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首页> 美国卫生研究院文献>other >Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington’s Disease
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Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington’s Disease

机译：亨廷顿舞蹈病HdhQ150 / Q150小鼠模型中通过纵向MRI和组织病理学评估的行为缺陷与脑病理学的关系

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A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington’s disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the “clinical horizon” of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.
机译：已经开发出了多种表达突变亨廷顿蛋白（mHTT）的小鼠模型，这些小鼠亨廷顿病导致了聚集体和内含物，从而模拟了亨廷顿舞蹈病中观察到的分子病理学。在这里，我们显示，尽管纯合的HdhQ150敲入小鼠在36周龄时出现了运动障碍（rotarod，运动活动，抓地力），但认知功能障碍（游泳T迷宫，恐惧条件，气味歧视，社交互动）并未见94周。伴随行为评估，T2加权MRI体积测量表明纹状体生长较慢，即使在15周时，野生型（WT）和HdhQ150小鼠之间也存在显着差异。确实，MRI显示在36周龄运动障碍的“临床视野”出现之前，体积发生了明显变化。在94周内观察到纹状体减少27％，其中皮质（12％）和海马（21％）也显示出明显的萎缩。使用基于张量的形态计量学进行的无假设分析通过对比脑部生长和区域神经变性突出了其他区域正在经历萎缩。组织学揭示了mHTT聚集体和细胞包裹体的广泛存在。但是，几乎没有证据表明这些结果指标之间存在相关性，这可能表明在将分子病理学与行为障碍的发生联系起来的因果级联中，其他因素也很重要。总之，HdhQ150小鼠模型复制了人类状况的许多方面，包括运动障碍出现之前的预知期延长。

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