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

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.

长期应激暴露是遗传易感个体出现认知衰退与精神病理症状的风险因素。现有初步人体研究证据表明，盐皮质激素受体（mineralocorticoid receptors, MRs）可能对这类应激相关的病理变化具有抵抗作用。我们采用经过严格对照的慢性应激小鼠模型，结合前脑盐皮质激素受体过表达的转基因实验体系，对这一假说开展了针对性验证。成年小鼠接受为期21天的不可预知应激刺激后，在低唤醒海马依赖型情境学习任务中表现出学习与记忆形成能力受损，但在应激性情境恐惧学习任务中其学习表现反而增强。我们仅在低唤醒条件下的情境记忆形成环节中，观察到MR背景对慢性应激产生的调节效应。为探究潜在的作用机制，我们对结构可塑性进行了分析：慢性应激可改变海马CA3区（hippocampal CA3 area）的树突形态，并降低齿状回下锥叶（infrapyramidal blade of the dentate gyrus）内双皮质素阳性（doublecortin-positive）未成熟神经元的总数量；而在MR过表达小鼠中，这一神经元数量减少的现象并未出现。综上，本研究为“盐皮质激素受体过表达可抵抗慢性应激对海马依赖型功能与结构可塑性的不良影响”这一观点提供了部分实验证据支持。