R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.
R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.
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DOI：
10.1523/jneurosci.0388-12.2012
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发表时间：
2012-05-09
期刊：
影响因子：
--
通讯作者：
Moreno H
中科院分区：
文献类型：
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作者：
Cepeda-Prado E;Popp S;Khan U;Stefanov D;Rodríguez J;Menalled LB;Dow-Edwards D;Small SA;Moreno H
亨廷顿病病理的一个显著特征是大脑区域的萎缩，包括但不限于纹状体。尽管MRI研究已经证实了几种HD小鼠模型的中枢神经系统结构的变化，但HD病理在疾病进展过程中的功能后果尚未使用体内功能磁共振成像(FMRI)进行研究。为了解决这个问题，我们首先建立了幼年HD小鼠模型R6/2在疾病早期和晚期的结构和功能MRI表型。在两个年龄组的特定脑区，fMRI信号(相对脑血容量-rCBV)和萎缩均显著增加。接下来，将功能磁共振成像结果与电生理分析相关联，电生理分析显示受影响大脑区域的神经元活动异常增加-从而确定了异常功能磁共振成像结果的机制。[14C]还生成了用于研究葡萄糖利用模式的脱氧葡萄糖(2DG)图。观察到rCBV的增加和葡萄糖摄取的减少之间存在有趣的不匹配。最后，我们评估了该小鼠系在病程早期对听源性惊厥的敏感性。我们发现R6/2小鼠对癫痫的易感性增加。总之，这些发现确定了R6/2小鼠的癫痫发作活动，并表明对氧代谢敏感的神经成像措施可以用作体内的生物标记物，在显性行为表型开始之前。由于fMRI-rCBV也可以在患者身上获得，我们建议它可以作为一种翻译工具来评估在人类和HD小鼠模型中的治疗反应。
A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several HD mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional magnetic resonance imaging (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI-signals (relative cerebral blood volumes-rCBV) and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions- thus identifying a mechanism accounting for the abnormal fMRI findings. [14C] deoxyglucose (2DG) maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice, and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models.