在zQ175 (190 CAG重复)亨廷顿病模型中,复杂的认知和动机缺陷先于运动功能障碍

IF 4.6 2区 医学 Q1 NEUROSCIENCES
D.J. Harrison , P. Linehan , Y. Patel , Z. Bayram-Weston , A.E. Rosser , S.B. Dunnett , S.P. Brooks , M.J. Lelos
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引用次数: 0

摘要

亨廷顿舞蹈病(HD)是一种进行性、遗传性神经退行性疾病,其特征是运动、认知和神经精神功能障碍,已经开发了几种小鼠模型。敲入模型,如zQ175,通过将CAG重复序列引入原生亨廷顿基因中,保留了在HD患者中观察到的遗传背景。在这项研究中,我们对zQ175小鼠的表型变化进行了全面的纵向分析,重点探讨了复杂认知过程的出现。我们的研究结果表明,在这个模型中,强烈的认知和动机缺陷先于运动功能障碍,并存在一些明显的性别差异。具体来说,雄性zQ175小鼠适应新环境的速度较慢,与雌性小鼠相比,它们表现出受损的感觉运动门控。在12周大的时候,在巴甫洛夫经典条件反射任务中观察到zQ175小鼠的认知缺陷。早在27周时就发现了为奖励而工作的动机降低,而在5选择系列反应时间任务中也发现了注意力和视觉空间缺陷。内隐学习缺陷在30周时被发现。zQ175小鼠在24周龄时表现为低活性,但在60周龄时表现为高活性。女性在24周出现运动障碍,男性在48周出现运动障碍。因此,我们观察到广泛的认知缺陷(注意、视觉空间、感觉运动、工具和内隐学习),以及运动变化的渐进进展。这个详细的表型时间线建立了该模型的面部有效性,因为这些小鼠表现出复杂的神经精神和认知障碍,这在HD患者中很明显。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Complex cognitive and motivational deficits precede motor dysfunction in the zQ175 (190 CAG repeat) Huntington's disease model
Huntington's disease (HD) is a progressive, inherited neurodegenerative disorder characterised by motor, cognitive, and neuropsychiatric dysfunction for which several mouse models have been developed. Knock-in models, such as zQ175, retain the genetic context observed in people with HD by introducing CAG repeats into the native huntingtin gene. In this study, we conducted a comprehensive, longitudinal analysis of phenotypic changes in the zQ175 mouse, with a focus on exploring the emergence of complex cognitive processes. Our findings indicate that robust cognitive and motivational deficits precede motor dysfunction in this model, with some apparent sex differences. Specifically, male zQ175 mice were slower to habituate to a novel environment and they showed impaired sensorimotor gating, in comparison to female mice. By 12 weeks old, cognitive deficits were observed in zQ175 mice of both sexes on a Pavlovian classical conditioning task. Reduced motivation to work for reward was identified as early as 27 weeks, while attentional and visuospatial deficits were also detected in the 5-choice serial reaction time task. Implicit learning deficits were identified at 30 weeks. zQ175 mice were hypoactive at ∼24 weeks but became hyperactive by 60 weeks of age. Motor impairments emerged by 24 weeks for females and 48 weeks for males. Thus, we observed a wide range of cognitive deficits (attentional, visuospatial, sensorimotor, instrumental and implicit learning), as well as a gradual progression of motor changes. This detailed phenotypic timeline establishes the face validity of this model insofar as these mice present with complex neuropsychiatric and cognitive impairments that are evident in people with HD.
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来源期刊
Experimental Neurology
Experimental Neurology 医学-神经科学
CiteScore
10.10
自引率
3.80%
发文量
258
审稿时长
42 days
期刊介绍: Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.
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