Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice
Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice
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DOI：
10.1016/j.neuroscience.2012.01.034
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发表时间：
2012-04
期刊：
影响因子：
3.3
通讯作者：
Kazuhiro Takuma;H. Mizoguchi;H. Mizoguchi;Y. Funatsu;Y. Hoshina;Y. Himeno;Emiko Fukuzaki;Yuko Kitahara;Yuko Kitahara;S. Arai;D. Ibi;D. Ibi;Hiroyuki Kamei;Hiroyuki Kamei;Toshio Matsuda;Koji Koike;Masaki Inoue;T. Nagai;T. Nagai;Kiyofumi Yamada;Kiyofumi Yamada
中科院分区：
文献类型：
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作者：
Kazuhiro Takuma;H. Mizoguchi;H. Mizoguchi;Y. Funatsu;Y. Hoshina;Y. Himeno;Emiko Fukuzaki;Yuko Kitahara;Yuko Kitahara;S. Arai;D. Ibi;D. Ibi;Hiroyuki Kamei;Hiroyuki Kamei;Toshio Matsuda;Koji Koike;Masaki Inoue;T. Nagai;T. Nagai;Kiyofumi Yamada;Kiyofumi Yamada
我们最近发现，卵巢切除(OVX)和慢性束缚应激(CS)联合应用可导致雌性大鼠海马锥体细胞丢失和认知功能障碍，雌激素替代可阻止OVX/CS引起的形态和行为改变。在本研究中，为了进一步阐明OVX/CS所致记忆障碍的机制，我们研究了胆碱能系统在OVX/CS所致小鼠记忆障碍中的作用。雌性SLC：ICR品系小鼠随机分为去卵巢组和假手术组。术后2周，将每组小鼠进一步分为CS组(6h/d)和非应激组。在3周的应激期后，所有的小鼠都接受了情景恐惧条件反射，并在条件作用后1或24小时进行了上下文和音调依赖记忆测试。从OVX后2周开始的3周CS可损害上下文和音调依赖的冰冻，OVX/CS导致显著的Nissl染色的神经元样细胞在海马CA3区丢失，尽管OVX和CS单独不能引起这种行为和组织学改变。去势后给予17β-雌二醇5周，可抑制去卵巢/CS所致的记忆障碍和海马尼氏阳性细胞的丢失。此外，与其他组相比，OVX/CS组小鼠海马区胆碱乙酰转移酶显著降低。胆碱酯酶抑制剂多奈哌齐和加兰他明可改善OVX/CS所致的记忆障碍。这些数据表明，胆碱能功能障碍可能参与了OVX/CS诱导的条件性恐惧记忆损害。总体而言，我们的发现表明，OVX/CS小鼠模型对于研究雌激素丢失导致记忆障碍的机制是有用的。
We have recently found that the combination of ovariectomy (OVX) and chronic restraint stress (CS) causes hippocampal pyramidal cell loss and cognitive dysfunction in female rats and that estrogen replacement prevents the OVX/CS-induced morphological and behavioral changes. In this study, to clarify the mechanisms underlying the OVX/CS-mediated memory impairment further, we examined the roles of cholinergic systems in the OVX/CS-induced memory impairment in mice. Female Slc:ICR strain mice were randomly divided into two groups: OVX and sham-operated groups. Two weeks after the operation, the mice of each group were further assigned to CS (6 h/day) or non-stress group. Following the 3-week-stress period, all mice were subjected to contextual fear conditioning, and context- and tone-dependent memory tests were conducted 1 or 24 h after the conditioning. Overburden with 3 weeks of CS from 2 weeks after OVX impaired context- and tone-dependent freezing and the OVX/CS caused significant Nissl-stained neuron-like cell loss in the hippocampal CA3 region, although OVX and CS alone did not cause such behavioral and histological changes. Replacement of 17β-estradiol for 5 weeks after OVX suppressed OVX/CS-induced memory impairment and hippocampal Nissl-positive cell loss. Furthermore, the OVX/CS mice exhibited a significant decrease in choline acetyltransferase in the hippocampus compared with other groups. The cholinesterase inhibitors donepezil and galantamine ameliorated OVX/CS-induced memory impairment. These data suggest that cholinergic dysfunction may be involved in the OVX/CS-induced conditioned fear memory impairment. Overall, our findings suggest that the OVX/CS mouse model is useful to study the mechanisms underlying estrogen loss-induced memory deficits.