Social stress and glucocorticoids alter PERIOD2 rhythmicity in the liver, but not in the suprachiasmatic nucleus.

Circadian (~24 h) rhythms in behavior and physiological functions are under control of an endogenous circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN directly drives some of these rhythms or serves as a coordinator of peripheral oscillators residing in other tissues and organs. Disruption of the circadian organization may contribute to disease, including stress-related disorders. Previous research indicates that the master clock in the SCN is resistant to stress, although it is unclear whether stress affects rhythmicity in other tissues, possibly mediated by glucocorticoids, released in stressful situations. In the present study, we examined the effect of uncontrollable social defeat stress and glucocorticoid hormones on the central and peripheral clocks, respectively in the SCN and liver. Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 (PER2) in SCN slices and liver tissue collected after 10 consecutive days of social defeat stress. The rhythmicity of PER2 expression in the SCN was not affected by stress exposure, whereas in the liver the expression showed a delayed phase in defeated compared to non-defeated control mice. In a second experiment, brain slices and liver samples were collected from transgenic mice and exposed to different doses of corticosterone. Corticosterone did not affect PER2 rhythm of the SCN samples, but caused a phase shift in PER2 expression in liver samples. This study confirms earlier findings that the SCN is resistant to stress and shows that clocks in the liver are affected by social stress, which might be due to the direct influence of glucocorticoids released from the adrenal gland.

Chronic social defeat stress suppresses locomotor activity but does not affect the free-running circadian period of the activity rhythm in mice.

In mammals, daily rhythms in behavior and physiology are under control of an endogenous clock or pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN assures an optimal temporal organization of internal physiological process and also synchronizes rhythms in physiology and behavior to the cyclic environment. The SCN receives direct light input from the retina, which is capable of resetting the master clock and thereby synchronizes internally driven rhythms to the external light-dark cycle. In keeping with its function as a clock and pacemaker, the SCN appears to be well buffered against influences by other stimuli and conditions that contain no relevant timing information, such as acute stressors. On the other hand, it has been suggested that chronic forms of stress may have gradually accumulating effects that can disturb normal clock function and thereby contribute to stress-related disorders. Therefore, in the present study we investigated whether chronic intermittent social stress affects the endogenous period and phase of the free-running activity rhythm in mice. Adult male mice were maintained in constant dim red light conditions and exposed to a daily 20 min social defeat stress session for 10 consecutive days, either during the first half of their activity phase or the first half of their resting phase. The overall amount of running wheel activity was strongly suppressed during the 10 days of social defeat, to about 50% of the activity in non-defeated control mice. Activity levels gradually normalized during post-defeat recovery days. Despite the strong suppression of activity in defeated animals, the endogenous free-running circadian period of the activity rhythm and the phase of activity onset were not affected. These findings are thus in agreement with earlier studies suggesting that the circadian pacemaker in the SCN that is driving the rhythmicity in activity is well-protected against stress. Even severe social defeat stress for 10 consecutive days, which has a major effect on the levels of activity, does not affect the pace of the endogenous clock.