Quality and timing of stressors differentially impact on brain plasticity and neuroendocrine-immune function in mice

Abstract

A growing body of evidence suggests that psychological stress is a major risk factor for psychiatric disorders. The basic mechanisms are still under investigation but involve changes in neuroendocrine-immune interactions, ultimately affecting brain plasticity. In this study we characterized central and peripheral effects of different stressors, applied for different time lengths, in adult male C57BL/6J mice. We compared the effects of repeated (7 versus 21 days) restraint stress (RS) and chronic disruption of social hierarchy (SS) on neuroendocrine (corticosterone) and immune function (cytokines and splenic apoptosis) and on a marker of brain plasticity (brain-derived neurotrophic factor, BDNF ). Neuroendocrine activation did not differ between SS and control subjects; by contrast, the RS group showed a strong neuroendocrine response characterized by a specific time-dependent profile. Immune function and hippocampal BDNF levels were inversely related to hypothalamic-pituitary-adrenal axis activation. These data show a fine modulation of the crosstalk between central and peripheral pathways of adaptation and plasticity and suggest that the length of stress exposure is crucial to determine its final outcome on health or disease.

Figure 1

Effect of restraint stress on CORT secretion in mice. All subjects undergoing RS showed a reduced response of the HPA axis on day 7 (a). Effect of social stress on CORT secretion in mice. The response to an acute challenge (represented by the Social Interaction Test) was effective in inducing an increase in CORT secretion in all groups, with no differences in relation to social stress exposure (b). Results are presented as mean + S.E.M. *P < 0.05.

Figure 2

Effects of restraint stress on hippocampal BDNF levels. BDNF levels were decreased following a chronic 21 days restraint procedure compared to 7 days of repeated restraint. Data shown are mean + S.E.M. *P < 0.05.

Figure 3

Effect of RS and SS on the immune system response. Restraint stress procedure. Following 7 days of restraint stress the proinflammatory cytokine TNF-α increases, (b) while the increase in IL-6 during days 7 and 21 just missed statistical significance (a); by contrast the anti-inflammatory cytokine IL-10 increased following 21 days (c). The percentage of apoptotic splenocytes was found to be decreased following 21 days of stress (d). Social stress procedure. Levels of IL-10 were increased already after 7 days of the SS procedure (f). Splenocytes apoptosis was increased after 7 days of SS and decreased following 21 days (g). No difference is evident as for levels of IL-6 (e). Results are presented as mean + S.E.M. **P < 0.01, *P < 0.05.