Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice
Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice
复制标题
DOI：
10.1016/j.expneurol.2004.05.005
复制
发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Fike, JR
中科院分区：
文献类型：
--
作者：
Rola, R;Raber, J;Fike, JR
儿科脑肿瘤治疗的进步提高了儿童的生存率，但由于辐射引起的认知缺陷，他们的生活质量受到损害。这些缺陷的发病机制尚不清楚，但可能涉及海马内神经发生减少。为了确定齿状核颗粒下区（SGZ）的急性放射敏感性，21日龄的C57 BL/J6雄性小鼠接受全脑照射（2-10戈伊），48 h后，使用免疫组织化学对组织进行评估。增殖的SGZ细胞及其后代，未成熟的神经元，以剂量依赖性的方式减少。为了确定急性变化是否转化为神经发生的长期改变，给予小鼠5戈伊的单次剂量，1或3个月后，用5-溴-2 '-脱氧尿苷（BrdU）标记增殖细胞。共聚焦显微镜用于确定显示成熟细胞表型的BrdU标记细胞的百分比。X射线在两个时间点都显著减少了新神经元的产生，而神经胶质成分没有变化或略有增加。活化的小胶质细胞和浸润的外周单核细胞的措施表明，减少神经发生与慢性炎症反应。照射后三个月，神经发生的变化与空间记忆保留缺陷确定使用Morris水迷宫。行为训练和测试增加了未成熟神经元的数量，在受辐射的动物中最为显著。这些数据提供的证据表明，年轻动物的辐射诱导的SGZ神经发生的长期损害，这是与海马依赖性记忆缺陷。(C)2004爱思唯尔公司All rights reserved.
Advances in the management of pediatric brain tumors have increased survival rates in children, but their quality of life is impaired due to cognitive deficits that arise from irradiation. The pathogenesis of these deficits remains unknown, but may involve reduced neurogenesis within the hippocampus. To determine the acute radiosensitivity of the dentate subgranular zone (SGZ), 21-day-old C57BL/J6 male mice received whole brain irradiation (2-10 Gy), and 48 h later, tissue was assessed using immunohistochemistry. Proliferating SGZ cells and their progeny, immature neurons, were decreased in a dose-dependent fashion. To determine if acute changes translated into long-term alterations in neurogenesis, mice were given a single dose of 5 Gy, and 1 or 3 months later, proliferating cells were labeled with 5-bromo-2'-deoxyuridine (BrdU). Confocal microscopy was used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes. X-rays significantly reduced the production of new neurons at both time points, while glial components showed no change or small increases. Measures of activated microglia and infiltrating, peripheral monocytes indicated that reduced neurogenesis was associated with a chronic inflammatory response. Three months after irradiation, changes in neurogenesis were associated with spatial memory retention deficits determined using the Morris water maze. Behavioral training and testing increased the numbers of immature neurons, most prominently in irradiated animals. These data provide evidence that irradiation of young animals induces a long-term impairment of SGZ neurogenesis that is associated with hippocampal-dependent memory deficits. (C) 2004 Elsevier Inc. All rights reserved.