Both subjective and electroencephalographic arousal diminish as a function of the duration of prior wakefulness. Data reported here suggest that the major criteria for a neural sleep factor mediating the somnogenic effects of prolonged wakefulness are satisfied by adenosine, a neuromodulator whose extracellular concentration increases with brain metabolism and which, in vitro, inhibits basal forebrain cholinergic neurons. In vivo microdialysis measurements in freely behaving cats showed that adenosine extracellular concentrations in the basal forebrain cholinergic region increased during spontaneous wakefulness as contrasted with slow wave sleep; exhibited progressive increases during sustained, prolonged wakefulness; and declined slowly during recovery sleep. Furthermore, the sleep-wakefulness profile occurring after prolonged wakefulness was mimicked by increased extracellular adenosine induced by microdialysis perfusion of an adenosine transport inhibitor in the cholinergic basal forebrain but not by perfusion in a control noncholinergic region.Abundant experimental evidence supports the commonsense notion that prolonged wakefulness decreases the degree of arousal, which is usually measured as electroencephalographic activation (EEG arousal to the duration of prior wakefulness (1). What might be the neural mediator of this effect of prior wakefulness? Our laboratory has provided evidence that the basal forebrain and mesopontine cholinergic neurons whose discharge activity plays an integral role in EEG arousal (2) are under the tonic inhibitory control of endogenous adenosine, an inhibition that is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current (3). Adenosine is of particular interest as a putative sleep-wakefulness neuromodulator (4) because (i) the production and concentration of adenosine in the extracellular space have been linked to neuronal metabolic activity (5); (ii) neural metabolism is much greater during wakefulness (W) than during delta slow wave sleep (SWS) (6); and (iii) caffeine and theophylline are powerful blockers of electrophysiologically relevant adenosine receptors, promoting both subjectively and EEGdefined arousal while suppressing recovery sleep after deprivation (7). Our laboratory has recently demonstrated that microdialysis perfusion of adenosine in the cholinergic basal forebrain and the mesopontine cholinergic nuclei reduces wakefulness and EEG arousal (8).Although the preceding evidence is consistent with adenosine as a neural sleep factor mediating the somnogenic effects of prolonged EEG arousal and wakefulness, key questions relevant to a demonstration of this role have remained unaddressed. (i) Are brain extracellular adenosine concentrations higher in spontaneous W than in SWS? (ii) Do adenosine concentrations increase with increasing duration of W and then decline slowly as recovery sleep occurs after W? (iii) Do pharmacological manipulations increasing brain adenosine concentra...

BackgroundSleep restriction, leading to deprivation of sleep, is common in modern 24-h societies and is associated with the development of health problems including cardiovascular diseases. Our objective was to investigate the immunological effects of prolonged sleep restriction and subsequent recovery sleep, by simulating a working week and following recovery weekend in a laboratory environment.Methods and FindingsAfter 2 baseline nights of 8 hours time in bed (TIB), 13 healthy young men had only 4 hours TIB per night for 5 nights, followed by 2 recovery nights with 8 hours TIB. 6 control subjects had 8 hours TIB per night throughout the experiment. Heart rate, blood pressure, salivary cortisol and serum C-reactive protein (CRP) were measured after the baseline (BL), sleep restriction (SR) and recovery (REC) period. Peripheral blood mononuclear cells (PBMC) were collected at these time points, counted and stimulated with PHA. Cell proliferation was analyzed by thymidine incorporation and cytokine production by ELISA and RT-PCR. CRP was increased after SR (145% of BL; p<0.05), and continued to increase after REC (231% of BL; p<0.05). Heart rate was increased after REC (108% of BL; p<0.05). The amount of circulating NK-cells decreased (65% of BL; p<0.005) and the amount of B-cells increased (121% of BL; p<0.005) after SR, but these cell numbers recovered almost completely during REC. Proliferation of stimulated PBMC increased after SR (233% of BL; p<0.05), accompanied by increased production of IL-1β (137% of BL; p<0.05), IL-6 (163% of BL; p<0.05) and IL-17 (138% of BL; p<0.05) at mRNA level. After REC, IL-17 was still increased at the protein level (119% of BL; p<0.05).Conclusions5 nights of sleep restriction increased lymphocyte activation and the production of proinflammatory cytokines including IL-1β IL-6 and IL-17; they remained elevated after 2 nights of recovery sleep, accompanied by increased heart rate and serum CRP, 2 important risk factors for cardiovascular diseases. Therefore, long-term sleep restriction may lead to persistent changes in the immune system and the increased production of IL-17 together with CRP may increase the risk of developing cardiovascular diseases.

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