Whoolery Cody W, Walker Angela K, Richardson Devon R, Lucero Melanie J, Reynolds Ryan P, Beddow David H, Clark K Lyles, Shih Hung-Ying, LeBlanc Junie A, Cole Mara G, Amaral Wellington Z, Mukherjee Shibani, Zhang Shichuan, Ahn Francisca, Bulin Sarah E, DeCarolis Nathan A, Rivera Phillip D, Chen Benjamin P C, Yun Sanghee, Eisch Amelia J
Department of a Psychiatry, UT Southwestern Medical Center, Dallas, Texas.
d Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Radiat Res. 2017 Nov;188(5):532-551. doi: 10.1667/RR14797.1. Epub 2017 Sep 25.
Astronauts traveling to Mars will be exposed to chronic low doses of galactic cosmic space radiation, which contains highly charged, high-energy (HZE) particles. Fe-HZE-particle exposure decreases hippocampal dentate gyrus (DG) neurogenesis and disrupts hippocampal function in young adult rodents, raising the possibility of impaired astronaut cognition and risk of mission failure. However, far less is known about how exposure to other HZE particles, such as Si, influences hippocampal neurogenesis and function. To compare the influence of Si exposure on indices of neurogenesis and hippocampal function with previous studies on Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice (NGFP; made and maintained for 10 or more generations on a C57BL/6J background) received whole-body Si-particle-radiation exposure (0, 0.2 and 1 Gy, 300 MeV/n, LET 67 KeV/μ, dose rate 1 Gy/min). For neurogenesis assessment, the NGFP mice were injected with the mitotic marker BrdU at 22 h postirradiation and brains were examined for indices of hippocampal proliferation and neurogenesis, including Ki67, BrdU, BrdUNeuN and DCX cell numbers at short- and long-term time points (24 h and 3 months postirradiation, respectively). In the short-term group, stereology revealed fewer Ki67, BrdU and DCX cells in 1-Gy-irradiated group relative to nonirradiated control mice, fewer Ki67 and DCX cells in 0.2 Gy group relative to control group and fewer BrdU and DCX cells in 1 Gy group relative to 0.2 Gy group. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Notably, there were fewer surviving BrdU cells in the 1 Gy group relative to 0- and 0.2-Gy-irradiated mice in the long-term group. When the short- and long-term groups were analyzed by sex, exposure to radiation had a similar effect on neurogenesis indices in male and female mice, although only male mice showed fewer surviving BrdU cells in the long-term group. Fluorescent immunolabeling and confocal phenotypic analysis revealed that most surviving BrdU cells in the long-term group expressed the neuronal marker NeuN, definitively confirming that exposure to 1 Gy Si radiation decreased the number of surviving adult-generated neurons in male mice relative to both 0- and 0.2-Gy-irradiated mice. For hippocampal function assessment, 9-week-old male C57BL/6J mice received whole-body Si-particle exposure and were then assessed long-term for performance on contextual and cued fear conditioning. In the context test the animals that received 0.2 Gy froze less relative to control animals, suggesting decreased hippocampal-dependent function. However, in the cued fear conditioning test, animals that received 1 Gy froze more during the pretone portion of the test, relative to controls and 0.2-Gy-irradiated mice, suggesting enhanced anxiety. Compared to previously reported studies, these data suggest that Si-radiation exposure damages neurogenesis, but to a lesser extent than Fe radiation and that low-dose Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.
前往火星的宇航员将长期暴露于低剂量的银河系宇宙空间辐射中,这种辐射含有高电荷、高能(HZE)粒子。铁-HZE粒子辐射会减少年轻成年啮齿动物海马齿状回(DG)的神经发生,并破坏海马功能,增加了宇航员认知受损和任务失败的风险。然而,对于暴露于其他HZE粒子(如硅)如何影响海马神经发生和功能,我们所知甚少。为了将硅暴露对神经发生指标和海马功能的影响与先前关于铁暴露的研究进行比较,9周龄的C57BL/6J和Nestin-GFP小鼠(NGFP;在C57BL/6J背景下培育和维持了10代或更多代)接受了全身硅粒子辐射暴露(0、0.2和1 Gy,300 MeV/n,线能量转移67 KeV/μm,剂量率1 Gy/min)。为了评估神经发生,在辐照后22小时给NGFP小鼠注射有丝分裂标记物BrdU,并检查大脑中海马增殖和神经发生的指标,包括短期和长期时间点(分别为辐照后24小时和3个月)的Ki67、BrdU、BrdUNeuN和DCX细胞数量。在短期组中,体视学分析显示,与未辐照的对照小鼠相比,1 Gy辐照组的Ki67、BrdU和DCX细胞数量减少;与对照组相比,0.2 Gy组的Ki67和DCX细胞数量减少;与0.2 Gy组相比,1 Gy组的BrdU和DCX细胞数量减少。与短期组中所有标记物均明显观察到的辐射诱导剂量依赖性减少相反,长期辐照组中只有少数神经发生指标发生了变化。值得注意的是,在长期组中,1 Gy组存活的BrdU细胞数量相对于0 Gy和0.2 Gy辐照的小鼠较少。当按性别分析短期和长期组时,辐射暴露对雄性和雌性小鼠的神经发生指标有类似影响,尽管只有雄性小鼠在长期组中存活的BrdU细胞数量较少。荧光免疫标记和共聚焦表型分析显示,长期组中大多数存活的BrdU细胞表达神经元标记物NeuN,明确证实相对于0 Gy和0.2 Gy辐照的小鼠,暴露于1 Gy硅辐射会减少雄性小鼠中成年后产生的存活神经元数量。为了评估海马功能,9周龄的雄性C~7BL/6J小鼠接受全身硅粒子暴露,然后长期评估其在情境性和线索性恐惧条件反射中的表现。在情境测试中,接受0.2 Gy辐射的动物相对于对照动物的僵立次数减少,表明海马依赖性功能下降。然而,在线索性恐惧条件反射测试中,接受1 Gy辐射的动物在测试的预音调部分相对于对照和0.2 Gy辐照的小鼠僵立次数更多,表明焦虑增强。与先前报道的研究相比,这些数据表明硅辐射暴露会损害神经发生,但程度小于铁辐射,并且低剂量硅暴露会导致海马功能异常,破坏恐惧记忆但也会诱发焦虑样行为。此外,长期雄性组中硅辐射暴露会减少新神经元的存活,但雌性组中没有,这表明在对太空旅行的宇航员进行脑健康风险评估时,性别可能是一个重要因素。