Effects of mineralocorticoid receptor stimulation on cognitive bias and social cognition in patients with major depression and healthy controls: what is the role of NMDA receptors?

应激反应释放类固醇激素皮质醇，并通过糖皮质激素(GR)和盐皮质激素受体(MR)作用于中枢神经系统。GR广泛分布于大脑各处，而MR主要在海马区和前额叶皮质表达，这两个脑区与记忆和执行功能密切相关。MR的刺激导致谷氨酸增加，谷氨酸作用于海马区和前额叶皮质中的谷氨酸能NMDA受体。在我们目前由DFG资助的研究中，我们已经表明，氟化可的松，一种盐皮质激素受体(MR)激动剂，可以改善抑郁症患者和健康对照组的记忆和执行功能。然而，抑郁症患者不仅在记忆或执行功能等传统神经心理领域表现出认知缺陷。此外，还有抑郁症特有的改变，如认知偏差和社会认知缺陷，这两个临床上高度相关的领域。因此，这项更新建议的具体目的有两个：检查氟可的松对抑郁症患者的有益作用是否可以扩展到抑郁症特有的认知偏差和社会认知，以确定氟可的松的有益作用是否依赖于NMDA受体功能，以及这些有益作用是否可以通过刺激NMDA受体来增强。我们假设氟可的松将改善抑郁症患者的认知偏向和社会认知，其有益作用依赖于NMDA受体。因此，我们进一步假设，联合应用部分NMDA受体激动剂D-环丝氨酸可以增强氟可的松的作用。我们的研究不仅通过进一步研究MR刺激对认知产生有益影响的作用机制来促进现有知识的发展，而且将这些影响扩展到抑郁症特有的认知偏差和社会认知的改变。此外，考虑到NMDA受体拮抗剂在治疗重度抑郁症方面的良好结果，MR和NMDA受体之间的潜在相互作用具有高度的临床意义。

The steroid hormone cortisol is released in response to stress and acts in the central nervous system upon glucocorticoid (GR) and mineralocorticoid receptors (MR). GR are widely distributed across the brain while MR are predominantly expressed in the hippocampus and prefrontal cortex, two brain areas closely related to memory and executive function. Stimulation of MR leads to an increase of glutamate that act on glutamatergic NMDA receptors in the hippocampus and prefrontal cortex. In our currently DFG-funded study, we have shown that fludrocortisone, a mineralocorticoid receptor (MR) agonist, improves memory and executive function in depressed patients and healthy controls. However, depressed patients not only exhibit cognitive deficits in traditional neuropsychological domains such as memory or executive function. In addition, there are depression-specific alterations such as cognitive bias and deficits in social cognition, two clinically highly relevant areas. Therefore, the specific aims of this renewal proposal are two-fold: To examine whether beneficial effects of fludrocortisone in depressed patients can be extended to depression-specific cognitive bias and to social cognition To determine whether beneficial effects of fludrocortisone depend on NMDA-receptor function and whether these beneficial effects can be enhanced by NMDA receptor stimulation. We hypothesize that fludrocortisone will improve cognitive bias and social cognition in depressed patients and that its beneficial effects depend on the NMDA receptor. Therefore, we further hypothesize that the effects of fludrocortisone can be enhanced by co-administration of the partial NMDA receptor agonist D-cycloserine. Our study not only advances current knowledge by further examining the mechanism of action by which MR stimulation exerts beneficial effects on cognition but extends these effects to depression-specific cognitive bias and alterations in social cognition. Furthermore, a potential interaction between MR and NMDA receptors is highly clinically relevant given the promising results with NMDA receptor antagonists in the treatment of major depression.