Elimination of microglia improves cognitive function following cranial irradiation.
Elimination of microglia improves cognitive function following cranial irradiation.
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DOI：
10.1038/srep31545
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发表时间：
2016-08-12
影响因子：
4.6
通讯作者：
Limoli CL
中科院分区：
文献类型：
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作者：
Acharya MM;Green KN;Allen BD;Najafi AR;Syage A;Minasyan H;Le MT;Kawashita T;Giedzinski E;Parihar VK;West BL;Baulch JE;Limoli CL
治疗脑癌的颅照射会导致与显著神经病理学相关的进行性和严重认知功能障碍。中枢神经系统的辐射损伤与持续的小胶质细胞活化有关，我们发现即使在辐射后6周，促炎基因也会上调。我们假设，在照射大脑中的小胶质细胞的耗竭将有神经保护作用。成年小鼠仅接受急性头部照射（9戈伊），并给予集落刺激因子-1受体（CSF 1 R）的饮食抑制剂（PLX 5622）以消耗照射后的小胶质细胞。4-6周后，使用一系列行为任务分析维持正常饮食和PLX 5662饮食的小鼠队列的认知变化。PLX 5622处理在处理3天内引起脑中小胶质细胞的快速和几乎完全消除。给予正常饮食的动物的辐射引起特征性行为缺陷，该缺陷旨在测试内侧前额叶皮层（mPFC）和海马学习和记忆，并引起小胶质细胞活化增加。接受PLX 5622饲料的动物未表现出辐射诱导的认知缺陷，并且表现出mPFC和海马中IBA-1和CD 68阳性小胶质细胞几乎完全丧失。我们的数据表明，通过CSF 1 R抑制消除小胶质细胞可以改善辐射诱导的小鼠认知缺陷。
Cranial irradiation for the treatment of brain cancer elicits progressive and severe cognitive dysfunction that is associated with significant neuropathology. Radiation injury in the CNS has been linked to persistent microglial activation, and we find upregulation of pro-inflammatory genes even 6 weeks after irradiation. We hypothesize that depletion of microglia in the irradiated brain would have a neuroprotective effect. Adult mice received acute head only irradiation (9 Gy) and were administered a dietary inhibitor (PLX5622) of colony stimulating factor-1 receptor (CSF1R) to deplete microglia post-irradiation. Cohorts of mice maintained on a normal and PLX5662 diet were analyzed for cognitive changes using a battery of behavioral tasks 4–6 weeks later. PLX5622 treatment caused a rapid and near complete elimination of microglia in the brain within 3 days of treatment. Irradiation of animals given a normal diet caused characteristic behavioral deficits designed to test medial pre-frontal cortex (mPFC) and hippocampal learning and memory and caused increased microglial activation. Animals receiving the PLX5622 diet exhibited no radiation-induced cognitive deficits, and exhibited near complete loss of IBA-1 and CD68 positive microglia in the mPFC and hippocampus. Our data demonstrate that elimination of microglia through CSF1R inhibition can ameliorate radiation-induced cognitive deficits in mice.