Roth Lynn, Van Dam Debby, Van der Donckt Carole, Schrijvers Dorien M, Lemmens Katrien, Van Brussel Ilse, De Deyn Peter P, Martinet Wim, De Meyer Guido R Y
Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
Physiol Behav. 2015 Feb;139:397-402. doi: 10.1016/j.physbeh.2014.11.047. Epub 2014 Nov 20.
Apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE(-/-) Fbn1(C1039G+/-) mice on WD for 20 weeks (n=21). ApoE(-/-) mice on WD (n=24) and ApoE(-/-) Fbn1(C1039G+/-) mice on normal diet (ND, n=21) served as controls. Starting from 10 weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13 weeks of diet to study spatial learning. At the end of the experiment (20 weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12 weeks onward, gait analysis of ApoE(-/-) Fbn1(C1039G+/-) mice on WD revealed a progressive increase in track width as compared to ApoE(-/-) mice on WD and ApoE(-/-) Fbn1(C1039G+/-) mice on ND (at 20 weeks: 29.8±0.6 mm vs. 25.8±0.4 mm and 26.0±0.5 mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE(-/-) Fbn1(C1039G+/-) mice on WD at 18 and 20 weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE(-/-) Fbn1(C1039G+/-) mice on WD. Furthermore, the parietal cortex of ApoE(-/-) Fbn1(C1039G+/-) mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE(-/-) Fbn1(C1039G+/-) mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice.
载脂蛋白E缺陷（ApoE(-/-)）且原纤维蛋白-1基因存在杂合突变（Fbn1(C1039G+/-)）的小鼠，在喂食西式饮食（WD）时会出现自发性动脉粥样硬化斑块破裂、脑血流紊乱和猝死。本研究聚焦于喂食WD 20周的ApoE(-/-) Fbn1(C1039G+/-)小鼠（n = 21）的运动协调性和空间学习能力。喂食WD的ApoE(-/-)小鼠（n = 24）和喂食正常饮食（ND，n = 21）的ApoE(-/-) Fbn1(C1039G+/-)小鼠作为对照。从饮食10周开始，每两周通过以下测试评估协调性：步态分析、固定梁测试、悬线测试和加速旋转杆测试。饮食13周后进行莫里斯水迷宫测试以研究空间学习能力。在实验结束时（WD 20周），处死小鼠并分离头臂动脉和脑。从12周起，与喂食WD的ApoE(-/-)小鼠和喂食ND的ApoE(-/-) Fbn1(C1039G+/-)小鼠相比，喂食WD的ApoE(-/-) Fbn1(C1039G+/-)小鼠的步态分析显示轨迹宽度逐渐增加（20周时：29.8±0.6毫米对25.8±0.4毫米和26.0±0.5毫米）。此外，固定梁测试显示喂食WD的ApoE(-/-) Fbn1(C1039G+/-)小鼠在18周和20周时运动协调性下降。悬线测试和加速旋转杆测试未检测到运动障碍迹象。空间学习能力也未受影响。对头臂动脉的组织学分析显示，喂食WD的ApoE(-/-) Fbn1(C1039G+/-)小鼠有更大且更狭窄的斑块。此外，喂食WD的ApoE(-/-) Fbn1(C1039G+/-)小鼠的顶叶皮质显示核固缩，这是缺氧的迹象，核固缩百分比与轨迹宽度相关。总之，步态分析可能是分析ApoE(-/-) Fbn1(C1039G+/-)小鼠模型中缺氧性脑损伤的有效方法。该测试对于评估小鼠潜在抗动脉粥样硬化疗法的效果可能有价值。
