Effects of radiation combined injury on hippocampal function are modulated in mice deficient in chemokine receptor 2 (CCR2).
Effects of radiation combined injury on hippocampal function are modulated in mice deficient in chemokine receptor 2 (CCR2).
复制标题
DOI：
10.1667/rr3344.1
复制
发表时间：
2013-07
影响因子：
3.4
通讯作者：
Fike JR
中科院分区：
文献类型：
--
作者：
Allen AR;Eilertson K;Sharma S;Schneider D;Baure J;Allen B;Rosi S;Raber J;Fike JR
趋化因子及其受体在正常的脑功能以及病理条件如损伤和疾病相关的神经炎症中起着至关重要的作用。趋化因子受体-2（CCR 2）介导浸润性和驻留性小胶质细胞向中枢神经系统（CNS）炎症部位的募集，其被电离辐射和创伤性脑损伤上调。我们的目的是确定CCR 2的缺陷和随后对脑小胶质细胞的影响是否会影响放射复合伤（RCI）后的神经发生和认知功能。CCR 2敲除（-/-）和野生型（WT）小鼠接受4戈伊的全身137 Cs照射。照射后立即使用受控皮质撞击系统诱导单侧创伤性脑损伤。照射后44天，在Morris水迷宫中测试动物的视皮层依赖性认知表现。在认知测试后，将动物安乐死，并将它们的大脑快速冷冻，用于海马齿状回中神经炎症（活化的小胶质细胞）和神经发生的免疫组织化学评估。所有动物都能够在水迷宫中定位可见和隐藏的平台位置;然而，当在探测试验（无平台）中评估空间记忆保持时，观察到给药效应。在接受联合损伤的WT动物中，在隐藏平台训练的第一天后的探测试验中观察到空间记忆保持的显著损伤（第一次探测试验）。这种损伤与同侧齿状回半球神经发生增加有关。相比之下，CCR 2 −/−小鼠在第一次探针试验中表现出显著的记忆保留，并且在接受辐射，创伤或联合损伤的动物中新生神经元的数量没有差异。虽然其机制尚不清楚，但我们的数据表明，CCR 2缺陷可以发挥保护作用，防止复合损伤后认知功能的损害。
Chemokines and their receptors play a crucial role in normal brain function as well as in pathological conditions such as injury and disease-associated neuroinflammation. Chemokine receptor-2 (CCR2), which mediates the recruitment of infiltrating and resident microglia to sites of central nervous system (CNS) inflammation, is upregulated by ionizing irradiation and traumatic brain injury. Our objective was to determine if a deficiency in CCR2 and subsequent effects on brain microglia affect neurogenesis and cognitive function after radiation combined injury (RCI). CCR2 knock-out (−/−) and wild-type (WT) mice received 4 Gy of whole body 137Cs irradiation. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohistochemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. All animals were able to locate the visible and hidden platform locations in the water maze; however, treatment effects were seen when spatial memory retention was assessed in the probe trials (no platform). In WT animals that received combined injury, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden platform training (first probe trial). This impairment was associated with increased neurogenesis in the ipsilateral hemisphere of the dentate gyrus. In contrast, CCR2−/− mice, independent of insult showed significant memory retention in the first probe trial and there were no differences in the numbers of newly born neurons in the animals receiving irradiation, trauma or combined injury. Although the mechanisms involved are not clear, our data suggests that CCR2 deficiency can exert a protective effect preventing the impairment of cognitive function after combined injury.