. J Neurosci Methods 2004, 135:159–168.CrossRefPubMed
53.
Scharf MT MM, Naidoo N, O’Callaghan JP, Pack AI: AMP-activated protein kinase phosphorylation in brain is dependent on method of killing and tissue preparation. J Neurochem 2008, 3:833–841.CrossRef
54.
Dijk DJ, Hayes B, Czeisler CA: Dynamics of electroencephalographic sleep spindles and slow wave activity in men: effect of sleep deprivation. Brain Res 1993, 626:190–199.CrossRefPubMed
55.
Cajochen C, Foy R, Dijk DJ: Frontal predominance of a relative increase in sleep delta and theta EEG activity after sleep loss in humans. Sleep Res Online 1999, 2:65–69.PubMed
56.
Steriade M, Nunez A, Amzica F: Intracellular analysis of relations between the slow (< 1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J Neurosci 1993, 13:3266–3283.PubMed
57.
Veasey SC, Yeou-Jey H, Thayer P, Fenik P: Murine Multiple Sleep Latency Test: phenotyping sleep propensity in mice. Sleep 2004, 27:388–393.PubMed
58.
Vyazovskiy VV, Tobler I: Theta activity in the waking EEG is a marker of sleep propensity in the rat. Brain Res 2005, 1050:64–71.CrossRefPubMed
59.
Mills PJ, von Kanel R, Norman D, Natarajan L, Ziegler MG, Dimsdale JE: Inflammation and sleep in healthy individuals. Sleep 2007, 30:729–735.PubMedPubMedCentral
60.
Bravo Mde L, Serpero LD, Barcelo A, Barbe F, Agusti A, Gozal D: Inflammatory proteins in patients with obstructive sleep apnea with and without daytime sleepiness. Sleep Breath 2007, 11:177–185.CrossRefPubMed
61.
Minoguchi K, Tazaki T, Yokoe T, Minoguchi H, Watanabe Y, Yamamoto M, Adachi M: Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome. Chest 2004, 126:1473–1479.CrossRefPubMed
62.
Ciftci TU, Kokturk O, Bukan N, Bilgihan A: The relationship between serum cytokine levels with obesity and obstructive sleep apnea syndrome. Cytokine 2004, 28:87–91.CrossRefPubMed
63.
Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP: Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997, 82:1313–1316.CrossRefPubMed
64.
Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP: Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000, 85:1151–1158.CrossRefPubMed
65.
Yue HJ, Mills PJ, Ancoli-Israel S, Loredo JS, Ziegler MG, Dimsdale JE: The roles of TNF-alpha and the soluble TNF receptor I on sleep architecture in OSA. Sleep Breath 2009, 13:263–269.CrossRefPubMedPubMedCentral
66.
El-Sheikh M, Kelly RJ, Buckhalt JA: Benjamin Hinnant J: Children’s sleep and adjustment over time: the role of socioeconomic context. Child Dev 2010, 81:870–883.CrossRefPubMed
67.
Ohayon MM: The effects of breathing-related sleep disorders on mood disturbances in the general population. J Clin Psychiatry 2003, 64:1195–1200. quiz, 1274–1196CrossRefPubMed
68.
File S: Behavioural detection of anxiolytic action. In Experimental Approaches to anxiety and depression Chichester. Edited by: Elliott JM, Heal DJ, Marsden CA. Wiley, UK; 1992:25–44.
69.
Pellow S, Chopin P, File SE, Briley M: Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985, 14:149–167.CrossRefPubMed
70.
Hui-guo L, Kui L, Yan-ning Z, Yong-jian X: Apocynin attenuate spatial learning deficits and oxidative responses to intermittent hypoxia. Sleep Med 2010, 11:205–212.CrossRefPubMed
71.
Djuricic B, Masirevic G, Susic V: Paradoxical sleep deprivation: effects on brain energy metabolism. Arch Int Physiol Biochim 1977, 85:213–219.PubMed
72.
Kalinchuk AV, Urrila AS, Alanko L, Heiskanen S, Wigren HK, Suomela M, Stenberg D, Porkka-Heiskanen T: Local energy depletion in the basal forebrain increases sleep. Eur J Neurosci 2003, 17:863–869.CrossRefPubMed
73.
