CREB signaling mediates dose-dependent radiation response in the murine hippocampus two years after low-dose total body exposure

The impact of low-dose ionizing radiation (IR) on human brain has recently attracted attention due to increased use of IR for diagnostic purposes. The aim of this study was to investigate low-dose radiation response in hippocampus. Female C57Bl/6 mice were irradiated with 0, 0.063, 0.125 or 0.5 Gy and quantitative label-free proteomic analysis of hippocampus was performed after 24 months. Key pathways were validated by immunoblotting. CREB signaling and CREB-associated pathways were the most affected ones at all doses. The two lower doses seemed to induce CREB pathway, whereas the exposure to 0.5 Gy deactivated CREB. Similarly, the lowest dose (0.063 Gy) was anti-inflammatory reducing the number of activated microglia (IBA-1), whilst induction of activated microglia and reactive astroglia (GFAP) was found at 0.5 Gy suggesting increased inflammation and astrogliosis, respectively. Apoptotic markers BAX and cleaved CASP-3 and oxidative stress markers (carbonylation, NRF-2) were increased only at the highest dose. Since activated CREB pathway plays a central role in learning and memory, these data suggest neuroprotection at the lowest dose (0.063 Gy) but neurodegeneration at 0.5 Gy. These effects become significant only in old animals (24 m) and support the hypothesis of radiation-induced accelerated aging in the brain.

鉴于低剂量电离辐射（low-dose ionizing radiation, IR）在诊断领域的应用日益增多，其对人脑的影响近来备受关注。本研究旨在探究海马体对低剂量辐射的应答反应，实验中将雌性C57Bl/6小鼠分别接受0（空白对照）、0.063、0.125或0.5 Gy剂量的辐射，并在辐射照射24个月后对其海马体组织开展无标记定量蛋白质组学分析，随后通过免疫印迹法对关键信号通路进行了验证。CREB（cAMP response element-binding protein，环腺苷酸应答元件结合蛋白）信号通路及其相关调控通路在所有辐射剂量下均受影响最为显著，两个较低剂量组似乎可激活CREB通路，而0.5 Gy剂量照射则会使该通路失活。与之类似，最低剂量（0.063 Gy）可发挥抗炎作用，减少活化小胶质细胞（IBA-1, ionized calcium-binding adapter molecule 1）的数量；而0.5 Gy剂量照射则会诱导活化小胶质细胞与反应性星形胶质细胞（GFAP, glial fibrillary acidic protein）的生成，分别提示炎症水平升高与星形胶质细胞增生。凋亡标志物BAX（BCL2-associated X protein，Bcl-2相关X蛋白）、活化半胱氨酸天冬氨酸蛋白酶3（cleaved CASP-3）以及氧化应激标志物（羰基化产物、NRF-2, nuclear factor erythroid 2-related factor 2）仅在最高辐射剂量组中出现表达上调。鉴于活化的CREB通路在学习与记忆过程中发挥核心作用，本研究数据表明，最低剂量（0.063 Gy）照射可产生神经保护作用，而0.5 Gy剂量照射则会引发神经退行性变，上述效应仅在老年动物（24月龄）中表现显著，这一结果支持了辐射可诱导大脑加速衰老的假说。