The synergism between estrogen and histone tail acetylation-mediated memory formation is not clearly understood. Here, we attempt to study the altered histone acetylation homeostasis mediated changes in cognition following ovariectomy and evaluate the protective effect of quercetin. A significant reduction in estradiol levels with subsequent depletion in spatial memory and learning functions assessed by Morris water maze, novel object recognition test and elevated plus maze was observed in ovariectomized (OVX) mice. Correspondingly, a significant decline in neuroplasticity markers like brain-derived neurotrophic factor (BDNF), synaptophysin (SYP) and postsynaptic density-95 (PSD-95) was observed in cortex and hippocampus of OVX animals. Notably, histone acetyltransferase (HAT)/histone deacetylase (HDAC) balance was significantly disrupted in cortex and hippocampus of OVX mice. Lowered extracellular signal regulated kinases (ERK) and cAMP response element binding protein activation observed in OVX brain regions might account for HAT/HDAC imbalance. Altered HAT/HDAC homeostasis results in lowered histone 3 acetylation in OVX brain that suppressed transcriptional activation of neuroplasticity-related genes. Quercetin supplementation to OVX mice for 4 weeks was able to ameliorate cognitive impairment by restoring HAT/HDAC homeostasis through ERK activation and reversing alterations in neuroplasticity markers in cortex and hippocampus of OVX mice. Taken together, our results suggest that quercetin alleviates ovariectomy-induced cognitive decline by modulating histone acetylation homeostasis.

雌激素和组蛋白尾巴乙酰化介导的记忆形成之间的协同作用尚不清楚。在这里，我们试图研究卵巢切除术后组蛋白乙酰化稳态介导的认知改变，并评估槲皮素的保护作用。在卵巢切除（OVX）小鼠中观察到雌二醇水平显着降低，随后空间记忆和学习功能耗竭，通过莫里斯水迷宫，新颖的物体识别测试和高架迷宫评估。相应地，在OVX动物的皮层和海马中观察到神经可塑性标记物，如脑源性神经营养因子（BDNF），突触素（SYP）和突触后密度95（PSD-95）显着下降。值得注意的是 组蛋白乙酰转移酶（HAT）/组蛋白去乙酰化酶（HDAC）的平衡在OVX小鼠的皮质和海马中被显着破坏。在OVX脑区域中观察到的细胞外信号调节激酶（ERK）和cAMP反应元件结合蛋白激活降低可能是HAT / HDAC不平衡的原因。改变的HAT / HDAC稳态导致OVX脑中组蛋白3乙酰化的降低，从而抑制了神经可塑性相关基因的转录激活。OVX小鼠补充槲皮素4周能够通过ERK激活恢复HAT / HDAC稳态并逆转OVX小鼠皮层和海马中神经可塑性标记的改变，从而减轻认知障碍。两者合计，我们的结果表明槲皮素通过调节组蛋白乙酰化稳态来减轻卵巢切除术引起的认知功能下降。