Department of Psychology and Neuroscience Program, Tulane University, New Orleans, Louisiana 70118, USA.
Endocrinology. 2010 Mar;151(3):1194-203. doi: 10.1210/en.2009-1245. Epub 2010 Jan 12.
We determined whether transient exposure to estradiol during middle age in ovariectomized rats would exert lasting effects on cognition and the brain beyond the period of exposure. Two experiments were conducted. Rats 10-11 months of age were ovariectomized and received vehicle control treatment throughout the experiment, continuous estradiol treatment throughout the experiment, or 40 d of transient exposure to estradiol that ended 3 d before behavioral training. In the first experiment, rats were trained on a radial-maze working memory task and killed 2 months after the termination of transient exposure to estradiol. The hippocampus was immunostained for choline acetyltransferase and estrogen receptors alpha (ER alpha) and beta (ER beta) by Western blotting. In a second experiment to determine the durability of treatment effects, rats were behaviorally tested every other month until brains were collected for Western blotting 8 months after the termination of transient exposure to estradiol. Maze testing included delay trials and scopolamine trials, in which dose-effect curves for the muscarinic receptor antagonist were determined. Transient exposure to estradiol enhanced working memory and attenuated amnestic effects of scopolamine as effectively as continuous estradiol exposure. Enhancements persisted for up to 7 months. Transient exposure to estradiol increased hippocampal levels of ER alpha and choline acetyltransferase 2 months and ER alpha 8 months after termination of the exposure. Neither estradiol treatment altered estrogen receptor beta levels. Results demonstrate that short-term treatment with estradiol during middle age enhances working memory well beyond the duration of treatment and suggest ER alpha as a potential mechanism for this effect.
我们确定在中年时对去卵巢大鼠短暂暴露于雌二醇是否会在暴露期之外对认知和大脑产生持久影响。进行了两项实验。10-11 月龄大鼠行卵巢切除术，整个实验过程中给予载体对照处理、持续雌二醇处理或短暂暴露于雌二醇 40 天，结束前 3 天进行行为训练。在第一个实验中，大鼠接受了放射迷宫工作记忆任务的训练，并在短暂暴露于雌二醇结束后 2 个月处死。通过 Western blot 对海马胆碱乙酰转移酶和雌激素受体 α（ERα）和β（ERβ）进行免疫染色。在第二个实验中，为了确定治疗效果的持久性，大鼠每隔一个月进行行为测试，直到在短暂暴露于雌二醇结束 8 个月后收集大脑进行 Western blot。迷宫测试包括延迟试验和东莨菪碱试验，其中确定了毒蕈碱受体拮抗剂的剂量效应曲线。与持续雌二醇暴露一样，短暂暴露于雌二醇可增强工作记忆并减轻东莨菪碱的健忘作用。增强作用持续长达 7 个月。短暂暴露于雌二醇可在暴露结束后 2 个月和 8 个月增加海马 ERα 和胆碱乙酰转移酶水平。两种雌二醇处理均未改变雌激素受体β水平。结果表明，中年时短期用雌二醇治疗可显著提高工作记忆，远远超过治疗时间，并提示 ERα 可能是这种作用的潜在机制。
