Department of Psychology, Williams College, Williamstown, MA 01267, USA.
Brain Res. 2012 Mar 14;1443:64-74. doi: 10.1016/j.brainres.2012.01.014. Epub 2012 Jan 17.
Estradiol protects against hippocampal damage and some learning impairments resulting from transient global ischemia in rats. Here, we seek to validate a mouse model of transient global ischemia and evaluate the effects of estradiol on ischemia-induced hippocampal damage and behavioral impairments. Female C57Bl6/J mice were ovariectomized and implanted with estradiol- or oil-secreting capsules. One week later, mice experienced 15-min of 2-vessel occlusion (2-VO) or sham surgical procedures. Five days later, mice were exposed to a fear conditioning protocol in which a specific context and novel tone were paired with mild footshock. Twenty-four hours following conditioning, contextual fear was assessed by measuring freezing behavior in the conditioned context (in the absence of the tone). This was followed by assessment of cue fear by measuring freezing behavior to the conditioned tone presented in a new context. When tested in the conditioned context, oil-treated mice that experienced 2-VO exhibited a significant reduction in freezing behavior whereas estradiol-treated mice that experienced 2-VO showed no disruption in freezing behavior. Freezing behavior when presented with the conditioned tone was unaffected by either surgery or hormone treatment. These findings suggest that global ischemia causes impairments in performance on the hippocampally-dependent contextual fear task but not conditioned cue-based fear. Furthermore, estradiol prevented the ischemia-induced impairment in contextual fear conditioning. Fluoro-Jade (FJ) staining revealed neuronal degeneration throughout the dorsal hippocampus of mice that experienced 2-VO. Estradiol treatment reduced the number of FJ+ cells in CA1 and CA2, but not in CA3 or in the dentate gyrus. Together, these findings suggest that 15 min of global ischemia causes extensive hippocampal neurodegeneration and disrupts contextual fear conditioning processes in mice and that estradiol protects against these adverse effects.
雌二醇可预防大鼠短暂性全脑缺血引起的海马损伤和某些学习障碍。在这里，我们试图验证一种短暂性全脑缺血的小鼠模型，并评估雌二醇对缺血诱导的海马损伤和行为障碍的影响。雌性 C57Bl6/J 小鼠被卵巢切除术，并植入雌二醇或油分泌胶囊。一周后，小鼠经历 15 分钟的 2 血管闭塞（2-VO）或假手术程序。五天后，小鼠接受了恐惧条件反射协议，其中特定的上下文和新的音调与轻度足底电击配对。条件反射后 24 小时，通过测量在条件化环境中（在没有音调的情况下）的冻结行为来评估上下文恐惧。随后通过测量在新环境中呈现条件化音调时的冻结行为来评估线索恐惧。在条件化环境中进行测试时，经历 2-VO 的油处理小鼠的冻结行为明显减少，而经历 2-VO 的雌二醇处理小鼠的冻结行为没有受到干扰。呈现条件化音调时的冻结行为不受手术或激素处理的影响。这些发现表明，全脑缺血导致在海马依赖性上下文恐惧任务上的表现受损，但不会导致基于条件的线索恐惧受损。此外，雌二醇可预防缺血引起的上下文恐惧条件反射损伤。氟金胺（FJ）染色显示经历 2-VO 的小鼠背侧海马体中有神经元变性。雌二醇处理减少了 CA1 和 CA2 中的 FJ+细胞数量，但 CA3 或齿状回中没有。总之，这些发现表明，15 分钟的全脑缺血会导致广泛的海马神经退行性变，并破坏小鼠的上下文恐惧条件反射过程，而雌二醇可预防这些不利影响。
