Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice
Introduction
Social defeat stress causes changes in immune function and behavior. In an animal model of social stress termed social disruption (SDR), resident mice are subjected to repeated attack and defeat in their home cage by an aggressive intruder mouse (Stark et al., 2001). Mice that display submissive behaviors during SDR are still attacked by the aggressor (Avitsur et al., 2001). After the 2-h session of SDR, defeated mice show a two-fold increase in plasma corticosterone (Avitsur et al., 2001) demonstrating the high magnitude of the ensuing stress response.
Social defeat has been shown to have immunosuppressive effects. For example, socially defeated mice had reduced mitogen-induced splenocyte proliferation, as compared with handled controls (Beitia et al., 2005). Similarly, splenocytes from socially defeated mice immunized with sheep red blood cells formed significantly fewer plaque-forming and rosette-forming cells than controls (Devoino et al., 2004). Defeat in the SDR model, however, causes an increase in the production of the proinflammatory cytokines IL-1α, IL-6, and TNF-α (Avitsur et al., 2002, Avitsur et al., 2003) and a marked insensitivity to the glucocorticoid hormone corticosterone (Stark et al., 2001). Similar to the observed differences in the immune effects of SDR, the biobehavioral response to SDR may also differ from that of other social stressors.
Social defeat has also been shown to cause lasting behavioral changes in rodents, including the development of anxiety-like behaviors. For example, rats that observed a partner rat as it received inescapable foot shock displayed increased defensive burying, a behavior associated with anxiety (Guttiérrez-García et al., 2006). Similarly in mice, repeated social defeat increased anxiety-like behavior in the light/dark preference test, with defeated mice spending more time in the light area of the apparatus, but had no effects on depressive-like behavior in the Porsolt forced swim test (Keeney and Hogg, 1999). However, mice that received just one 8-min session of social defeat showed increased immobility in the Porsolt forced swim test (Hebert et al., 1998).
The effects of repeated social defeat in the social disruption model on anxiety- and depressive-like behaviors have not been explored. Like the immunological effects of SDR, the behavioral response to social disruption may differ from other social stressors. Thus, this study tested the effects of SDR on anxiety-like and depressive-like behaviors. Changes in cytokine production, splenic cell populations, and glucocorticoid insensitivity were also measured. These effects were measured in both inbred and outbred mouse strains.
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Animals
Male C57BL/6 and CD-1 mice were purchased from Charles River and housed in groups of 3–5 in polycarbonate cages and maintained under 12:12 light cycle in a temperature (21 ± 1 °C) and humidity (50 ± 5%) controlled, Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) accredited facility at the Ohio State University for the duration of this experiment. Standard laboratory diet and tap water were available ad libitum. All mice were aged 8–10 weeks and were experimentally
Experiment 1: Effects of social disruption on anxiety-like behavior in C57BL/6
Social disruption stress caused an increase in anxiety-like behaviors in the light/dark preference test. Individual mice were placed in the corner of the brightly lit box and allowed to freely explore the apparatus. Each mouse moved about and explored the apparatus. Defeated mice spent significantly more time in the smaller, dark box of the apparatus than did non-defeated controls (F(1, 39) = 4.13; p < 0.05; Fig. 1A). Latency to enter the dark box did not differ between treatment groups; both
Discussion
The data confirm and extend previous reports on the effects of repeated social defeat on the immune system (Avitsur et al., 2001, Bailey et al., 2004, Padgett et al., 1998), showing that the noted effects are not limited to inbred mouse strains. Social disruption (SDR) stress resulted in a significant enlargement of the spleen, due to an increase in trafficking of CD11b+ myeloid cells from the bone marrow to the spleen (Engler et al., 2005). In addition, splenocytes from mice exposed to SDR
Acknowledgments
This work would not have been possible without the excellent technical assistance of Amy Hufnagle, Melissa Keeley, Evava Pietri, and Jacqueline Verity. The authors thank Michael Farrow, Natalie Shook, and Scott Wray for editorial assistance with the manuscript. This research was supported by NIH Grants RO1 MH46801-13 and T32 DE014320-04.
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