Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's disease
Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer's disease
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DOI：
10.1101/lm.51002
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发表时间：
2002-09-01
影响因子：
2
通讯作者：
Maren, S
中科院分区：
文献类型：
--
作者：
Corcoran, KA;Lu, Y;Maren, S
阿尔茨海默病的病理学特征之一是淀粉样蛋白斑块在整个大脑中的沉积，特别是在海马体和杏仁核内。过表达瑞典突变的人类淀粉样前体蛋白（bAPPswe; Tg 2576）的转基因小鼠在依赖于校园的团队任务中表现出年龄依赖性记忆缺陷。然而，老年Tg 2576小鼠在杏仁核依赖性学习任务中的表现尚未得到彻底评估。我们训练年轻（2-4个月）和老年（16-18个月）Tg 2576和野生型小鼠在T-迷宫交替任务（杏仁核和杏仁核依赖）和巴甫洛夫恐惧条件反射任务。如前所述，老年Tg 2576小鼠表现出获得奖励交替的受损;这些小鼠中没有一只在连续三天内达到六个正确反应中至少五个的标准。与此相反，老Tg 2576小鼠表现出正常水平的条件冻结的听觉条件刺激（CS），并获得了正常的上下文歧视。然而，当恐惧条件反射的显著性降低时，老年（12-14个月）Tg 2576小鼠在获得对条件反射的恐惧时受损，但对音调CS不受损。对一部分小鼠的组织学检查证实了老年Tg 2576小鼠的皮质、海马和杏仁核中存在淀粉样蛋白斑块，但年轻Tg 2576小鼠没有。因此，老年Tg 2576小鼠的学习和记忆缺陷仅限于大脑皮层依赖性任务，尽管在皮质、海马和杏仁核中广泛存在淀粉样蛋白沉积。
One of the hallmarks of the pathology in Alzheimer's disease is the deposition of amyloid plaques throughout the brain, especially within the hippocampus and amygdala. Transgenic mice that overexpress the Swedish mutation of human amyloid precursor protein (bAPPswe; Tg2576) show age-dependent memory deficits in hippocampus-dependent teaming tasks. However, the performance of aged Tg2576 mice in amygdala-dependent learning tasks has not been thoroughly assessed. We trained young (2-4 mo) and old (16-18 mo) Tg2576 and wild-type mice in a T-maze alternation task (hippocampus-dependent) and a Pavlovian fear-conditioning task (amygdala- and hippocampus-dependent). As previously reported, old Tg2576 mice showed impaired acquisition of rewarded alternation; none of these mice reached the criterion of at least five out of six correct responses over three consecutive days. In contrast, old Tg2576 mice showed normal levels of conditional freezing to an auditory conditional stimulus (CS) and acquired a contextual discrimination normally. However, when the salience of the fear-conditioning context was decreased, old (12-14 mo) Tg2576 mice were impaired at acquiring fear to the conditioning context, but not to the tone CS. Histological examination of a subset of the mice verified the existence of amyloid plaques in the cortex, hippocampus, and amygdala of old, but not young, Tg2576 mice. Hence, learning and memory deficits in old Tg2576 mice are limited to hippocampus-dependent tasks, despite widespread amyloid deposition in cortex, hippocampus, and amygdala.