脑灌注不足小鼠模型中的脑白质病变、脑炎症与认知功能

White matter lesions, cerebral inflammation and cognitive function in a mouse model of cerebral hypoperfusion.

机构信息

Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Hadassah BrainLabs - National Knowledge Center for Research on Brain Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Hadassah BrainLabs - National Knowledge Center for Research on Brain Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Departments of Psychology and Life Sciences, School of Sciences, Achva Academic College, Be'er Tuvia, Israel.

出版信息

Brain Res. 2019 May 15;1711:193-201. doi: 10.1016/j.brainres.2019.01.017. Epub 2019 Jan 16.

Abstract

Development of specific treatments for vascular dementia requires appropriate animal models. Bilateral carotid artery stenosis (BCAS) employs metal coils wrapped around both common carotid arteries to induce cerebral hypoperfusion, white matter lesions and memory impairment in mice. We focused on the relationship of memory impairment induced by BCAS to white matter lesions demonstrated by ex vivo magnetic resonance imaging (MRI). We found a significant effect of BCAS on perceptual learning in the novel object recognition test and on number of errors and latency to platform in the radial arm water maze. MRI analysis revealed a significant effect of BCAS on diffusion tensor imaging (DTI) parameters in white matter areas. After correction for multiple testing, significantly lower fractional anisotropy (FA) values were found in the corpus callosum and anterior commissure and significantly higher mean diffusivity values in the internal capsule. Focusing on the corpus callosum, we found that correlations between FA and number of errors on the RAWM test were significant after controlling for treatment. We further found that the effects of BCAS on cognition were partly mediated by its effects on white matter integrity. Immunofluorescence studies demonstrated significantly higher microglia cell density and soma size in the corpus callosum of BCAS mice compared to controls, and these parameters were correlated with the imaging data. The results of this study indicate that cognitive deficits induced by cerebral hypoperfusion due to BCAS result in part from microglia activation and disruption of white matter integrity, supporting the face and construct validity of this unique model of vascular dementia.

摘要

开发针对血管性痴呆的特定治疗方法需要适当的动物模型。双侧颈总动脉狭窄(BCAS)采用金属丝缠绕在双侧颈总动脉上,以诱导小鼠脑灌注不足、白质病变和记忆障碍。我们关注的是 BCAS 诱导的记忆障碍与体外磁共振成像(MRI)显示的白质病变之间的关系。我们发现 BCAS 对新奇物体识别测试中的知觉学习以及放射臂水迷宫测试中的错误数量和到达平台的潜伏期有显著影响。MRI 分析显示 BCAS 对白质区弥散张量成像(DTI)参数有显著影响。经过多重检验校正后,在胼胝体和前连合的分数各向异性(FA)值显著降低,在内囊的平均扩散系数值显著升高。在胼胝体上,我们发现 FA 值与 RAWM 测试中的错误数量之间的相关性在控制治疗后是显著的。我们进一步发现,BCAS 对认知的影响部分是通过其对白质完整性的影响介导的。免疫荧光研究表明,BCAS 小鼠的胼胝体中的小胶质细胞密度和胞体大小显著高于对照组,这些参数与成像数据相关。这项研究的结果表明,由于 BCAS 引起的脑灌注不足导致的认知缺陷部分是由于小胶质细胞激活和白质完整性破坏所致,支持了这种独特的血管性痴呆模型的表面效度和结构效度。

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