Laboratory of Neurodegeneration and Infection at the University Hospital João de Barros Barreto, Federal University of Pará, Belém, Pará, Brazil.
Prion. 2011 Jul-Sep;5(3):215-27. doi: 10.4161/pri.5.3.16936. Epub 2011 Jul 1.
Behavioral and neuropathological changes have been widely investigated in murine prion disease but stereological based unbiased estimates of key neuropathological features have not been carried out. After injections of ME7 infected (ME7) or normal brain homogenates (NBH) into dorsal CA1 of albino Swiss mice and C57BL6, we assessed behavioral changes on hippocampal-dependent tasks. We also estimated by optical fractionator at 15 and 18 weeks post-injections (w.p.i.) the total number of neurons, reactive astrocytes, activated microglia and perineuronal nets (PN) in the polymorphic layer of dentate gyrus (PolDG), CA1 and septum in albino Swiss mice. On average, early behavioral changes in albino Swiss mice start four weeks later than in C57BL6. Cluster and discriminant analysis of behavioral data in albino Swiss mice revealed that four of nine subjects start to change their behavior at 12 w.p.i. and reach terminal stage at 22 w.p.i and the remaining subjects start at 22 w.p.i. and reach terminal stage at 26 w.p.i. Biotinylated dextran-amine BDA-tracer experiments in mossy fiber pathway confirmed axonal degeneration, and stereological data showed that early astrocytosis, microgliosis and reduction in the perineuronal nets are independent of a change in the number of neuronal cell bodies. Statistical analysis revealed that the septal region had greater levels of neuroinflammation and extracellular matrix damage than CA1. This stereological and multivariate analysis at early stages of disease in an outbred model of prion disease provided new insights connecting behavioral changes and neuroinflammation and seems to be important to understand the mechanisms of prion disease progression.
在鼠朊病毒病中，行为和神经病理学变化已得到广泛研究，但尚未进行基于体视学的关键神经病理学特征的无偏估计。在向白化瑞士小鼠和 C57BL6 的背侧 CA1 注射 ME7 感染（ME7）或正常脑匀浆（NBH）后，我们评估了在海马依赖性任务中的行为变化。我们还通过光学分选区在注射后 15 和 18 周（w.p.i.）估计了白化瑞士小鼠多形层（PolDG）、CA1 和隔区中神经元、反应性星形胶质细胞、活化小胶质细胞和周围神经网（PN）的总数。平均而言，白化瑞士小鼠的早期行为变化比 C57BL6 晚四周开始。白化瑞士小鼠行为数据的聚类和判别分析表明，9 个实验对象中有 4 个在 12 w.p.i.开始改变行为，在 22 w.p.i.达到终末期，其余对象在 22 w.p.i.开始改变行为，在 26 w.p.i.达到终末期。苔藓纤维通路中的生物素化葡聚糖胺 BDA 示踪实验证实了轴突变性，体视学数据显示早期星形胶质细胞增生、小胶质细胞增生和周围神经网减少与神经元细胞体数量的变化无关。统计分析显示，隔区的神经炎症和细胞外基质损伤水平高于 CA1。这种在朊病毒病的杂种模型的疾病早期进行的立体学和多变量分析提供了新的见解，将行为变化与神经炎症联系起来，似乎对于理解朊病毒病进展的机制很重要。
