Raber Jacob, Allen Antiño R, Sharma Sourabh, Allen Barrett, Rosi Susanna, Olsen Reid H J, Davis Matthew J, Eiwaz Massarra, Fike John R, Nelson Gregory A
a Departments of Behavioral Neuroscience and.
b Neurology Radiation Medicine and.
Radiat Res. 2016 Jan;185(1):20-30. doi: 10.1667/RR14222.1. Epub 2015 Dec 31.
The space radiation environment contains protons and (56)Fe, which could pose a significant hazard to space flight crews during and after missions. The space environment involves complex radiation exposures, thus, the effects of a dose of protons might be modulated by a dose of heavy-ion radiation. The brain, and particularly the hippocampus, may be susceptible to space radiation-induced changes. In this study, we first determined the dose-response effect of proton radiation (150 MeV) on hippocampus-dependent cognition 1 and 3 months after exposure. Based on those results, we subsequently exposed mice to protons alone (150 MeV, 0.1 Gy), (56)Fe alone (600 MeV/n, 0.5 Gy) or combined proton and (56)Fe radiations (protons first) with the two exposures separated by 24 h. At one month postirradiation, all animal groups showed novel object recognition. However, at three months postirradiation, mice exposed to either protons or combined proton and (56)Fe radiations showed impaired novel object recognition, which was not observed in mice irradiated with (56)Fe alone. The mechanisms in these impairments might involve inflammation. In mice irradiated with protons alone or (56)Fe alone three months earlier, there was a negative correlation between a measure of novel object recognition and the number of newly born activated microglia in the dentate gyrus. Next, cytokine and chemokine levels were assessed in the hippocampus. At one month after exposure the levels of IL-12 were higher in mice exposed to combined radiations compared with sham-irradiated mice, while the levels of IFN-γ were lower in mice exposed to (56)Fe radiation alone or combined radiations. In addition, IL-4 levels were lower in (56)Fe-irradiated mice compared with proton-irradiated mice and TNF-α levels were lower in proton-irradiated mice than in mice receiving combined radiations. At three months after exposure, macrophage-derived chemokine (MDC) and eotaxin levels were lower in mice receiving combined radiations. The levels of MDC and eotaxin correlated and the levels of MDC, but not eotaxin, correlated with the percentage of newly born activated microglia in the blades of the dentate gyrus. Finally, hippocampal IL-6 levels were higher in mice receiving combined radiations compared with mice receiving (56)Fe radiation alone. These data demonstrate the sensitivity of novel object recognition for detecting cognitive injury three months after exposure to proton radiation alone, and combined exposure to proton and (56)Fe radiations, and that newly-born activated microglia and inflammation might be involved in this injury.
空间辐射环境包含质子和（56）铁，这可能在任务期间及之后对航天机组人员构成重大危害。空间环境涉及复杂的辐射暴露，因此，质子剂量的影响可能会受到重离子辐射剂量的调节。大脑，尤其是海马体，可能易受空间辐射引起的变化影响。在本研究中，我们首先确定了暴露后1个月和3个月质子辐射（150 MeV）对海马体依赖性认知的剂量反应效应。基于这些结果，我们随后将小鼠单独暴露于质子（150 MeV，0.1 Gy）、单独暴露于（56）铁（600 MeV/n，0.5 Gy）或质子与（56）铁联合辐射（先质子辐射），两次暴露间隔24小时。辐照后1个月，所有动物组均表现出对新物体的识别能力。然而，辐照后3个月，暴露于质子或质子与（56）铁联合辐射的小鼠表现出新物体识别能力受损，而单独接受（56）铁辐照的小鼠未观察到这种情况。这些损伤的机制可能涉及炎症。在3个月前单独接受质子或（56）铁辐照的小鼠中，新物体识别能力的测量值与齿状回中新生活化小胶质细胞的数量呈负相关。接下来，评估海马体中的细胞因子和趋化因子水平。暴露后1个月，与假辐照小鼠相比，联合辐射暴露小鼠的IL-12水平较高，而单独接受（56）铁辐射或联合辐射的小鼠的IFN-γ水平较低。此外，与质子辐照小鼠相比，（56）铁辐照小鼠的IL-4水平较低，质子辐照小鼠的TNF-α水平低于接受联合辐射的小鼠。暴露后3个月，接受联合辐射的小鼠中巨噬细胞衍生趋化因子（MDC）和嗜酸性粒细胞趋化因子水平较低。MDC和嗜酸性粒细胞趋化因子水平相关，且MDC水平与齿状回叶片中新生活化小胶质细胞的百分比相关，而嗜酸性粒细胞趋化因子水平不相关。最后，与单独接受（56）铁辐射的小鼠相比，接受联合辐射的小鼠海马体IL-6水平较高。这些数据表明，新物体识别对检测单独质子辐射以及质子与（56）铁联合辐射暴露3个月后的认知损伤具有敏感性，并且新生活化小胶质细胞和炎症可能参与了这种损伤。
