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?

类固醇激素皮质醇在应激反应中释放，并在中枢神经系统中作用于糖皮质激素（GR）和矿皮质激素受体（MR）。GR在大脑中广泛分布，而MR主要表达在海马和前额叶皮层，这两个与记忆和执行功能密切相关的大脑区域。MR刺激导致作用于海马和前额皮质谷氨酸能NMDA受体的谷氨酸增加。在我们目前dfg资助的研究中，我们已经表明氟化可的松，一种矿物皮质激素受体（MR）激动剂，可以改善抑郁症患者和健康对照者的记忆和执行功能。然而，抑郁症患者不仅表现出传统神经心理学领域的认知缺陷，如记忆或执行功能。此外，还有抑郁症特有的改变，如认知偏差和社会认知缺陷，这是两个临床高度相关的领域。因此，本更新建议的具体目的有两个：检验氟化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异性认知偏差和社会认知；确定氟化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NMDA受体刺激而增强。我们假设氟化可的松会改善抑郁症患者的认知偏差和社会认知，其有益效果取决于NMDA受体。因此，我们进一步假设氟化可的松的作用可以通过与部分NMDA受体激动剂d -环丝氨酸共同使用来增强。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推进现有的知识，而且将这些影响扩展到抑郁症特有的认知偏见和社会认知的改变。此外，鉴于NMDA受体拮抗剂在治疗重度抑郁症方面的有希望的结果，MR和NMDA受体之间的潜在相互作用具有高度的临床相关性。

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.