Endocrinology Unit, Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Psychoneuroendocrinology. 2013 May;38(5):648-58. doi: 10.1016/j.psyneuen.2012.08.007. Epub 2012 Sep 11.
An imbalance between central glucocorticoid (GR) and mineralocorticoid (MR) receptors is proposed to underlie the HPA axis dysregulation that associates with susceptibility to psychopathology (anxiety, PTSD). To test this 'balance hypothesis' we examined whether the impact of MR levels upon HPA-axis control and behaviour depended on the relative levels of GR and vice versa. Avoiding antenatal maternal 'programming' effects by using littermates, we generated mice with forebrain MR over-expression (MR(hi)) and/or simultaneous global GR under-expression (GR(lo)). We found a significant interaction between MR and GR in control of the HPA-axis under stressed but not basal conditions. With reduced GR levels, HPA-axis activity in response to restraint stress was enhanced, likely due to impaired negative feedback. However, high MR in concert with reduced GR minimised this HPA-axis overshoot in response to stress. MR:GR balance also played a role in determining strategies of spatial memory during a watermaze probe trial: when coupled with GR under-expression, MR(hi) show enhanced perseveration, suggesting enhanced spatial recall or reduced exploratory flexibility. Other alterations in cognitive functions were specific to a single receptor without interaction, with both MR(hi) and GR(lo) manipulations independently impairing reversal learning in spatial and fear memory tasks. Thus, MR and GR interact in specific domains of neuroendocrine and cognitive control, but for other limbic-associated behaviours each receptor mediates its own repertoire of responses. Since modulation of HPA-axis and behavioural dysfunction associated with high levels of MR, selective ligands or transcriptional regulators may afford novel therapeutic approaches to affective psychopathologies.
中枢糖皮质激素 (GR) 和盐皮质激素 (MR) 受体的失衡被认为是 HPA 轴失调的基础，而 HPA 轴失调与易感性精神病理学（焦虑、创伤后应激障碍）有关。为了验证这一“平衡假说”，我们研究了 MR 水平对 HPA 轴控制和行为的影响是否取决于 GR 的相对水平，反之亦然。通过使用同窝仔避免产前母体“编程”效应，我们生成了大脑前部 MR 过度表达（MR(hi)）和/或同时全局 GR 低表达（GR(lo)）的小鼠。我们发现，在应激而非基础条件下，MR 和 GR 对 HPA 轴的控制存在显著的相互作用。由于负反馈受损，GR 水平降低时，束缚应激对 HPA 轴的反应活性增强，但高 MR 与低 GR 相结合可使应激时 HPA 轴过度反应最小化。MR:GR 平衡在确定水迷宫探测试验中的空间记忆策略中也起着重要作用：当与 GR 低表达相结合时，MR(hi)表现出增强的坚持性，这表明增强的空间记忆或减少的探索灵活性。认知功能的其他改变仅与单个受体有关，而没有相互作用，MR(hi)和 GR(lo)的操作都独立地损害了空间和恐惧记忆任务中的反转学习。因此，MR 和 GR 在神经内分泌和认知控制的特定领域相互作用，但对于其他边缘相关行为，每个受体都介导其自身的反应谱。由于 HPA 轴和与高 MR 相关的行为功能障碍的调节，选择性配体或转录调节剂可能为情感精神病理学提供新的治疗方法。
