幼龄期音乐暴露调控的BDNF表观遗传修饰在成年期恐惧记忆中的作用

Anxiety and fear extinction difficulties with long-lasting re-experience of traumatic events can affect cognitive ability and result in Post Traumatic Stress Disorder (PTSD). Recent study suggests that the boosting brain-derived neurotrophic factor (BDNF) activity in hippocampal-infralimbic circuits may ameliorate disorders of learned fear. Our results demonstrate that music exposure in the juvenile age range could promote conditioned fear extinction and decrease anxiety-like behaviors induced by foot shock in adulthood. In particular, BDNF levels in the medial prefrontal cortex (mPFC) in the music group were significantly increased after the fear conditioning session and were higher than those of the controls. In the present project, we therefore aim to detect the expression of BDNF levels and neurons activation markers in the mPFC and amygdala to analyze the neuroanatomical and chemical pathway relative to fear extinction; to intervene in BDNF expressions to test the role of BDNF in conditioned fear extinction in turn by injection of BDNF siRNA and transfected with BDNF adenovirus; to observe the promoter methylation and histone acetylating by MSP, BSP, ChIP, Western Blot, and so on; to investigate the role of regular music exposure in juvenile rats on conditioned fear extinction in adulthood and the possible epigenetic mechanisms, which may provide a potential strategy for prevention of negative outcomes after stressors in adulthood.

恐惧记忆消退困难是引发创伤后应激障碍（PTSD）的主要原因。环境和遗传因素共同影响其发生与发展。新近研究发现BDNF的表达变化参与调控恐惧消退记忆。而我们前期在大鼠幼龄期给予其音乐暴露，发现成年后大鼠mPFC中的 BDNF基因表达明显上调；经历条件性恐惧刺激后，其恐惧记忆明显消退。因此，本课题拟在前期工作基础上，利用我们已建立的模型，检测大鼠mPFC与杏仁核内的BDNF mRNA、神经元激活标志物等的表达变化，对恐惧记忆消退行为相关的神经解剖与化学通路进行分析；采用立体定向给予BDNF siRNA，以及转染BDNF腺病毒等干预方法，验证成年后BDNF调控恐惧记忆消退的作用；结合MSP、BSP、ChIP等技术，动态观察启动子上的甲基化、组蛋白乙酰化情况，获取遗传调控相关信息，探讨幼龄期音乐暴露调控的BDNF表观遗传修饰在成年期恐惧记忆中的作用，为PTSD的防治提供新的突破点。