Differential Regulation of Hippocampal Glucocorticoid Receptors mRNA and Fast Feedback: Relevance to Post‐Traumatic Stress Disorder
Differential Regulation of Hippocampal Glucocorticoid Receptors mRNA and Fast Feedback: Relevance to Post‐Traumatic Stress Disorder
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DOI：
10.1046/j.1365-2826.1999.00288.x
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发表时间：
1999-01
影响因子：
3.2
通讯作者：
Isreal Liberzon;J. F. Lopez;S. Flagel;D. Vázquez;E. Young
中科院分区：
文献类型：
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作者：
Isreal Liberzon;J. F. Lopez;S. Flagel;D. Vázquez;E. Young
海马糖皮质激素受体（GR和MR）在糖皮质激素负反馈中起重要作用。在抑郁症和创伤后应激障碍（PTSD）中发现了负反馈异常，提示GR和MR可能参与了这些疾病的病理生理。通过单一长时间应激（SPS）模式（在一个长时间的应激过程中使用多个不同的应激源，“无应激”间隔和一周后的测试过程），可以在动物中诱导增强的负反馈，即创伤后应激障碍特异性神经内分泌异常。在当前的研究中，我们在SPS后表现出改变的负反馈的同一动物中检测了海马GR和MR mRNA的分布。两项研究使用了7组成年雄性大鼠（每组7只），将非应激对照组与急性应激动物（SPS: 24 h组）、SPS动物（7天和14天）和SPS+慢性应激动物进行比较。用35S标记的cRNA探针原位杂交研究海马亚区GR和MR mRNA的分布。急性应激导致所有海马亚区GR和mrmrna下调。7天后（SPS‐7组），有差异恢复，GR mRNA达到高于预应力水平，MR mRNA保持下调。在14天组中也存在相同的差异调节。表现出正常快速反馈的慢性应激动物的GR和MR mRNA水平也趋于正常。MR/GR比仅在快速反馈增强的动物中降低。这些发现表明，海马GR的增加与SPS动物中观察到的快速反馈超敏反应有关，也可能是PTSD中地塞米松敏感性增强的基础。由于GR和MR的不同激活可以调节记忆、行为反应性、焦虑和恐惧，MR/GR比值的变化也可以解释其他与PTSD相关的现象。
Hippocampal glucocorticoid receptors (GR and MR) play an important role in glucocorticoid negative feedback. Abnormalities in negative feedback are found in depression and in post‐traumatic stress disorder (PTSD), suggesting that GR and MR might be involved in the pathophysiology of these disorders. Enhanced negative feedback, the PTSD‐specific neuroendocrine abnormality, can be induced in animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session, ‘no stress’ interval and a testing session one week later). In the current study, we examined hippocampal GR and MR mRNA distribution in the same animals that exhibited altered negative feedback following the SPS. Seven groups of adult Sprague‐Dawley male rats (seven animals each) were used in two studies, comparing unstressed controls to acutely stressed animals (SPS: 24 h group), SPS animals (seven and 14 days), and SPS+chronic stress animals. GR and MR mRNA distribution across hippocampal subfields was studied using in‐situ hybridization with 35S‐labelled cRNA probes. Acute stress produced down‐regulation of GR and MR mRNA across all hippocampal subfields. Seven days later (SPS‐7 group), there was a differential recovery, with GR mRNA reaching higher than the prestress levels, and MR mRNA remaining down‐regulated. The same differential regulation was present in the 14‐day group. Chronically stressed animals that exhibited normal fast feedback also had normalization in their GR and MR mRNA levels. The MR/GR ratio was decreased only in animals that had enhanced fast feedback. These findings suggest that the increase in GR, in hippocampus is involved in the fast feedback hypersensitivity observed in the SPS animals, and might also underlie enhanced dexamethasone sensitivity found in PTSD. Since differential activation of GR and MR can modulate memory, behavioural responsivity, anxiety and fear, change in MR/GR ratio might also explain other PTSD‐related phenomena.