Chronic Sleep Restriction Disrupts Sleep Homeostasis and Behavioral Sensitivity to Alcohol by Reducing the Extracellular Accumulation of Adenosine

Abstract

Sleep impairments are comorbid with a variety of neurological and psychiatric disorders including depression, epilepsy, and alcohol abuse. Despite the prevalence of these disorders, the cellular mechanisms underlying the interaction between sleep disruption and behavior remain poorly understood. In this study, the impact of chronic sleep loss on sleep homeostasis was examined in C57BL/6J mice following 3 d of sleep restriction. The electroencephalographic power of slow-wave activity (SWA; 0.5-4 Hz) in nonrapid eye movement (NREM) sleep and adenosine tone were measured during and after sleep restriction, and following subsequent acute sleep deprivation. During the first day of sleep restriction, SWA and adenosine tone increased, indicating a homeostatic response to sleep loss. On subsequent days, SWA declined, and this was accompanied by a corresponding reduction in adenosine tone caused by a loss of one source of extracellular adenosine. Furthermore, the response to acute sleep deprivation (6 h) was significantly attenuated in sleep-restricted mice. These effects were long-lasting with reduced SWA and adenosine tone persisting for at least 2 weeks. To investigate the behavioral consequences of chronic sleep restriction, sensitivity to the motor-impairing effects of alcohol was also examined. Sleep-restricted mice were significantly less sensitive to alcohol when tested 24 h after sleep restriction, an effect that persisted for 4 weeks. Intracerebroventricular infusion of an adenosine A1 receptor antagonist produced a similar decrease in sensitivity to alcohol. These results suggest that chronic sleep restriction induces a sustained impairment in adenosine-regulated sleep homeostasis and consequentially impacts the response to alcohol.

Response to chronic sleep restriction, extension, and subsequent total sleep deprivation in humans: adaptation or preserved sleep homeostasis?

“…Ref. 24), in some rodent studies allostasis was referred to as an additional process needed in order to explain the absence or attenuation of a homeostatic response under chronic sleep restriction conditions [20,22,23]. In our study, we investigated whether a deviation from a homeostatic response (adaptation) could be observed, similar to the allostasis concept of Kim et al [23].…”

“…Other animal studies reported an initial increase in SWA after which SWA values were maintained at or fell below baseline [22,23]. This attenuated or missing homeostatic response to sleep restriction was implicitly assumed to reflect an allostatic response [20,22,23]. Whether this interpretation is in line with the original definition of allostasis can be discussed (see Discussion) [21,24].…”

“…Clasadonte et al [22] reported an attenuated response to acute sleep deprivation in sleep restricted mice. In our study, however, participants showed an intact homeostatic response to total sleep deprivation (sustained wakefulness for 41 hr after sleep restriction).…”

“…Furthermore, adenosine receptor upregulation increases vulnerability to performance impairment during waking [47]. In rodents, sleep deprivation led to adenosine-dependent inhibition of synaptic activity, and this effect was attenuated during the 3 days of sleep restriction [22]. It is also conceivable that allostatic changes are different biological responses to chronic sleep restriction which act to adjust the set point of the homeostatic equilibrium to keep homeostasis functional [48].…”

“…Within this context, allostasis refers to an adaptive response to a change in an environment, which maintains stability through physiological or behavioral changes [21]. Other animal studies reported an initial increase in SWA after which SWA values were maintained at or fell below baseline [22,23]. This attenuated or missing homeostatic response to sleep restriction was implicitly assumed to reflect an allostatic response [20,22,23].…”