Overexpression of Mineralocorticoid Receptors Partially Prevents Chronic Stress-Induced Reductions in Hippocampal Memory and Structural Plasticity

Abstract

Exposure to chronic stress is a risk factor for cognitive decline and psychopathology in genetically predisposed individuals. Preliminary evidence in humans suggests that mineralocorticoid receptors (MRs) may confer resilience to these stress-related changes. We specifically tested this idea using a well-controlled mouse model for chronic stress in combination with transgenic MR overexpression in the forebrain. Exposure to unpredictable stressors for 21 days in adulthood reduced learning and memory formation in a low arousing hippocampus-dependent contextual learning task, but enhanced stressful contextual fear learning. We found support for a moderating effect of MR background on chronic stress only for contextual memory formation under low arousing conditions. In an attempt to understand potentially contributing factors, we studied structural plasticity. Chronic stress altered dendritic morphology in the hippocampal CA3 area and reduced the total number of doublecortin-positive immature neurons in the infrapyramidal blade of the dentate gyrus. The latter reduction was absent in MR overexpressing mice. We therefore provide partial support for the idea that overexpression of MRs may confer resilience to the effects of chronic stress on hippocampus-dependent function and structural plasticity.

Effects of Mineralocorticoid Receptor Overexpression on Anxiety and Memory after Early Life Stress in Female Mice

“…We observed that MR overexpressing females were heavier at 4 months of age when compared to control animals, a finding we observed before at the age of 3 months old, both in female (Kanatsou et al, 2015a ) and male animals (Kanatsou et al, 2015b ). A previous study showed that mice with MR deletion in the forebrain have a reduced bodyweight (Ter Horst et al, 2012 ).…”

“…All mice were bred in-house by crossing male MR-tg mice with C57BL/6J females. One male animal was housed for 1 week with two female mice (Kanatsou et al, 2015a , b ). The mouse line with forebrain MR overexpression (MR-tg) was generated by inserting the HA-tagged human MR cDNA using the CamKIIα promoter (Lai et al, 2007 ).…”

“…To examine the mice for context-dependent learning and memory object recognition we used the object in-context task, as described previously (Smith and Mizumori, 2006 ; Balderas et al, 2008 ; Spanswick and Sutherland, 2010 ; Kanatsou et al, 2015a , b ). Briefly, mice ( n = 13–17 per group) were tested for three subsequent days using boxes of identical measurements (W × L × H; 33 cm × 54 cm × 37 cm), either with or without visual cues on the walls and all contexts containing bedding material.…”

Stress and Depression: a Crucial Role of the Mineralocorticoid Receptor

“…MR overexpression restored the reduced learning in the low arousing task only. This change in behaviour was paralleled by normalisation of the chronic stress‐induced reductions in neurogenesis observed in the infrapyramidal blade of the dentate gyrus . The finding agrees with a previous study by Ferguson and Sapolsky conducted in rats involving viral overexpression of MR in the dentate gyrus.…”

“…The idea that increased hippocampal MR may provide resilience was tested further in MR hi mice exposed for 3 weeks daily to an unpredictable stress paradigm , mimicking the chronic stress conditions that predispose humans to depression. In wild‐type mice, such a chronic stress experience reduced learning in a low arousing hippocampus contextual learning task but enhanced stressful contextual learning.…”