Abstract
Psychological stressors prominently affect diurnal rhythms, including locomotor activity, sleep, blood pressure, and body temperature, in humans. Here, we found that a novel continuous stress imposed by the perpetual avoidance of water on a wheel (PAWW) affected several physiological diurnal rhythms in mice. One week of PAWW stress decayed robust circadian locomotor rhythmicity, while locomotor activity was evident even during the light period when the mice are normally asleep. Daytime activity was significantly upregulated, whereas nighttime activity was downregulated, resulting in a low amplitude of activity. Total daily activity gradually decreased with increasing exposure to PAWW stress. The mice could be exposed to PAWW stress for over 3 weeks without adaptation. Furthermore, continuous PAWW stress enhanced food intake, but decreased body weight and plasma leptin levels, indicating that sleep loss and PAWW stress altered the energy balance in these mice. The diurnal rhythm of corticosterone levels was not severely affected. The body temperature rhythm was diurnal in the stressed mice, but significantly dysregulated during the dark period. Plasma catecholamines were elevated in the stressed mice. Continuous PAWW stress reduced the duration of daytime sleep, especially during the first half of the light period, and increased nighttime sleepiness. Continuous PAWW stress also simultaneously obscured sleep/wake and locomotor activity rhythms compared with control mice. These sleep architecture phenotypes under stress are similar to those of patients with insomnia. The stressed mice could be entrained to the light/dark cycle, and when they were transferred to constant darkness, they exhibited a free-running circadian rhythm with a timing of activity onset predicted by the phase of their entrained rhythms. Circadian gene expression in the liver and muscle was unaltered, indicating that the peripheral clocks in these tissues remained intact.
Highlights
Exposure to stress is related to an increase in the incidence of various psychiatric illnesses, anxiety, and mood disorders in humans [1]
The mice were more active under L:D during the night and less active during the day, which is normal for nocturnal mice
Total locomotor activity was significantly enhanced on the first day of exposure to perpetual avoidance of water on a wheel (PAWW) stress, when the mice ran on the wheels almost all day
Summary
Exposure to stress is related to an increase in the incidence of various psychiatric illnesses, anxiety, and mood disorders in humans [1]. Abnormal circadian rhythms, sleep disorders, and psychiatric illnesses can be inseparably linked and mutually regulated. The circadian clock regulates the daily rhythms of the sleep/wake cycles, body temperature (BT), hormone levels, and even cognition, attention, and mood. The molecular basis of circadian rhythm generation has been extensively studied, and circadian rhythms are generated from interacting transcriptional translational feedback loops involving clock genes such as Clock, Bmal, Periods, and Crys [7]. Mood stabilizers, such as lithium chloride, which are used to treat these disorders, can restore the circadian clock [8]. Lithium chloride inhibits GSK3b activity and stabilizes PER2 protein [9], whereas chronic stress reduces PER2 protein expression in the brains of mice with reduced activity [10,11]
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