miR-9参与学习记忆（恐惧制约反应）的作用机制研究

In recent years, there has been a surge of interest in the epigenetic mechanisms that regulate neural plasticity and cognitive functions, as well as their roles in neurological disorders. Accumulating evidence suggests that non-coding RNAs, the "dark matter" within the genome, play a fundamental role in development and plasticity. Recently, we have found that spatiotemporal-specific perturbations of miR-9, in prelimbic frontal cortex (PL) during dendritogenesis affected dendrite complexity, which in turn influenced fear learning and memory in adulthood. On the other hand, we also found that expression levels of miR-9 in cortical neurons respond to neural activity. Moreover, constitutive overexpression of miR-9 in PL enhanced fear memory. The objective of this proposal is to tease out the developmental and the potential adult-onset roles of this brain-enriched microRNA (miRNA), miR-9 in regulating neural plasticity and fear-related learning and memory. The overarching goal is to address whether and how a single small non-coding RNA may be used repetitively during development and in adulthood to modulate adaptive behavior via distinct epigenetic mechanisms, linking environmental signals, genomic responses, neuronal functions, and animal behavior

神经发育异常疾病中神经可塑性和认知功能紊乱的表观遗传学机制目前尚不清楚。microRNA作为基因转录后水平的重要表观遗传修饰方式，在神经发育和神经可塑性调控过程中发挥着重要作用。前期研究中，我们发现在小鼠胚胎期干预miR-9的表达，内侧前额叶皮质区树突形态将被改变，并可以一直影响到成体期小鼠的恐惧学习和记忆。在本项目中，首先，我们将通过研究miR-9下游和神经元树突形态发生相关的基因Diap1，探索胚胎期miR-9作用的分子机制；其次，我们将采用多西环素诱导的miR-9 过表达和下调系统，在小鼠成体期干预miR-9及其下游和神经元突触可塑性相关的基因，评价小鼠突触可塑性的变化和恐惧学习记忆功能，并阐明成体期miR-9作用的分子机制。本项目的完成将阐明：miR-9在小鼠胚胎期和成体期采用不同的分子机制调控神经元功能，从而影响恐惧学习和记忆。

近年来的研究表明：个体胚胎期的脑发育过程能够影响成体大脑的功能，从而影响成体期的行为。表观遗传调控是机体应答于外界环境变化的反应机制，已有研究报道抑郁症、焦虑症、自闭症与胚胎期神经发育异常相关。在本课题中我们发现miR-9通过在胚胎神经元发育时期调控细胞骨架蛋白基因Diap1的表达，影响内侧前额叶皮质区（mPFC）树突的发育和新生神经元间突触的形成，从而影响成体期的恐惧学习记忆功能。因此揭示表观遗传调控胚胎期神经发育的分子机制，有助于我们揭示神经系统疾病、情绪和创伤，恐惧症或创伤后应激障碍潜在的致病机理，为探索这类疾病的 miRNA 靶向的替代治疗干预策略做出贡献。