Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013;8(4):e60133.
doi: 10.1371/journal.pone.0060133. Epub 2013 Apr 2.

Social Agonistic Distress in Male and Female Mice: Changes of Behavior and Brain Monoamine Functioning in Relation to Acute and Chronic Challenges

Affiliations
Free PMC article

Social Agonistic Distress in Male and Female Mice: Changes of Behavior and Brain Monoamine Functioning in Relation to Acute and Chronic Challenges

Shlomit Jacobson-Pick et al. PLoS One. .
Free PMC article

Abstract

Stressful events promote several neuroendocrine and neurotransmitter changes that might contribute to the provocation of psychological and physical pathologies. Perhaps, because of its apparent ecological validity and its simple application, there has been increasing use of social defeat (resident-intruder) paradigms as a stressor. The frequency of stress-related psychopathology is much greater in females than in males, but the typical resident-intruder paradigm is less useful in assessing stressor effects in females. An alternative, but infrequently used procedure in females involves exposing a mouse to a lactating dam, resulting in threatening gestures being expressed by the resident. In the present investigation we demonstrated the utility of this paradigm, showing that the standard resident-intruder paradigm in males and the modified version in females promoted elevated anxiety in a plus-maze test. The behavioral effects that reflected anxiety were more pronounced 2 weeks after the stressor treatment than they were 2 hr afterward, possibly reflecting the abatement of the stress-related of hyper-arousal. These treatments, like a stressor comprising physical restraint, increased plasma corticosterone and elicited variations of norepinephrine and serotonin levels and turnover within the prefrontal cortex, hippocampus and central amygdala. Moreover, the stressor effects were exaggerated among mice that had been exposed to a chronic or subchronic-intermittent regimen of unpredictable stressors. Indeed, some of the monoamine changes were more pronounced in females than in males, although it is less certain whether this represented compensatory changes to deal with chronic stressors that could result in excessive strain on biological systems (allostatic overload).

