A detailed analysis of the early context extinction deficits seen in APPswe/PS1dE9 female mice and their relevance to preclinical Alzheimer's disease
A detailed analysis of the early context extinction deficits seen in APPswe/PS1dE9 female mice and their relevance to preclinical Alzheimer's disease
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DOI：
10.1016/j.bbr.2011.03.041
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发表时间：
2011-09-12
影响因子：
2.7
通讯作者：
Pardon, Marie-Christine
中科院分区：
文献类型：
--
作者：
Bonardi, Charlotte;de Pulford, Felicity;Pardon, Marie-Christine
阿尔茨海默病（AD）是一种无法治愈的与年龄相关的神经退行性疾病，其特征在于认知和身体功能的进行性下降以及广泛的脑损伤。识别伴随早期AD的认知缺陷是至关重要的，因为伴随的突触变化可以被当前的治疗有效地靶向-目前AD通常直到建立脑病理学才被诊断，并且治疗相对无效。因此，我们研究了4个月大的小鼠（APPswe/PS1 d9小鼠系）的早期认知变化，这些小鼠过度表达了2种导致AD的基因。实验1测试了4个月大的雌性APPswe/PS1 dE 9小鼠和它们的野生型同窝仔在4个验证的任务，涉及8个认知和非认知措施。我们观察到在APPswe/PS1 dE 9小鼠的背景恐惧灭绝的选择性缺陷。为了扩展这一发现的一般性，实验2研究了条件反射和消光的听觉刺激与蔗糖增敏剂配对。基因型没有影响。第三个实验研究了背景消退障碍是否可以归因于注意力缺陷。一个条件刺激（CS）预先暴露没有后果，然后它和第二个，新的听觉CS与食物配对。预曝光产生相等的延迟预曝光CS在两种基因型的空调。然而，在实验2中，并略有在实验3中，额外的测试显示，在转基因小鼠的背景灭绝的选择性损害的证据。这些数据表明，在APPswe/PS1 dE 9小鼠中，背景消退缺陷先于其他认知障碍，这种效应与轻度AD患者的发现有有趣的相似之处。(C)2011 Elsevier B. V.保留所有权利。
Alzheimer's disease (AD) is an incurable age-related neurodegenerative condition, characterised by progressive decline in cognitive and physical functions, and extensive brain damage. Identifying cognitive deficits that accompany early AD is critical, as the accompanying synaptic changes can be effectively targeted by current treatments - at present AD is typically not diagnosed until brain pathology is established, and treatment relatively ineffective. We therefore examined early cognitive changes in 4-month-old mice over-expressing 2 genes responsible for AD (APPswe/PS1d9 mouse line). Experiment 1 tested 4-month-old female APPswe/PS1dE9 mice and their wild-type littermates on 4 validated tasks involving 8 cognitive and non cognitive measures. We observed a selective deficit in extinction of contextual fear in APPswe/PS1dE9 mice. To extend the generality of this finding, Experiment 2 examined conditioning and extinction of an auditory stimulus paired with a sucrose reinforcer. No effect of genotype was observed. A third experiment investigated whether the context extinction impairment could be attributed to an attentional deficit. One conditioning stimulus (CS) was preexposed without consequence, and then it and a second, novel auditory CS were paired with food. Preexposure produced equal retardation of conditioning of the preexposed CS in both genotypes. However, in Experiment 2, and marginally in Experiment 3, additional tests revealed evidence of a selective impairment in context extinction in transgenic mice. These data suggest that context extinction deficits precede other cognitive impairments in APPswe/PS1dE9 mice, an effect that has intriguing parallels with findings in patients with mild AD. (C) 2011 Elsevier B.V. All rights reserved.