Evidence of functional brain reorganization on the basis of blood flow changes in the CAG140 knock-in mouse model of Huntington's disease.
Evidence of functional brain reorganization on the basis of blood flow changes in the CAG140 knock-in mouse model of Huntington's disease.
复制标题
基于亨廷顿病 CAG140 敲入小鼠模型血流变化的功能性大脑重组的证据。
DOI：
10.1097/wnr.0000000000000587
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发表时间：
2016
期刊：
影响因子：
1.7
通讯作者：
Holschneider,DanielP
中科院分区：
文献类型：
--
作者：
Wang,Zhuo;Stefanko,DanielP;Guo,Yumei;Toy,WilliamA;Petzinger,GiselleM;Jakowec,MichaelW;Holschneider,DanielP
神经影像学，特别是功能性脑图谱，可以深入了解与局部区域病理学经典相关的疾病中多个大脑区域和环路的分布参与。亨廷顿舞蹈症 (HD) 就是一个例子，通常被归类为基底神经节疾病。在这里，我们报告了 HD 小鼠模型中脑灌注图的基因型差异，其特征是人类外显子 1 CAG 140 扩展重复序列（CAG 140 KI 小鼠）的基因敲入（KI）。动物在 6 个月大时进行检查，并与野生型同窝动物进行比较。使用[14C]-碘安替比林放射自显影技术绘制清醒、不受约束、休息时的雄性小鼠的区域脑血流量（rCBF），并通过统计参数绘图在三维重建的大脑中进行分析。我们的结果显示，CAG 140 KI 和 WT 小鼠之间的 rCBF 存在显着变化，例如 CAG 140 KI 动物表现出基底神经节运动回路灌注不足以及小脑丘脑和体感区域灌注过度。 CAG 140 KI 小鼠的前边缘和扣带皮层（内侧前额叶区）以及海马体（与认知处理和情绪相关的区域）也出现了明显的灌注不足。在没有运动缺陷（旋转试验）或纹状体（尾壳核）或半球体积萎缩的情况下，rCBF 的变化是明显的。我们的结果表明，CAG 140 KI 小鼠在症状发生前阶段，全脑网络发生了功能重组。动物的功能性大脑图谱将来可能作为转化生物标志物，用于识别 HD 大脑中早期突触变化的位点，并用于指导有针对性的临床前分子研究和临床治疗。
Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is Huntington’s disease (HD), typically classified as a basal ganglia disorder. Here, we report genotypic differences in cerebral perfusion mapping in an HD mouse model characterized by a gene knock-in (KI) of a human exon 1 CAG 140 expansion repeat (CAG 140 KI mice). Animals were examined at 6 months and compared with wild-type littermates. Regional cerebral blood flow (rCBF) was mapped in the awake, nonrestrained, male mouse at rest using [14 C]-iodoantipyrine autoradiography and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. Our results showed significant changes in rCBF between CAG 140 KI and WT mice, such that CAG 140 KI animals showed hypoperfusion of the basal ganglia motor circuit and hyperperfusion of cerebellar–thalamic and somatosensory regions. Significant hypoperfusion was also noted in CAG 140 KI mice in the prelimbic and cingulate cortex (medial prefrontal area) and the hippocampus–areas associated with cognitive processing and mood. Changes in rCBF were apparent in the absence of motor deficits (rotarod test) or atrophy in the striatum (caudate-putamen) or hemispheric volume. Our results suggest a functional reorganization of whole-brain networks at a presymptomatic stage in the life of the CAG 140 KI mouse. Functional brain mapping in animals may, in the future, serve as a translational biomarker for identifying sites of early synaptic change in the HD brain and for directing targeted preclinical molecular studies and clinical therapies.