Repeated psychosocial stress at night, but not day, affects the central molecular clock

Abstract

We have recently demonstrated that the outcome of repeated social defeat (SD) on behavior, physiology and immunology is more negative when applied during the dark/active phase as compared with the light/inactive phase of male C57BL/6 mice. Here, we investigated the effects of the same stress paradigm, which combines a psychosocial and novelty stressor, on the circadian clock in transgenic PERIOD2::LUCIFERASE (PER2::LUC) and wildtype (WT) mice by subjecting them to repeated SD, either in the early light phase (social defeat light = SDL) or in the early dark phase (social defeat dark = SDD) across 19 days. The PER2::LUC rhythms and clock gene mRNA expression were analyzed in the suprachiasmatic nucleus (SCN) and the adrenal gland, and PER2 protein expression in the SCN was assessed. SDD mice showed increased PER2::LUC rhythm amplitude in the SCN, reduced Per2 and Cryptochrome1 mRNA expression in the adrenal gland, and increased PER2 protein expression in the posterior part of the SCN compared with single-housed control (SHC) and SDL mice. In contrast, PER2::LUC rhythms in the SCN of SDL mice were not affected. However, SDL mice exhibited a 2-hour phase advance of the PER2::LUC rhythm in the adrenal gland compared to SHC mice. Furthermore, plasma levels of brain-derived neurotrophic factor (BDNF) and BDNF mRNA in the SCN were elevated in SDL mice. Taken together, these results show that the SCN molecular rhythmicity is affected by repeated SDD, but not SDL, while the adrenal peripheral clock is influenced mainly by SDL. The observed increase in BDNF in the SDL group may act to protect against the negative consequences of repeated psychosocial stress.

Stress-Related and Circadian Secretion and Target Tissue Actions of Glucocorticoids: Impact on Health

“…Therefore, the circadian rhythm in peripheral clocks phase shifts from that of central clock under the regulation of the HPA axis, leading to transient uncoupling of the central and peripheral clocks (48). Following termination of the acute stress, the central clock can reset peripheral clocks to their initial phase within a few days (65, 83). hGRα-induced transcriptional activity may be influenced by phase-shifted peripheral clocks in local tissues, but the specific mechanisms remain to be elucidated (Figure 2).…”

The mammalian circadian clock and its entrainment by stress and exercise

“…However, the SCN clock is sometimes affected by long-term stressors [22–25]. Kinoshita et al [23], for example, demonstrated that 3 h of restraint stress at Zeitgeber time (ZT)6–9 for 7 consecutive days produced elevated glycogen synthase kinase (GSK)-3β phosphorylation and blunted PER2 rhythms in the SCN of mice (ZT0 and 12 are defined as the start and end of the light period, respectively).…”

“…Kinoshita et al [23], for example, demonstrated that 3 h of restraint stress at Zeitgeber time (ZT)6–9 for 7 consecutive days produced elevated glycogen synthase kinase (GSK)-3β phosphorylation and blunted PER2 rhythms in the SCN of mice (ZT0 and 12 are defined as the start and end of the light period, respectively). In addition, 19 days of social defeat stress during the day or night induced changes in the expression of Per2 and Cry1 in the SCN of mice [22]. Moreover, chronic (4 weeks) mild stress caused decreased amplitude of PER2 rhythms in the SCN of rats, whereas 7 days of mild stress caused no alterations [25].…”

Repeated Psychosocial Stress at Night Affects the Circadian Activity Rhythm of Male Mice

“…The C57BL/6N substrain was used in our previous study (Bartlang et al, 2012;Bartlang et al, 2014), whereas the C57BL/6J substrain served as an adequate congenic control group for the Per1/2 double mutants that carried this genetic background. The C57BL/6N substrain was used in our previous study (Bartlang et al, 2012;Bartlang et al, 2014), whereas the C57BL/6J substrain served as an adequate congenic control group for the Per1/2 double mutants that carried this genetic background.…”

“…Yet, exposure of rats to a novel environment or restraint stress, as psychological means to raise GC levels, resulted in stronger hypothalamic-pituitary-adrenal (HPA) axis responses at early day compared with early night. SD during the early dark phase (zeitgeber time [ZT] 13 to ZT15; social defeat dark [SDD]), but not during the early light phase (ZT1-ZT3; social defeat light [SDL]), resulted in blunted activity rhythms, flattened or shifted GC rhythms (Bartlang et al, 2012), and increased PER2 protein expression and PER2 rhythm amplitudes in the SCN (Bartlang et al, 2014). In line, we have previously shown that repeated social defeat (SD) has different effects on the central clock in the SCN and peripheral output rhythms, depending on the time of day of stressor exposure.…”