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Experimental design of experiments 1, 2 and 3.
In Experiment 1, mice were assigned to either nonstressed, a restraint stressor, or a social stressor conditions. 3 minutes following the stressor session, trunk blood was collected for corticosterone determination. Mice brains were rapidly removed and mPFC, hippocampus and amygdala were collected for subsequent High-performance liquid chromatography (HPLC) analyses (Fig. 1A). In Experiment 2, male and female mice were assigned to either a nonstressed, acute stressor, chronic stressor, or subchronic-intermittent stressor. Nonstressed mice left undisturbed over the course of the experiment, the acute stressor group were exposed to a single social stressor, chronic stressor group were stressed daily for 21 consecutive days and the subchronic- intermittent condition mice were stressed 7 times over 21 days period. Mice in the chronic stressor and subchronic- intermittent conditions were exposed to the following stressors: tight restraint, forced swim, wet bedding, tail pinch, soiled bedding, startle stimulus and on the last day mice undergone social stressor. Three minutes after the social stressor, mice were decapitated and blood and brain samples collected as described in Experiment 1 (Fig. 1B). Experiment 3, was conducted to assess the effects of the stressor conditions, precisely as described in Experiment 2, on anxiety-related behaviors measured on an elevated plus maze 2 hr and then again 2 weeks following exposure to the stressor conditions (Fig. 1C).
Figure 2
Figure 2. NE and 5-HT variations in the prefrontal cortex following an acute stressor.
Mean (±SEM) concentration of MHPG and NE (Panels A and B) and 5-HIAA and 5-HT (Panels C and D) of the prefrontal cortex (PFC) among male and female mice that had experienced either no stress, restraint for 15 min, or a resident-intruder stressor. In males, the resident-intruder paradigm was essentially the same as that used in most social defeat paradigms (an intruder is placed in the cage of a resident who then defends his territory), whereas in females the paradigm comprised mice being placed in the cage of a lactating dam. *p<.05 relative to nonstressed mice of the same sex.
Figure 3
Figure 3. NE and 5-HT variations in the hippocampus following an acute stressor.
Mean (± SEM) concentration of hippocampal MHPG and NE (Panels A and B) and 5-HIAA and 5-HT (Panels C and D) among male and female mice that had experienced either no stress, restraint for 15 min, or a resident-intruder stressor. *p<.05 relative to nonstressed mice of the same sex.
Figure 4
Figure 4. NE and 5-HT variations in the amygdala following an acute stressor.
Mean (± SEM) concentration of MHPG and NE (Panels A and B) and 5-HIAA and 5-HT (Panels C and D) of the central amygdala among male and female mice that had experienced either no stress, restraint for 15 min, or a resident-intruder stressor. *p<.05 relative to nonstressed mice of the same sex.
Figure 5
Figure 5. Corticosterone levels following an acute stressor.
Mean (± SEM) plasma corticosterone concentrations (µg/dl) among male (upper) and female (lower) mice that had experienced either no stress, restraint for 15 min, or a resident-intruder stressor. *p<.05 relative to nonstressed mice of the same sex. # p<.05 relative to acutely stressed mice.
Figure 6
Figure 6. NE variations in the prefrontal cortex following chronic, sub-chronic and acute stressors.
Mean (± SEM) concentration of MHPG and NE in the prefrontal cortex of male (Panels A and B) and female mice (Panel C and D) that had not been stressed (control), exposed to an acute stressor (resident intruder paradigms for the two sexes), a subchronic-intermittent stressor (7 stress sessions over 21 days) followed by the resident-intruder paradigm on Day 22, or a chronic stressor (variable stressor exposure on each off 21 days) followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice.
Figure 7
Figure 7. 5-HT variations in the prefrontal cortex following chronic, subchronic-intermittent and acute stressors.
Mean (± SEM) concentration of 5-HIAA and 5-HT in the prefrontal cortex of male (Panels A and B) and female mice (Panel C and D) that had not been stressed (control),exposed to an acute stressor (resident intruder paradigms for the two sexes), a subchronic-intermittent stressor (7 stress sessions over 21 days) followed by the resident-intruder paradigm on Day 22, or a chronic stressor (variable stressor exposure on each off 21 days) followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice.
Figure 8
Figure 8. NE variations in the hippocampus following chronic, subchronic-intermittent and acute stressors.
Mean (± SEM) concentration of MHPG and NE in the hippocampus of male (Panels A and B) and female mice (Panel C and D) that had not been stressed (control), exposed to an acute stressor (resident intruder paradigms for the two sexes), a subchronic-intermittent stressor followed by the resident-intruder paradigm, or a chronic stressor followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice.
Figure 9
Figure 9. NE variations in the central amygdala following chronic, subchronic-intermittent and acute stressors.
Mean (± SEM) concentration of MHPG and NE in the central amygdala of male (Panels A and B) and female mice (Panel C and D) that had not been stressed (control), exposed to an acute stressor (resident intruder paradigms for the two sexes), a subchronic-intermittent stressor followed by the resident-intruder paradigm, or a chronic stressor followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice of the same sex. # p<.05 relative to acutely stressed mice.
Figure 10
Figure 10. 5-HT variations in the central amygdala following chronic, subchronic-intermittent and acute stressors.
Mean (± SEM) concentration of 5-HIAA and 5-HT in the central amygdala of male (Panels A and B) and female mice (Panel C and D) that had not been stressed (control), exposed to an acute stressor (resident intruder paradigms for the two sexes), a subchronic-intermittent stressor followed by the resident-intruder paradigm, or a chronic stressor followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice of the same sex.
Figure 11
Figure 11. Effects of chronic, subchronic-intermittent and acute stressors on anxiety-related behaviors in male mice.
Mean (± SEM) stretch attend responses (A), latency to enter the open arms (B), Time in the open Arms (C), Number of entries into the open arms (D), Time in the closed arms (E) and number of entries into the closed arms 2 he and again 2 weeks following treatment. Male mice had either not been stressed (control), exposed to an acute stressor (resident intruder paradigms for the two sexes), a subchronic-intermittent stressor followed by the resident-intruder paradigm, or a chronic stressor followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice. o p<.05 relative to performance measured 2 hr following the treatment.
Figure 12
Figure 12. Effects of chronic, subchronic-intermittent and acute stressors on anxiety-related behaviors in female mice.
Mean (± SEM) stretch attend responses (A), latency to enter the open arms (B), Time in the open Arms (C), Number of entries into the open arms (D), Time in the closed arms (E) and number of entries into the closed arms 2 he and again 2 weeks following treatment. Female mice had either not been stressed (control), exposed to an acute stressor (resident intruder paradigms for the two sexes), a sub subchronic-intermittent chronic stressor followed by the resident-intruder paradigm, or a chronic stressor followed by the resident-intruder stressor. *p<.05 relative to nonstressed mice. o p<.05 relative to performance measured 2 hr following the treatment.

Similar articles

See all similar articles

Cited by 18 articles

See all "Cited by" articles

References

    1. Anisman H, Gibb J, Hayley S (2008) Influence of continuous infusion of interleukin-1 beta on depression-related processes in mice: corticosterone, circulating cytokines, brain monoamines, and cytokine mRNA expression. Psychopharmacology (Berl) 199(2): 231–244. - PubMed
    1. McEwen BS (2012) Brain on stress: How the social environment gets under the skin. Proc Natl Acad Sci U S A 109(2): 17180–17185. - PMC - PubMed
    1. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB (1993) Sex and depression in the National Comorbidity Survey. I: lifetime prevalence, chronicity and recurrence. J Affect Disord 29 (2–3): 85–96. - PubMed
    1. Seedat S, Scott KM, Angermeyer MC, Berglund P, Bromet EJ, et al. (2009) Cross-National Associations between Gender and Mental Disorders in the World Health Organization World Mental Health Surveys. Arch Gen Psychiatry 66(7): 785–795. - PMC - PubMed
    1. Cohen H, Yehuda R (2011) Gender differences in animal models of posttraumatic stress disorder. Dis Markers 30(2–3): 141–150. Review. - PMC - PubMed

Publication types

Grant support

The research was supported by the Natural Sciences and Engineering Research Council of Canada. HA holds a Canada Research Chair in Neuroscience. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Feedback