Dominance status alters restraint-induced neural activity in brain regions controlling stress vulnerability

Abstract

Understanding the cellular mechanisms that control resistance and vulnerability to stress is an important step toward identifying novel targets for the prevention and treatment of stress-related mental illness. In Syrian hamsters, dominant and subordinate animals exhibit different behavioral and physiological responses to social defeat stress, with dominants showing stress resistance and subordinates showing stress vulnerability. We previously found that dominant and subordinate hamsters show different levels of defeat-induced neural activity in brain regions that modulate coping with stress, although the extent to which status-dependent differences in stress vulnerability generalize to non-social stressors is unknown. In this study, dominant, subordinate, and control male Syrian hamsters were exposed to acute physical restraint for 30min and restraint-induced c-Fos immunoreactivity was quantified in select brain regions. Subordinate animals showed less restraint-induced c-Fos immunoreactivity in the infralimbic (IL), prelimbic (PL), and ventral medial amygdala (vMeA) compared to dominants, which is consistent with the status-dependent effects of social defeat stress. Subordinate animals did not show increased c-Fos immunoreactivity in the rostroventral dorsal raphe nucleus (rvDRN), which is in contrast to the effects of social defeat stress. These findings indicate that status-dependent changes in neural activity generalize from one stressor to another in a brain region-dependent manner. These findings further suggest that while some neural circuits may support a generalized form of stress resistance, others may provide resistance to specific stressors.

Keywords: Anxiety; Coping; Dorsal raphe nucleus; Medial amygdala; Resilience; Social dominance.

Figure 1

A) Stereotaxic atlas images indicate the location of brain regions selected for c-Fos quantification [71]. Although some boxes are indicated unilaterally for bilateral brain regions, images were collected from both hemispheres when possible. Values on the right side indicate distance from bregma. Dimensions of the photomicrographs used for quantification were as follows: 870 × 660 μm (PL, IL, dMeA, vMeA); 440 × 330 μm (PVN); 500 × 300 μm (rdDRN, cdDRN, lDRN); 250 × 300 μm (rvDRN, cvDRN). B) Representative photomicrographs at 4× magnification for each of the regions of interest. Black nuclear staining represent c-Fos positive cells and scale bars are 500 μM.

Figure 2

The number (mean ± SEM) of c-Fos immunopositive cells were quantified in (a) the IL, PL, dMeA, vMeA, and PVN, as well as in (b) several subdivisions of the DRN. Dominant and subordinate animals were exposed to daily dyadic encounters for two weeks during which time they established a dominance relationship. Then, dominant, subordinate, and social status control animals received 30 min physical restraint, whereas handled controls did not establish dominance status and were unrestrained. Sample sizes range 8–10 per group. * indicates a significant difference compared to all other groups in that brain region (p < 0.05).^a indicates a significant difference compared to dominants in that brain region (p < 0.05).^b indicates a significant difference compared to dominants and social status controls in that brain region (p < 0.05).^c indicates a significant difference compared to handled controls in that brain region (p < 0.05).

Figure 3

The relative number (mean ± SEM) of c-Fos immunopositive cells was calculated as a proportion of non-stressed handled controls in each brain region. c-Fos immunoreactivity was quantified in (a) the IL, PL, dMeA, vMeA, and PVN, as well as in (b) several subdivisions of the DRN. Social status controls (SC), dominants (D), and subordinates (S) were exposed to either 30 min physical restraint or three 5-min social defeat episodes at 5-min intervals. Handled controls for the restraint study were transported to the testing room and gentled handled by experimenters, whereas handled controls for the social defeat study were exposed to the empty cages of three unfamiliar animals. The c-Fos data for socially defeated animals were previously reported (Morrison et al., 2012; Cooper et al., 2015). We specifically tested for restraint × social defeat interactions, and * indicates a significant pairwise comparison when the overall interaction was significant (p < 0.05).