核受体TLX调控神经发生在短波辐射致认知损伤中作用的基础研究

With the development and application of electromagnetic technology, electromagnetic radiation pollution exists everywhere. Shortwave radiation could impair cognitive function, but the mechanism remains unclear. Hippocampal neurogenesis is closely related to cognitive function, and nuclear receptor tailless like protein (TLX) is a master regulator that determines the proliferation and differentiation of neural stem cells (NSCs) and regulates neurogenesis. Studies showed that inhibition of neurogenesis might be involved in the pathophysiological process of cognitive impairment induced by shortwave radiation; our preliminary exploration found that shortwave radiation could reduce the expression of TLX and lead to a decrease in neurosphere formation in NSCs. Correspondingly, we speculate that the regulation of TLX on neurogenesis may play an important role in cognitive impairment induced by shortwave radiation; no similar studies have been reported currently. Therefore, this project plans to induce cognitive impairment by shortwave radiation in mice model, and make clear the effects of shortwave radiation on hippocampal neurogenesis and its relevance to cognitive impairment, and explore the expression changes of nuclear receptor TLX and its major downstream targets. Additionally, nuclear receptor TLX of NSCs in vitro will be intervened, and the effects of shortwave radiation on NSCs proliferation, differentiation and TLX targets will be investigated after intervention, to clarify the mechanism of nuclear receptor TLX regulating neurogenesis in cognitive impairment induced by shortwave radiation. Generally, this study will be of important significance for elucidating the cognitive impairment caused by shortwave radiation and related molecular mechanism, and screening prevention and treatment targets.

随着电磁技术发展与应用，电磁辐射污染普遍存在。短波辐射可导致神经认知损伤，但机制未明。海马区神经发生与认知功能密切相关，核受体Tailless样蛋白TLX是决定神经干细胞NSCs增殖分化、调控神经发生的关键分子。研究表明神经发生受抑制可能参与短波辐射致认知损伤的病理生理过程；我们前期研究发现，短波辐射后NSCs核受体TLX表达降低、神经球形成尺寸变小。据此推测TLX对神经发生的调控在短波辐射致认知损伤中具有重要作用，目前国内外尚未见类似报道。本项目拟建立短波辐射致认知损伤小鼠模型，明确短波辐射对海马区神经发生的影响及其与认知损伤相关性，研究核受体TLX及其重要靶基因改变；并对NSCs核受体TLX进行干预，研究TLX干预对短波辐射后NSCs增殖分化及下游靶基因的影响，以揭示TLX调控神经发生在短波辐射致认知损伤中机制。本研究对于阐明短波辐射的认知损伤效应及分子机制、筛选防治靶点具有重要意义。

海马区神经发生与认知密切相关，核受体Tailless样蛋白TLX是决定神经干细胞NSCs增殖分化、调控神经发生的关键分子。研究表明神经发生受抑制可能参与短波辐射致认知损伤的病理生理过程；我们前期研究发现，短波辐射后NSCs核受体TLX表达降低、神经球形成尺寸变小。据此推测TLX对神经发生的调控在短波辐射致认知损伤中具有重要作用。本课题通过行为学、病理学、分子生物学和细胞生物学等方法研究了短波辐射对小鼠神经行为、海马神经发生和核受体TLX及其下游靶基因的影响。首先，研究了短波辐射对小鼠认知损伤和神经发生的影响。结果显示：短波辐射可导致小鼠一定程度的认知行为受损，主要表现为空间学习记忆和识别记忆受损；短波辐射可导致小鼠海马组织形态和超微结构损伤，抑制小鼠海马区齿状回神经发生。然后研究了短波辐射对小鼠海马组织核受体TLX及其靶基因的影响。结果显示：短波辐射可导致小鼠海马组织TLX蛋白表达在辐射后14d明显降低，其mRNA相对水平在辐射后7d明显增加；Wnt7a蛋白及其mRNA均表现出先增加后降低的趋势；Mash1蛋白在辐射后7d有升高趋势，其mRNA在辐射后1d明显降低。最后研究了核受体TLX干预对短波辐射后NSCs增殖、分化和靶基因影响。结果显示：离体水平TLX过表达可减轻短波辐射导致的NSCs增殖和分化能力的降低，TLX和Mash1分子水平的改变参与了短波辐射致NSCs损伤的过程。上述研究结果为探寻短波辐射损伤防治新靶点提供实验支持。