Van Kempen Tracey A, Gorecka Jolanta, Gonzalez Andreina D, Soeda Fumio, Milner Teresa A, Waters Elizabeth M
Brain and Mind Research Institute (T.A.V.K., T.A.M.) and Graduate Program in Neuroscience (T.A.V.K., A.D.G.), Weill Cornell Medical College, and Laboratory of Neuroendocrinology (J.G., T.A.M., E.M.W.), The Rockefeller University, New York, New York 10065; and Department of Environmental and Molecular Health Sciences (F.S.), Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Endocrinology. 2014 Sep;155(9):3610-23. doi: 10.1210/en.2014-1190. Epub 2014 Jun 13.
Accelerated ovarian failure (AOF) can be induced in young mice with low doses of 4-vinylcyclohexene diepoxide (VCD), modeling the hormone changes observed across menopause. We assessed markers of synaptic plasticity in the hippocampus, anxiety-like behavior, and spatial learning longitudinally at 4 time points across the AOF model: premenopause, early perimenopause, late perimenopause, and postmenopause (POST). As others have shown, VCD administration decreased ovarian follicle counts and increased acyclicity as the model progressed to POST but with no impact on organ or body weights. The morphology of Iba1 immunoreactive microglia did not differ between vehicle- and VCD-administered mice. Hippocampal postsynaptic density 95 levels were minimally altered across the AOF model but decreased at POST in CA3b 24 hours after exogenous estradiol benzoate (EB). In contrast, hippocampal phosphorylated AKT levels transiently decreased in premenopause but increased at POST after 24 hours of EB in select subregions. Electron microscopy revealed fewer estrogen receptor α containing dendritic spines and terminals in CA1 stratum radiatum at POST. mRNA levels of most brain-derived neurotrophic factor exons (except V and VI) were lower in POST compared with ovariectomized mice. Exon V was sensitive to 24 hours of EB administration in POST-VCD. Anxiety-like behavior was unaffected at any menopause phase. Spatial learning was unaffected in all groups, but POST-VCD mice performed below chance. Our results suggest that the AOF model is suitable for longitudinal studies of neurobiological changes across the menopause transition in mice. Our findings also point to complex interactions between estrogen receptors and pathways involved in synaptic plasticity.
低剂量的4-乙烯基环己烯二环氧化物（VCD）可诱导年轻小鼠出现卵巢早衰（AOF），模拟绝经过程中观察到的激素变化。我们在AOF模型的4个时间点纵向评估了海马体中突触可塑性的标志物、焦虑样行为和空间学习能力，这4个时间点分别为：绝经前、围绝经期早期、围绝经期晚期和绝经后（POST）。正如其他人所表明的，随着模型进展到POST阶段，VCD给药会减少卵巢卵泡数量并增加无周期性，但对器官或体重没有影响。给予载体和VCD的小鼠之间，离子钙结合衔接分子1（Iba1）免疫反应性小胶质细胞的形态没有差异。在整个AOF模型中，海马体突触后致密蛋白95水平变化极小，但在给予外源性苯甲酸雌二醇（EB）24小时后，CA3b区域的POST阶段该水平下降。相比之下，海马体磷酸化蛋白激酶B（AKT）水平在绝经前短暂下降，但在POST阶段，特定亚区域在给予EB 24小时后升高。电子显微镜显示，POST阶段CA1辐射层中含有雌激素受体α的树突棘和终末较少。与卵巢切除小鼠相比，POST阶段大多数脑源性神经营养因子外显子（V和VI除外）的mRNA水平较低。外显子V对POST-VCD阶段给予24小时的EB敏感。在任何绝经阶段，焦虑样行为均未受影响。所有组的空间学习能力均未受影响，但POST-VCD小鼠的表现低于随机水平。我们的结果表明，AOF模型适用于对小鼠绝经过渡期间神经生物学变化的纵向研究。我们的研究结果还指出了雌激素受体与参与突触可塑性的信号通路之间存在复杂的相互作用。
