Time matters: pathological effects of repeated psycho social stress during the active, but not inactive, phase of male mice

Abstract

Recent findings in rats employing repeated restraint stress indicated that the physiological consequences of stressor exposure are strongly dependent on the time of day of stressor exposure. To investigate whether this is also true for clinically more relevant chronic/repeated psychosocial stressors and whether repeated stressor exposure during light- or dark-phase is more detrimental for an organism, we exposed male C57BL/6 mice to social defeat (SD; 2 h) for 19 consecutive days (except day 7 and 14) either in the light-phase between Zeitgeber-time (ZT)1 and ZT3 (SDL mice) or in the dark-phase between ZT13 and ZT15 (SDD mice) and compared them with single-housed control mice in four different experiments. While SDL mice showed a more prolonged increase in adrenal weight and an attenuated adrenal responsiveness to ACTH in vitro after stressor termination, SDD mice showed reduced dark-phase home-cage activity on observation days 7, 14 and 20, flattening of the diurnal corticosterone rhythm, lack of social preference towards an unfamiliar male conspecific and higher in vitro IFN-γ secretion from mesenteric lymph node cells on day 20/21. In addition, the colitis-aggravating effect of stressor exposure was more pronounced in SDD than SDL mice, indicated by increased body weight loss and inflammatory shortening of the colon following 8 days of dextran sulphate sodium treatment. In conclusion, the present findings demonstrate that chronic/intermittent SD effects on behaviour, physiology and immunology strongly depend on the time of day of stressor exposure. While physiological parameters were more affected by SD during the light-phase, that is, the inactive phase of mice, behavioural and immunological parameters were more affected by SD during the dark-phase. Our results imply that repeated daily psychosocial stressor exposure has a more negative outcome when applied during the dark/active phase. In contrast, the minor physiological changes seen in SDL mice might represent beneficial adaptations preventing the formation of those maladaptive consequences. Grant Support: This study was supported by the Deutsche Forschungsgemeinschaft (DFG FO-207/13-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords

• psychosocial stress
• social defeat
• time of day
• light-phase
• dark-phase
• behaviour
• physiology
• immunology