Vyazovskiy VV, Cirelli C, Tononi G, Tobler I: Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice. Brain Res Bull 2008, 75:591–597.CrossRefPubMed
74.
Nikonova EV, Naidoo N, Zhang L, Romer M, Cater JR, Scharf MT, Galante RJ, Pack AI: Changes in components of energy regulation in mouse cortex with increases in wakefulness. Sleep 2010, 33:889–900.PubMedPubMedCentral
75.
76.
Petit JM, Tobler I, Kopp C, Morgenthaler F, Borbely AA, Magistretti PJ: Metabolic response of the cerebral cortex following gentle sleep deprivation and modafinil administration. Sleep 2010, 33:901–908.PubMedPubMedCentral
77.
Mongrain VHS, Pradervand S, Dorsaz S, Curie T, Hagiwara G, Gip P, Heller HC, Franken P: Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. Sleep 2010, 9:1147–1157.
78.
Fang J, Wang Y, Krueger JM: Mice lacking the TNF 55 kDa receptor fail to sleep more after TNFalpha treatment. J Neurosci 1997, 17:5949–5955.PubMed
79.
Deboer T, Fontana A, Tobler I: Tumor necrosis factor (TNF) ligand and TNF receptor deficiency affects sleep and the sleep EEG. J Neurophysiol 2002, 88:839–846.PubMed
80.
Yoshida H, Peterfi Z, Garcia-Garcia F, Kirkpatrick R, Yasuda T, Krueger JM: State-specific asymmetries in EEG slow wave activity induced by local application of TNFalpha. Brain Res 2004, 1009:129–136.CrossRefPubMed
81.
Baracchi F, Opp MR: Sleep-wake behavior and responses to sleep deprivation of mice lacking both interleukin-1 beta receptor 1 and tumor necrosis factor-alpha receptor 1. Brain Behav Immun 2008, 22:982–993.CrossRefPubMedPubMedCentral
82.
Khalyfa A, Serpero LD, Kheirandish-Gozal L, Capdevila OS, Gozal D: TNF-alpha gene polymorphisms and excessive daytime sleepiness in pediatric obstructive sleep apnea. J Pediatr 2011, 158:77–82.CrossRefPubMed
83.
84.
Kastin AJ, Pan W, Maness LM, Banks WA: Peptides crossing the blood–brain barrier: some unusual observations. Brain Res 1999, 848:96–100.CrossRefPubMed
85.
Cai DJ, Shuman T, Gorman MR, Sage JR, Anagnostaras SG: Sleep selectively enhances hippocampus-dependent memory in mice. Behav Neurosci 2009, 123:713–719.CrossRefPubMed
86.
Patti CL, Zanin KA, Sanday L, Kameda SR, Fernandes-Santos L, Fernandes HA, Andersen ML, Tufik S, Frussa-Filho R: Effects of sleep deprivation on memory in mice: role of state-dependent learning. Sleep 2010, 33:1669–1679.PubMedPubMedCentral
87.
Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown KM, Li XY, Descalzi G, et al.: Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 2009, 461:1122–1125.CrossRefPubMedPubMedCentral
88.
Fonken LK, Finy MS, Walton JC, Weil ZM, Workman JL, Ross J, Nelson RJ: Influence of light at night on murine anxiety- and depressive-like responses. Behav Brain Res 2009, 205:349–354.CrossRefPubMed
89.
Krueger JM, Majde JA, Rector DM: Cytokines in immune function and sleep regulation. Handb Clin Neurol 2011, 98:229–240.CrossRefPubMed
90.
Krueger JM, Taishi P, De A, Davis CJ, Winters BD, Clinton J, Szentirmai E, Zielinski MR: ATP and the purine type 2 X7 receptor affect sleep. J Appl Physiol 2010, 109:1318–1327.CrossRefPubMedPubMedCentral
Metadata
Title
Disrupted sleep without sleep curtailment induces sleepiness and cognitive dysfunction via the tumor necrosis factor-α pathway
Authors
Vijay Ramesh
Deepti Nair
Shelley X L Zhang
Fahed Hakim
Navita Kaushal
Foaz Kayali
Yang Wang
Richard C Li
Alba Carreras
David Gozal
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-91

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