Radiation Physiology Lab, Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore.
The School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou 434023, China.
Cells. 2021 Sep 18;10(9):2476. doi: 10.3390/cells10092476.
Early life radiation exposure causes abnormal brain development, leading to adult depression. However, few studies have been conducted to explore pre- or post-natal irradiation-induced depression-related neuropathological changes. Relevant molecular mechanisms are also poorly understood. We induced adult depression by irradiation of mice at postnatal day 3 (P3) to reveal hippocampal neuropathological changes and investigate their molecular mechanism, focusing on MicroRNA (miR) and its target mRNA and protein. P3 mice were irradiated by γ-rays with 5Gy, and euthanized at 1, 7 and 120 days after irradiation. A behavioral test was conducted before the animals were euthanized at 120 days after irradiation. The animal brains were used for different studies including immunohistochemistry, CAP-miRSeq, Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) and western blotting. The interaction of miR-34a-5p and its target T-cell intracytoplasmic antigen-1 (Tia1) was confirmed by luciferase reporter assay. Overexpression of Tia1 in a neural stem cell (NSC) model was used to further validate findings from the mouse model. Irradiation with 5 Gy at P3 induced depression in adult mice. Animal hippocampal pathological changes included hypoplasia of the infrapyramidal blade of the stratum granulosum, aberrant and impaired cell division, and neurogenesis in the dentate gyrus. At the molecular level, upregulation of miR-34a-5p and downregulation of Tia1 mRNA were observed in both animal and neural stem cell models. The luciferase reporter assay and gene transfection studies further confirmed a direct interaction between miR-43a-5p and Tia1. Our results indicate that the early life γ-radiation-activated miR-43a-5p/Tia1 pathway is involved in the pathogenesis of adult depression. This novel finding may provide a new therapeutic target by inhibiting the miR-43a-5p/Tia1 pathway to prevent radiation-induced pathogenesis of depression.
早期生活中的辐射暴露会导致大脑发育异常，进而引发成年抑郁症。然而，目前很少有研究探讨过产前或产后辐射引起的与抑郁相关的神经病理学变化，相关的分子机制也知之甚少。我们通过在出生后第 3 天（P3）对小鼠进行照射来诱导成年抑郁，以揭示海马神经病理学变化，并研究其分子机制，重点关注 microRNA（miRNA）及其靶 mRNA 和蛋白。P3 小鼠接受 5Gyγ射线照射，照射后 1、7 和 120 天处死。在照射后 120 天处死动物前进行行为测试。对动物大脑进行免疫组织化学、CAP-miRSeq、实时定量逆转录 PCR（qRT-PCR）和 Western blot 等不同研究。通过荧光素酶报告实验证实了 miR-34a-5p 与其靶标 T 细胞胞浆抗原 1（Tia1）之间的相互作用。在神经干细胞（NSC）模型中过表达 Tia1 进一步验证了从小鼠模型中得到的发现。P3 时 5Gy 的照射会导致成年小鼠抑郁。动物海马的病理变化包括颗粒层下锥体带发育不良、细胞分裂异常和齿状回神经发生受损。在分子水平上，动物模型和神经干细胞模型中均观察到 miR-34a-5p 上调和 Tia1mRNA 下调。荧光素酶报告实验和基因转染研究进一步证实了 miR-43a-5p 与 Tia1 之间的直接相互作用。我们的结果表明，早期生活中的γ射线激活的 miR-43a-5p/Tia1 通路参与了成年抑郁症的发病机制。这一新颖的发现可能通过抑制 miR-43a-5p/Tia1 通路提供新的治疗靶点，以预防辐射引起的抑郁症发病机制。
