Initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in rats with humanizing mutations in the Aβ-coding region of App.
Initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in rats with humanizing mutations in the Aβ-coding region of App.
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DOI：
10.1371/journal.pone.0263546
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
D'Adamio, Luciano
中科院分区：
文献类型：
--
作者：
Pham, Hoa;Yin, Tao;D'Adamio, Luciano
模拟人类疾病发病机制的模型生物可用于识别致病机制和测试针对其的化合物的治疗功效。阿尔茨海默病（AD）和相关痴呆症（ADRD）模型旨在重现与这些神经退行性疾病相关的大脑病理学。转基因模型涉及在人工启动子的控制下随机插入致病基因，是实现这一目标的有效手段。然而，转基因方法存在一些混杂因素，包括靶基因过度表达、转基因整合位点内源基因表达失调以及模拟功能丧失机制的局限性。此外，物种的选择很重要，并且有解剖学、生理学和认知方面的原因，选择大鼠而不是小鼠，而小鼠一直是神经变性和痴呆模型的标准。我们报告了对敲入 (KI) Long-Evans 大鼠的空间学习、逆转和测序任务能力的初步评估，该大鼠的 Aβ 编码区具有人性化突变，App 编码淀粉样前体蛋白 (Apph/h 大鼠)，使用 IntelliCage（一种自动化操作的社交家庭笼系统）在 6-8 周龄，然后在 4-5 月龄再次进行评估。这些大鼠之前是作为对照生物体产生的，用于涉及我们实验室的其他敲入大鼠模型的神经变性研究。任何性别的 Apph/h 大鼠都可以获得位置学习和逆转任务。它们还可以在 6-8 周龄时完成对角线测序任务，但无法完成涉及交替对角线的更高级的连续逆转任务，甚至在 4-5 个月大时也是如此。因此，在后续研究中，使用 IntelliCage 系统进行纵向行为分析可有助于确定家族性 AD (FAD)、散发性迟发性 AD (LOAD) 和 ADRD 的 KI 大鼠模型是否会出现衰老依赖性学习和记忆缺陷。
Model organisms mimicking the pathogenesis of human diseases are useful for identifying pathogenic mechanisms and testing therapeutic efficacy of compounds targeting them. Models of Alzheimer’s disease (AD) and related dementias (ADRD) aim to reproduce the brain pathology associated with these neurodegenerative disorders. Transgenic models, which involve random insertion of disease-causing genes under the control of artificial promoters, are efficient means of doing so. There are confounding factors associated with transgenic approaches, however, including target gene overexpression, dysregulation of endogenous gene expression at transgenes’ integration sites, and limitations in mimicking loss-of-function mechanisms. Furthermore, the choice of species is important, and there are anatomical, physiological, and cognitive reasons for favoring the rat over the mouse, which has been the standard for models of neurodegeneration and dementia. We report an initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in (KI) Long-Evans rats with humanizing mutations in the Aβ-coding region of App, which encodes amyloid precursor protein (Apph/h rats), using the IntelliCage, an automated operant social home cage system, at 6–8 weeks of age, then again at 4–5 months of age. These rats were previously generated as control organisms for studies on neurodegeneration involving other knock-in rat models from our lab. Apph/h rats of either sex can acquire place learning and reversal tasks. They can also acquire a diagonal sequencing task by 6–8 weeks of age, but not a more advanced serial reversal task involving alternating diagonals, even by 4–5 months of age. Thus, longitudinal behavioral analysis with the IntelliCage system can be useful to determine, in follow-up studies, whether KI rat models of Familial AD (FAD), sporadic late onset AD (LOAD), and of ADRD develop aging-dependent learning and memory deficits.
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影响因子：
3
作者：
Iman IN;Yusof NAM;Talib UN;Ahmad NAZ;Norazit A;Kumar J;Mehat MZ;Jayabalan N;Muthuraju S;Stefaniuk M;Kaczmarek L;Muzaimi M
通讯作者：
Muzaimi M
影响因子：
3.7
作者：
Barbagallo AP;Weldon R;Tamayev R;Zhou D;Giliberto L;Foreman O;D'Adamio L
通讯作者：
D'Adamio L
影响因子：
5.3
作者：
Grover, A;England, E;Hutton, M
通讯作者：
Hutton, M
影响因子：
56.9
作者：
Hong, M;Zhukareva, V;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1016/s0169-328x(99)00079-0
发表时间：
1999-05-07
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Janke, C;Beck, M;Arendt, T
通讯作者：
Arendt, T