The type of stress matters: repeated injection and permanent social isolation stress in male mice have a differential effect on anxiety- and depressive-like behaviours, and associated biological alterations

Abstract

Chronic stress can alter the immune system, adult hippocampal neurogenesis and induce anxiety- and depressive-like behaviour in rodents. However, previous studies have not discriminated between the effect(s) of different types of stress on these behavioural and biological outcomes. We investigated the effect(s) of repeated injection vs. permanent social isolation on behaviour, stress responsivity, immune system functioning and hippocampal neurogenesis, in young adult male mice, and found that the type of stress exposure does indeed matter. Exposure to 6 weeks of repeated injection resulted in an anxiety-like phenotype, decreased systemic inflammation (i.e., reduced plasma levels of TNFα and IL4), increased corticosterone reactivity, increased microglial activation and decreased neuronal differentiation in the dentate gyrus (DG). In contrast, exposure to 6 weeks of permanent social isolation resulted in a depressive-like phenotype, increased plasma levels of TNFα, decreased plasma levels of IL10 and VEGF, decreased corticosterone reactivity, decreased microglial cell density and increased cell density for radial glia, s100β-positive cells and mature neuroblasts—all in the DG. Interestingly, combining the two distinct stress paradigms did not have an additive effect on behavioural and biological outcomes, but resulted in yet a different phenotype, characterized by increased anxiety-like behaviour, decreased plasma levels of IL1β, IL4 and VEGF, and decreased hippocampal neuronal differentiation, without altered neuroinflammation or corticosterone reactivity. These findings demonstrate that different forms of chronic stress can differentially alter both behavioural and biological outcomes in young adult male mice, and that combining multiple stressors may not necessarily cause more severe pathological outcomes.

P2X7R antagonists in chronic stress-based depression models: a review

“…However, the models reviewed here mostly lack psychosocial stressors and thus are much more CPPS than CPSS models [ 25 , 154 ]. In this regard and in line with existing research [ 155 – 157 ], Du Preez et al [ 158 ] previously showed distinct behavioural and neurobiological differences between CPSS, CPPS and combined CPSS/CPPS paradigms in male mice. Repeated saline injections led to anxiety-like behaviour in the OFT and NSFT, increased M/Ms activation and reduced TNF-α serum levels, corticosterone reactivity and hippocampal neuroplasticity.…”

Physical Stress Induced Reduction of Proliferating Cells and Differentiated Neuroblasts Is Ameliorated by Fermented Laminaria japonica Extract Treatment

“…Other groups demonstrated that psychological stress using a communication box increased acutely blood corticosterone levels but did not change after 15 or 30 days-stress exposure [45,50]. Repeated injection stress for 6 weeks increased corticosterone reactivity, while the social isolation decreased the corticosterone reactivity [51]. We assumed that corticosterone is more reactive to physical stress than psychological stress and we observed the significant reduction of corticosterone levels in physical, not psychological stress.…”

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…Rats growing in post-weaning social isolation (SI-reared) develop an "isolation-induced stress syndrome" with excessive reactivity to handling, anxiety-like behavior and high emotionality [75,235]. Male and female SI-reared rats demonstrate good face validity of the depressive-like phenotype with increased motor locomotion [75][76][77] and decreased time spent in the arena center [78] in the open field test, and increased anxiety-like behaviors tested by the elevated plus maze [79][80][81]. These effects are irreversible by resocialization [236], as observed in males but not in females [237,238].…”