Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA.
Neuroscience. 2012 Oct 25;223:163-73. doi: 10.1016/j.neuroscience.2012.07.047. Epub 2012 Jul 31.
Single prolonged stress (SPS) is a rodent model of post traumatic stress disorder that is comprised of serial application of restraint (r), forced swim (fs), and ether (eth) followed by a 7-day quiescent period. SPS induces extinction retention deficits and it is believed that these deficits are caused by the combined stressful effect of serial exposure to r, fs, and eth. However, this hypothesis remains untested. Neurobiological mechanisms by which SPS induces extinction retention deficits are unknown, but SPS enhances glucocorticoid receptor (GR) expression in the hippocampus, which is critical for contextual modulation of extinction retrieval. Upregulation of GRs in extinction circuits may be a mechanism by which SPS induces extinction retention deficits, but this hypothesis has not been examined. In this study, we systematically altered the stressors that constitute SPS (i.e. r, fs, eth), generating a number of partial SPS (p-SPS) groups, and observed the effects SPS and p-SPSs had on extinction retention and GR levels in the hippocampus and prefrontal cortex (PFC). PFC GRs were assayed, because regions of the PFC are critical for maintaining extinction. We predicted that only exposure to full SPS would result in extinction retention deficits and enhance hippocampal and PFC GR levels. Only exposure to full SPS induced extinction retention deficits. Hippocampal and PFC GR expression was enhanced by SPS and most p-SPSs, however hippocampal GR expression was significantly larger following the full SPS exposure than all other conditions. Our findings suggest that the combined stressful effect of serial exposure to r, fs, and eth results in extinction retention deficits. The results also suggest that simple enhancements in GR expression in the hippocampus and PFC are insufficient to result in extinction retention deficits, but raise the possibility that a threshold-enhancement in hippocampal GR expression contributes to SPS-induced extinction retention deficits.
单一延长应激（SPS）是一种创伤后应激障碍的啮齿动物模型，它由连续应用束缚（r）、强迫游泳（fs）和乙醚（eth）组成，随后是 7 天的静止期。SPS 诱导消退保留缺陷，据信这些缺陷是由于连续暴露于 r、fs 和 eth 的联合应激作用引起的。然而，这一假设尚未得到验证。SPS 诱导消退保留缺陷的神经生物学机制尚不清楚，但 SPS 增强了海马中的糖皮质激素受体（GR）表达，这对于上下文调节消退检索至关重要。在消退回路中上调 GRs 可能是 SPS 诱导消退保留缺陷的一种机制，但这一假设尚未得到检验。在这项研究中，我们系统地改变了构成 SPS 的应激源（即 r、fs、eth），产生了一些部分 SPS（p-SPS）组，并观察了 SPS 和 p-SPS 对消退保留和海马和前额叶皮质（PFC）中 GR 水平的影响。检测了 PFC 的 GR，因为 PFC 的区域对于维持消退至关重要。我们预测只有暴露于完整的 SPS 才会导致消退保留缺陷并增强海马和 PFC 的 GR 水平。只有暴露于完整的 SPS 才会引起消退保留缺陷。SPS 和大多数 p-SPS 增强了海马和 PFC 的 GR 表达，但 SPS 暴露后海马的 GR 表达明显大于其他所有条件。我们的研究结果表明，连续暴露于 r、fs 和 eth 的联合应激作用导致了消退保留缺陷。结果还表明，海马和 PFC 中 GR 表达的简单增强不足以导致消退保留缺陷，但提出了海马 GR 表达的阈值增强可能导致 SPS 诱导的消退保留缺陷的可能性。
