Temporal profiling of an acute stress-induced behavioral phenotype in mice and role of hippocampal DRR1

Understanding the neurobiological mechanisms underlying the response to an acute stressor may provide novel insights into successful stress-coping strategies. Acute behavioral stress-effects may be restricted to a specific time window early after stress-induction. However, existing behavioral test batteries typically span multiple days or even weeks, limiting the feasibility for a broad behavioral analysis following acute stress. Here, we designed a novel comprehensive behavioral test battery in male mice that assesses multiple behavioral dimensions within a sufficiently brief time window to capture acute stress-effects and its temporal profile. Using this battery, we investigated the behavioral impact of acute social defeat stress (ASD) early thereafter (ASD-early, similar to 4 h), when circulating corticosterone levels were elevated, and late after stress-induction (ASD-late, similar to 8 h), when corticosterone were returned to timed control levels. ASD-early, but not ASD-late, displayed hippocampal-dependent cognitive impairments in the Y-maze and in the spatial object recognition test. The actin-binding protein (ABP) Tumor suppressor down-regulated in renal cell carcinoma 1 (DRR1) has been described as resilience-promoting factor but the potential of DRR1 to curb stress-effects has not been investigated. Hippocampal DRR1 mRNA-expression was increased in ASD-early and ASD-late whereas DRR1-protein levels were increased only in ASDlate. We hypothesized that the absence of hippocampal DRR1 protein-upregulation in ASD-early caused the associated cognitive impairments. Hence, virus-mediated hippocampal DRR1-overexpression was induced as putative treatment, but cognitive deficits in ASD-early were not improved. We conclude that hippocampal DRR1-overexpression is insufficient to protect from the detrimental cognitive effects following acute social stress where perhaps a more global response in local actin dynamics, involving multiple stress-responsive ABPs that act synergistically, was warranted.