Acute Social Defeat Stress Increases Sleep in Mice

Abstract

Social conflict is a major source of stress in humans. Animals also experience social conflicts and cope with them by stress responses that facilitate arousal and activate sympathetic and neuroendocrine systems. The effect of acute social defeat (SoD) stress on the sleep/wake behavior of mice has been reported in several models based on a resident-intruder paradigm. However, the post-SoD stress sleep/wake effects vary between the studies and the contribution of specific effects in response to SoD or non-specific effects of the SoD procedure (e.g., sleep deprivation) is not well established. In this study, we established a mouse model of acute SoD stress based on strong aggressive mouse behavior toward unfamiliar intruders. In our model, we prevented severe attacks of resident mice on submissive intruder mice to minimize behavioral variations during SoD. In response to SoD, slow-wave sleep (SWS) strongly increased during 9 h. Although some sleep changes after SoD stress can be attributed to non-specific effects of the SoD procedure, most of the SWS increase is likely a specific response to SoD. Slow-wave activity was only enhanced for a short period after SoD and dissipated long before the SWS returned to baseline. Moreover, SoD evoked a strong corticosterone response that may indicate a high stress level in the intruder mice after SoD. Our SoD model may be useful for studying the mechanisms and functions of sleep in response to social stress.

Keywords: homeostatic sleep need; mouse model; slow-wave activity; slow-wave sleep; social defeat stress.

FIGURE 1

Protocol for social defeat (SoD) stress based on a resident-intruder paradigm. (A) Schedule of sleep recording and SoD session. (B) Cage used for SoD or EEG/EMG recording and partition for diagonal separation of the cage. (C) Cage with inserted partition. (D) Schematic diagram of the SoD procedure. The intruder mouse was placed behind the partition of the resident cage. The partition was repeatedly removed for multiple defeat experiences of the intruder mouse by the resident mouse during a 1-h period. After the SoD session, the intruder mouse was returned to the home cage for sleep recording. (E) Control experiments to differentiate between the specific effects of SoD and non-specific effects of the SoD procedure. The mouse was placed in the cage for 1 h under each condition.

FIGURE 2

Slow-wave sleep (SWS) increased after social defeat (SoD) stress. (A) Time-course of SWS, rapid eye movement sleep (REMS), and wakefulness for 21 h after SoD sessions with two (n = 8), four (n = 8), or eight (n = 7) defeats. ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001 compared with baseline, assessed by two-way repeated measures ANOVA followed by Bonferroni’s post hoc comparisons. (B) Time-course of SWS, REMS, and wakefulness for 3 h after SoD sessions. ^∗P < 0.05 compared with baseline, assessed by paired two-tailed Student’s t-test. (C) Total amounts of SWS, REMS, and wakefulness for 9 h after SoD sessions. ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001 compared with baseline, assessed by paired two-tailed Student’s t-test. (D) Changes in total amounts of SWS, REMS, and wakefulness for 9 h between baseline and after SoD sessions. ^∗P < 0.05, compared between groups, assessed by the Kruskal–Wallis test (SWS and wakefulness) or one-way ANOVA (REMS) followed by Bonferroni’s post hoc comparisons. (E) Deviation of changes in total amounts of SWS and wakefulness. The deviation was calculated by subtracting the mean from the experimental values of each animal for changes in the total amounts of SWS and wakefulness for 9 h in each condition. ^∗P < 0.05 and ^∗∗P < 0.01, compared between groups, assessed by one-way ANOVA followed by Bonferroni’s post hoc comparisons. (F) Blood plasma corticosterone levels from undisturbed mice (n = 6) at zeitgeber time 12 of the baseline day or mice after a “No resident” (n = 7) or SoD sessions (n = 6). ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001 compared between groups, assessed by one-way ANOVA followed by Bonferroni’s post hoc comparisons. Data are presented as means ± SEM. NS, not significant.

FIGURE 3

Social defeat (SoD) is essential for a strong slow-wave sleep (SWS) increase. (A) Total amounts of SWS, rapid eye movement sleep (REMS), and wakefulness for 9 h after a “Sleep deprivation” (n = 4), “No resident” (n = 4), “No contact” (n = 8), or SoD (n = 8) session with four defeats. ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001 compared with baseline, assessed by paired two-tailed Student’s t-test. (B) Changes in the total amounts of SWS, REMS, and wakefulness for 9 h between baseline and experimental days. ^∗P < 0.05, ^∗∗P < 0.01, and ^∗∗∗P < 0.001 compared with SoD, assessed by one-way ANOVA followed by Dunnett’s post hoc comparisons. Data are presented as means ± SEM. NS, not significant.

FIGURE 4

Sleep architecture after social defeat (SoD) stress. (A–C) Episode numbers (A), mean episode durations (B), and numbers of stage transitions (C) for 9 h after SoD session with four defeats. ^∗P < 0.05 and ^∗∗P < 0.01 compared with baseline, assessed by paired two-tailed Student’s t-test. (D) Power density of EEG during SWS for 30 min after SoD session with four defeats or onset of the dark phase on the baseline day. ^∗P < 0.05 compared with baseline, assessed by two-way repeated measures ANOVA followed by Bonferroni’s post hoc comparisons. (E) Changes in the SWA (0.5–4 Hz) relative to the baseline for 30 min after a “Sleep deprivation,” “No resident,” “No contact,” or SoD session. ^∗P < 0.05 compared with baseline, assessed by paired two-tailed Student’s t-test, #P < 0.05 compared with SoD, assessed by one-way ANOVA followed by Dunnett’s post hoc comparisons. (F) Time-course of SWA changes after SoD session. ^∗∗∗P < 0.001 compared with baseline, assessed by two-way repeated measures ANOVA followed by Bonferroni’s post hoc comparisons.