Dysfunction in Motor Coordination in Neonatal White Matter Injury Model Without Apparent Neuron Loss
Dysfunction in Motor Coordination in Neonatal White Matter Injury Model Without Apparent Neuron Loss
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DOI：
10.3727/096368915x689893
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发表时间：
2016-01-01
影响因子：
3.3
通讯作者：
Hida, Hideki
中科院分区：
文献类型：
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作者：
Misumi, Sachiyo;Ueda, Yoshitomo;Hida, Hideki
采用右侧颈总动脉结扎加6%氧气60min的方法，于出生后第3天(P3)建立白质损伤(WMI)模型，其中活跃增殖的少突胶质细胞(OL)祖细胞主要受损。为了了解该模型是否适用于使用OL祖细胞进行细胞治疗，我们观察了神经元和OL系细胞对轻度缺氧-缺血(H-I)的病理反应和髓鞘功能障碍，并进行了基因表达分析。在WMI模型大鼠中，通过加速转杆试验评估的协调运动功能受损。这种功能障碍伴随着感觉运动皮质I-IV层的髓鞘功能衰竭。虽然在脑缺血后24 h，皮质和白质中有几个寡核苷酸阳性神经元呈caspase3阳性，但很少有NeuN阳性神经元发生凋亡。Argyrophil-III染色显示，模型中受损神经元的退化细胞数量没有增加。7d后，大脑皮层NeuN阳性神经元总数与对照组相当。用荧光金逆行标记皮质脊髓束未见明显的V层神经元丢失。此外，运动区和感觉区的皮质投射神经元和V-VI层神经元的数量也没有减少。有趣的是，对小白蛋白、钙视黄素或生长抑素免疫反应的GABA能抑制细胞的数量保留在P26皮质。P5的基因表达分析显示，98个上调基因和65个下调基因可能与细胞存活、髓鞘丢失和OL的分化有关。这些数据表明，运动协调性受损不是由神经元丢失引起的，而是由I-IV层的髓鞘形成失败引起的。由于OL系细胞主要受损，这种WMI模型通过替代OL祖细胞，可能对基于细胞的治疗有用。
We made a white matter injury (WMI) model with mild hindlimb dysfunction by right common carotid artery occlusion followed by 6% oxygen for 60 min at postnatal day 3 (P3), in which actively proliferating oligodendrocyte (OL) progenitors are mainly damaged. To know whether this model is appropriate for cell therapy using OL progenitors, the pathological response to mild hypoxia-ischemia (H-I) in neurons and OL lineage cells and myelination failure were investigated along with gene expression analysis. In WMI model rats, coordinated motor function, as assessed by the accelerating rotarod test, was impaired. The dysfunction was accompanied by myelination failure in layers I-IV of the sensorimotor cortex. Although several oligo2-positive OLs stained positive for active caspase 3 in the cortex and white matter at 24 h after H-I, few NeuN-positive neurons were apoptotic. Argyrophil-III staining for damaged neurons revealed no increase in the number of degenerating cells in the model. Moreover, the total number of NeuN-positive neurons in the cortex was comparable to that of controls 7 days later. Retrograde labeling of the corticospinal tract with Fluoro-Gold revealed no significant loss of layer V neurons. In addition, no decrease in the numbers of cortical projecting neurons and layers V-VI neurons in both motor and sensory areas was observed. Interestingly, the numbers of inhibitory GABAergic cells immunoreactive for parvalbumin, calretinin, or somatostatin were preserved in the P26 cortex. Gene expression analysis at P5 revealed 98 upregulated and 65 downregulated genes that may relate to cell survival, myelin loss, and differentiation of OLs. These data suggest that impaired motor coordination was not induced by neuron loss but, rather, myelination failure in layers I-IV. As OL lineage cells are mainly damaged, this WMI model might be useful for cell-based therapy by replacing OL progenitors.