Anxiogenic Potential of Experimental Sleep Fragmentation Is Duration‐Dependent and Mediated via Oxidative Stress State

Abstract

Sleep architecture alterations, among which sleep fragmentation is highly prevalent, represent risk factors for a variety of diseases, ranging from cardiovascular to brain disorders, including anxiety. What mediates anxiety occurrence upon sleep fragmentation is still a matter of debate. We hypothesized that the sleep fragmentation effects on anxiety are dependent on its duration and mediated by increased oxidative stress and alterations in the number of parvalbumin (PV+) interneurons in the hippocampus. Sleep was fragmented in rats by the treadmill method during a period of 14 days (SF group). Rats with undisturbed sleep in the treadmill (TC group) and those receiving equal amounts of treadmill belt motion (EC group) served as controls. To assess anxiety, we subjected rats to the open field, elevated plus maze, and light-dark tests on the 0, 7th, and 14th day. Upon the last test, brain structures were sampled for oxidative stress assessment and PV+ interneuron immunohistochemistry. The results of ethological tests of anxiety-linked behavior suggested duration-dependent anxiogenic potential of sleep fragmentation. Rats’ anxiety-linked behavior upon sleep fragmentation significantly correlated with oxidative stress. The rats with fragmented sleep (SF) showed significantly higher oxidative stress in the hippocampus, thalamus, and cortex, compared to controls (TC and EC), while the antioxidant enzymes’ activity was significantly decreased. No significant differences were observed in hippocampal PV+ interneurons among these groups. Our results showed that duration of sleep fragmentation is a significant determinant of anxiety-linked behavior, and these effects are mediated through oxidative distress in the brain. Herein, it is revealed that the sleep fragmentation-oxidative stress-anxiety axis contributes to our better understanding of pathophysiological processes, occurring due to disrupted sleep patterns.

Explicit memory, anxiety and depressive like behavior in mice exposed to chronic intermittent hypoxia, sleep fragmentation, or both during the daylight period

“…In the literature there is a discrepancy about the effect of sleep disorders or IH on the motor activity of mice. Some studies have shown similar results to current findings ( Andersen et al, 2005 ; Araujo et al, 2006 ; Meng et al, 2020 ; Onaolapo et al, 2016 ), while others found a modulation of locomotion ( Baitharu et al, 2013 ; Grubac et al, 2019 ; Grubač et al, 2021 ; Yuan et al, 2015 ). The method of fragmentation used in those studies consisted of a treadmill forced locomotion, which can induce per se a reduction in motor activity, and as such the effect may not be attributable to SF.…”

“…As such, future exploration of the temporal trajectories of the performance in each of the cognitive and behavioral tests used herein in the context of SF may uncover heretofore unknown patterns of response. We should remark that sleep deprivation induced by different methods ( Patti et al, 2010 ; Pokk and Väli, 2002 ; Suchecki et al, 2002 ; Tai et al, 2020 ; Yaoita et al, 2020 ) can lead to different alterations in sleep architecture and basal anxiety levels of mice along with evidence of oxidative stress in the brain ( Grubac et al, 2019 ; Grubač et al, 2021 ; Nair et al, 2011a ; Tartar et al, 2009 ).…”

Glutamate, GABA and glutathione in adults with persistent post-concussive symptoms

“…While GSH levels did not differ between PPCS and controls, GSH showed significant positive association with functional impact of headache and daytime sleepiness, although the relationship with sleepiness was not significant after correction for multiple comparisons. Oxidative stress has been linked to various headache disorders, including migraine, that share features with post-traumatic headache ( Geyik et al, 2016 , Ashina et al, 2019 , Capi et al, 2020 ) and is often implicated in pre-clinical models of sleep disruption ( Villafuerte et al, 2015 , Hill et al, 2018 , Grubač et al, 2021 ). We suggest that PPCS symptoms such as headache are related to oxidative stress such that more symptomatic PPCS patients have higher GSH while noting that oxidative stress is not unique to mTBI ( Ghezzi et al, 2018 ) thus levels are still within normal GSH ranges.…”

Neurophysiology of stress: From historical to modern approach

“…Negative stress causes anxiety or withdrawal (depression and anxiety), and is accompanied by unpleasant feelings, reduced work ability leading to mental and physical illnesses (32). Recent studies indicated that anxiety-related behavior in rats can also been enhanced by a lack of sleep and sleep deprivation, which can be considered as stress (33,34). Besides, it has been showed that sleep deprivation can even make brain more susceptible to seizures by changing brain production of interleukins (35).…”