已有证据表明，青春期成瘾药物暴露对大脑发育会产生影响，导致成年后精神障碍和再次成瘾的风险增高，但其确切机制尚不清楚。为探讨青春期甲基苯丙胺（METH）暴露对小鼠脑发育的影响及作用机制，本项目拟通过构建METH行为敏化小鼠模型，运用旷场、高架十字迷宫、Y迷宫及Morris水迷宫等行为学方法，观察青春期METH暴露小鼠成年后焦虑与冲动样行为及学习记忆的变化，以及对再次METH暴露的反应。同时，利用透射电镜、激光共聚焦等形态学方法，观察小鼠成年后前额叶皮质和伏隔核神经元的改变；利用RT-qPCR、Western blot等分子生物学方法，检测DNA甲基化相关基因Dnmt1，Dnmt3a/b，Mecp2 mRNA及蛋白在上述脑区的表达变化；利用生物信息学方法研究这些基因的信号传导通路，探讨DNA甲基化在青春期METH暴露影响小鼠脑发育过程中的调控作用，旨在为揭示METH成瘾的神经生物学机制奠定基础

Previous studies found that addictive drugs exposure during adolescence caused adverse effects on the development of the brain, and led to increased risk of psychiatric disorders and addiction behaviors in adulthood. However, the effect of adolescent methamphetamine (METH) exposure on the brain development of mice as well as the underlying mechanism remains unclear. This proposal will establish mice model of adolescent METH-induced sensitization and examine the effects of adolescent METH exposure on their anxiety-like behavior, impulsive behavior, spatial learning and memory/working memory, as well as the sensitization of the METH re-exposure in adult using the behavior methods of elevated plus maze, Y maze, Morris’ water maze, and open field. Meanwhile, the morphological methods of the transmission electron microscope (TEM), and laser confocal scanning microscopy (LCSM) are used to detect the changes of neuronal plasticity in the nucleus accumbens (NAc) and the prefrontal cortex (PFC). Besides, we will examine the changes of DNA methylation regulation–related genes by using of Real-time qPCR and Western Blot. Furthermore, to explore the regulatory role of the DNA methylation in brain development of mice after adolescent METH-exposed, we will perform bioinformatic analyses of the signal transduction pathways involved by these genes. With a combination of above strategies, our research will lay a solid foundation for revealing the underlying neurobiological mechanism of METH addiction.