Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour
Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour
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DOI：
10.1016/j.psyneuen.2012.08.007
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发表时间：
2013-05-01
影响因子：
3.7
通讯作者：
Seckl, J. R.
中科院分区：
文献类型：
--
作者：
Harris, A. P.;Holmes, M. C.;Seckl, J. R.
中枢糖皮质激素(GR)和盐皮质激素(MR)受体之间的失衡被认为是HPA轴调节失调的基础，HPA轴失调与精神病理(焦虑、PTSD)的易感性有关。为了检验这一“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。为了避免母体通过产仔的“程序化”影响，我们产生了前脑MR过度表达(MRHI)和/或同时全局GR低表达(GR(Lo))的小鼠。我们发现，在应激条件下，MR和GR在控制HPA轴方面存在显著的交互作用，而不是在基础条件下。随着GR水平的降低，HPA轴对束缚应激的反应增强，这可能是由于负反馈受损所致。然而，随着GR的降低，高MR可以最大限度地减少对压力的HPA轴超调。MR：在水迷宫探测试验中，GR Balance也在决定空间记忆策略方面发挥了作用：当与GR表达不足相结合时，MRHI表现出更强的持久力，表明空间记忆增强或探索灵活性降低。认知功能的其他变化是特定于单个感受器的，没有相互作用，MRHI和GR(Lo)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，每个受体都调节自己的反应谱系。由于HPA轴的调节和行为障碍与高水平的MR相关，选择性配体或转录调节因子可能为情感性精神病理提供新的治疗方法。(C)2012爱思唯尔有限公司。保留所有权利。
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 (MRhi) and/or simultaneous global GR underexpression (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, MRhi 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 MRhi 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 psychopathologles. (C) 2012 Elsevier Ltd. All rights reserved.