Extreme sensitivity of adult neurogenesis to low doses of X-irradiation.
Extreme sensitivity of adult neurogenesis to low doses of X-irradiation.
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发表时间：
2003-07
期刊：
影响因子：
11.2
通讯作者：
S. Mizumatsu;Michelle Monje;Duncan R. Morhardt;R. Rola;T. Palmer;J. Fike
中科院分区：
文献类型：
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作者：
S. Mizumatsu;Michelle Monje;Duncan R. Morhardt;R. Rola;T. Palmer;J. Fike
脑的治疗性照射与许多不良反应有关，包括认知障碍。虽然放射性认知损伤的发病机制尚不清楚，但它可能涉及海马齿状回颗粒下带(SGZ)的神经前体细胞的丢失和新细胞产生的变化(神经发生)。青年雄性C57BL小鼠接受全脑照射，6~48h后取海马区组织，用免疫组织化学方法检测细胞凋亡、增殖细胞和未成熟神经元的数量。细胞凋亡率在照射后12h达高峰，且程度呈剂量依赖性。照射后48h，增殖的SGZ细胞减少93-96%，未成熟神经元减少40-60%，呈剂量依赖关系。为了确定急性细胞敏感性是否转化为长期变化，我们在0、2、5或10Gy射线照射后2个月量化了神经发生。多次注射BrdUrd标记增殖细胞，3周后用共聚焦显微镜观察BrdUrd标记的成熟细胞表型的百分比。X射线显著减少了新神经元的产生；这种变化是剂量依赖性的。相反，对新的星形胶质细胞或少突胶质细胞的产生没有明显的影响。对激活的小胶质细胞的测量表明，神经发生的变化与显著的炎症反应有关。鉴于辐射对认知功能的已知影响以及海马神经发生和相关记忆形成之间的关系，我们的数据表明，前体细胞辐射反应和改变的神经发生可能在辐射诱导的认知损害中起贡献作用。
Therapeutic irradiation of the brain is associated with a number of adverse effects, including cognitive impairment. Although the pathogenesis of radiation-induced cognitive injury is unknown, it may involve loss of neural precursor cells from the subgranular zone (SGZ) of the hippocampal dentate gyrus and alterations in new cell production (neurogenesis). Young adult male C57BL mice received whole brain irradiation, and 6-48 h later, hippocampal tissue was assessed using immunohistochemistry for detection of apoptosis and numbers of proliferating cells and immature neurons. Apoptosis peaked 12 h after irradiation, and its extent was dose dependent. Forty-eight h after irradiation, proliferating SGZ cells were reduced by 93-96%; immature neurons were decreased from 40 to 60% in a dose-dependent fashion. To determine whether acute cell sensitivity translated into long-term changes, we quantified neurogenesis 2 months after irradiation with 0, 2, 5, or 10 Gy. Multiple injections of BrdUrd were given to label proliferating cells, and 3 weeks later, confocal microscopy was used to determine the percentage of BrdUrd-labeled cells that showed mature cell phenotypes. The production of new neurons was significantly reduced by X-rays; that change was dose dependent. In contrast, there were no apparent effects on the production of new astrocytes or oligodendrocytes. Measures of activated microglia indicated that changes in neurogenesis were associated with a significant inflammatory response. Given the known effects of radiation on cognitive function and the relationship between hippocampal neurogenesis and associated memory formation, our data suggest that precursor cell radiation response and altered neurogenesis may play a contributory if not causative role in radiation-induced cognitive impairment.