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

Abstract

BackgroundSleepiness 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.MethodsThe 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.ResultsMice 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.ConclusionsTaken 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.

Early-life physical activity reverses metabolic and Foxo1 epigenetic misregulation induced by gestational sleep disturbance

“…1) (23, 36, 41). The SF paradigm does not elicit increases in stress hormones and after short reductions in rapid eye movement sleep during the initial 12-24 h of SF, sleep recovery occurs with normalization of overall sleep duration and sleep state distribution (36,41). Furthermore, SF during late gestation did not affect the litter size and birth weight.…”

“…To induce moderate to severe sleep fragmentation, we chose a 2-min interval between each sweep, implemented during the light period (7 AM to 7 PM). This paradigm is not associated with any increases in the plasma levels of the stress hormones (36,41). Pregnant mice were sleepfragmented from day 14 until day 19 of gestation.…”

“…The sleep fragmentation device used to induce SF in rodents has been previously described (23,36,41) and employs intermittent tactile stimulation of freely behaving mice in a standard laboratory mouse cage, using a near-silent motorized mechanical sweeper (model no. 80391, LaFayette Instruments, LaFayette, IN).…”

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

“…More importantly, the induction of low-grade inflammation by sleep deprivation has been recognized as a pathological consequence that has the potential for causing various morbidities, especially by inducing low-grade inflammation [22][23][24][25][26] . Low-grade oxidative stress and neuroinflammation typically precede clinical symptoms of neurodegeneration 27 .…”

Reduced NADPH oxidase type 2 activity mediates sleep fragmentation-induced effects on TC1 tumors in mice

“…15,26,27 3-mo-old WT and gp91 phox-/Y mice were exposed to either SF or normal sleep conditions (SC; the SF cage was used but the sweeper remained immobile). To induce moderate to severe SF, we chose a 2-min interval between each sweep, implemented during the light period (7:00 am-7:00 pm).…”