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铁颗粒暴露导致基因组不稳定性细胞指数长期增加,并短暂抑制成年海马神经发生。

Fe Particle Exposure Results in a Long-Lasting Increase in a Cellular Index of Genomic Instability and Transiently Suppresses Adult Hippocampal Neurogenesis .

作者信息

DeCarolis Nathan A, Rivera Phillip D, Ahn Francisca, Amaral Wellington Z, LeBlanc Junie A, Malhotra Shveta, Shih Hung-Ying, Petrik David, Melvin Neal, Chen Benjamin P C, Eisch Amelia J

机构信息

Dept Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.

Dept Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA.

出版信息

Life Sci Space Res (Amst). 2014 Jul 1;2:70-79. doi: 10.1016/j.lssr.2014.06.004.

Abstract

The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreER/R26R:YFP mice, respectively). Mice were subjected to Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24h), intermediate (7d), and/or long time points (2-3mo) post-irradiation. Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support the regenerative capacity of the adult SGZ after HZE particle exposure and encourage additional inquiry into the relationship between radial glia stem cells and cognitive function after HZE particle exposure.

摘要

来自银河宇宙辐射的高传能线密度重离子(HZE)粒子对宇航员构成了巨大的健康风险,因为它们可能会引发阈下脑损伤或适应不良,进而导致认知障碍。HZE粒子对健康的影响难以预测且无法预防。这凸显了评估对整个中枢神经系统以及对特定脑区(如对学习和记忆至关重要的海马体)的辐射风险的重要性。鉴于海马体中的神经发生与学习和记忆有关,我们使用两种巢蛋白转基因报告小鼠品系来标记和追踪放射状胶质干细胞(分别为Nestin-GFP和Nestin-CreER/R26R:YFP小鼠),研究了成年小鼠海马齿状回在受到HZE粒子照射后神经发生和神经干细胞的反应及恢复情况。小鼠接受铁粒子照射(0或1 Gy,能量为300或1000 MeV/n),并在照射后的早期(24小时)、中期(7天)和/或长期(2 - 3个月)时间点采集大脑。铁粒子照射导致照射后中期和长期时间点的53BP1+病灶显著增加,表明大脑存在长期的基因组不稳定。然而,铁粒子照射仅在中期时间点使未成熟神经元数量短暂减少,照射后长期时间点无显著减少。铁粒子照射同样使分裂祖细胞短暂减少,早期时间点标记的祖细胞较少,但中期时间点标记的祖细胞数量相等,表明神经发生有所恢复。值得注意的是,铁粒子照射并未改变表达巢蛋白的神经干细胞总数。这些结果表明,尽管基因组不稳定指标持续存在,但铁粒子诱导的成年海马神经发生缺陷可能是短暂的。这些数据支持了成年海马下颗粒层在受到HZE粒子照射后的再生能力,并鼓励进一步探究放射状胶质干细胞与HZE粒子照射后认知功能之间的关系。

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