以甲基苯丙胺（Meth）为代表的新型毒品滥用已成为危害人类健康的重大公共卫生问题。神经系统一直是Meth毒性研究的热点，其中以神经元直接毒性作用研究为主，而由小胶质细胞介导的炎症微环境对神经元的影响尚未清楚。本课题组前期发现：Meth激活小胶质细胞产生的炎症微环境明显减少神经元树突、棘突数量及突触蛋白的表达；此外，Toll样受体3、4及下游Peli1泛素化酶等蛋白显著上调。因此，我们认为TLR3、4-Peli1轴介导的炎症微环境可能在Meth引起神经元损伤的过程中发挥作用。该项目拟基于神经元-小胶质细胞混合培养模型，借助Sigma-1R-/-, MyD88-/- ,TRIF-/-小鼠，通过行为学、电生理等方法，系统阐述Sigma-1R-Toll样受体-Peli1轴在Meth引起的炎性微环境及在神经元损伤中的作用。该研究可望为Meth引起神经元损伤的及早干预提供新靶点和策略。

The new-type drug abusing, mostly referred to as methamphetamine (Meth), in recent years, have increased significantly. Therefore, Meth abusing has posed serious challenges for both human health and social stability. As one of the main targets for Meth, the central nervous system is more vulnerable to Meth exposure. To date, accumulating data showed that Meth exposure contributed to neural damage from a direct way, however, the interactions between neurons and other glial cells during Meth exposure are still yet to be known. In our previous work, we found that the inflammatory micro-environment mediated by Meth through the activated microglia significantly decreased neural dendrites and spines, and down-regulated the expression of post-synapse protein. Moreover, toll like receptor 3 (TLR3), 4 (TLR4) as well as Peli1, which facilitated inflammation, was significantly up-regulated in our research. Therefore, we hypothesized that Meth-mediated microglia activation and inflammatory reaction “cross-talked” with the hippocampal neurons, and caused neural damage. To support the hypothesis, microglia and neurons were co-cultured with transwell assay, furthermore, Sigma-1R-/-,MyD88-/- ,TRIF-/- mouse, behavior research, electrophysiology and other assays were performed to elucidate the effects of Sigma-1 receptor-Toll like receptor 3,4-Peli1 axis in Meth-mediated inflammatory reaction and the potential damage of the neurons. These studies, taken together, might provide the newly insights into the early interventional strategies for Meth-mediated neural damage and the corresponding cognitive defects.