小鼠海马背侧齿状回中的Dnmt3a表达调控恐惧记忆更新的机制探究

恐惧记忆更新是限制暴露疗法疗效的关键因素，我们前期研究发现小鼠海马背侧齿状回（dDG）中的Dnmt3a表达对恐惧记忆更新有重要的调控作用，但是Dnmt3a调控恐惧记忆更新的机制还不清楚。Dnmt3a编码的是DNA甲基转移酶（DNMTs）的一种，根据文献报道，DNMTs通过调节下游靶基因和神经可塑性的调节、学习记忆的形成有很大的相关性。dDG区主要与空间记忆有关，也能对情绪记忆进行调控。我们推测Dnmt3a通过调节下游靶基因，增强恐惧记忆消退过程中dDG区神经元的活动，通过某种方式改变了小鼠恐惧记忆消退过程中环境相关记忆的编码，从而抑制了恐惧记忆的更新。在本项目中，我们将结合分子生物学、化学遗传调控、光纤记录、行为学等研究手段，探究小鼠海马齿状回中的Dnmt3a调节恐惧记忆更新的机制，为开发更有效的抑制恐惧记忆恢复的治疗方案提供研究基础。

Renewal of extinguished fear memory in an altered context is widely believed to be a major limiting issue for exposure therapy in treating various psychiatric diseases. Our earlier study found that Dnmt3a in the hippocampal dentate gyrus(dDG) had an important regulatory effect on fear memory renewal, but the mechanism of Dnmt3a regulating fear memory renewal was not clear. Dnmt3a encodes one of the DNA methyltransferase (DNMTs). According to literature reports, DNMTs is highly correlated with neural plasticity and the formation of memory, while dDG is mainly related to spatial memory and can also regulate emotional memory. We speculated that Dnmt3a, by regulating the downstream target gene, promoted the neural activity in the dDG during the fear memory extinction process, and in some way changed the encoding of environment-related memories during the fear memory extinction, thereby inhibiting the fear memory renewal. In this project, we will explore the mechanism of Dnmt3a regulating fear memory renewal in dDG by combining molecular biology, chemical genetic regulation, fiber optic recording, behavioral research and other means for founding the new therapy of PTSD.