Epitranscriptomic mechanisms of fear-related learning and memory

 描述(申请人提供)：RNA修饰，特别是N6甲基腺苷(M6A)，是一种新发现的成人大脑中的表观遗传机制，最近被证明是高度动态的，正如我们的初步证据所表明的，似乎参与了与恐惧相关的学习和记忆。这项研究计划的首要目标是首次建立表型转录调控之间的因果关系。 恐惧相关焦虑症临床前模型中的基因表达与记忆的形成和维持。然后，我们可以利用这些信息来设计更好的治疗以认知功能障碍为特征的神经精神障碍的方法。这些实验的成功完成也有可能极大地改变我们思考适应性可塑性机制的方式，因为它揭示了RNA的质量性质，而不是它的整体丰度，是如何参与一个关键的学习过程的，这对我们理解以异常强烈的记忆为特征的神经精神障碍是有意义的。这将通过先进的高通量测序方法、强大的行为范例和病毒介导的成人大脑基因活动操纵的有效组合来实现。

 DESCRIPTION (provided by applicant): RNA modification, and N6 methyladenosine (m6A) in particular, is a newly discovered epigenetic mechanism in the adult brain that is has recently been shown to be highly dynamic and, as indicated by our preliminary evidence, appears to be involved in fear-related learning and memory. The overarching goal of this research program is to establish, for the first time, a causal relationship between the epitranscriptomic regulation of gene expression and the formation and maintenance of memory in a preclinical model of fear-related anxiety disorder. We can then capitalize on this information to design better treatments for neuropsychiatric disorders characterized by impairments in cognitive function. Successful completion of these experiments also has the potential to dramatically change the way we think about mechanisms of adaptive plasticity by shedding new light on how the qualitative nature of RNA, rather than its overall abundance, is involved in a key learning process with implications for our understanding of neuropsychiatric disorders characterized by abnormally intense memories. This will be achieved through a potent combination of advance high-throughput sequencing approaches, robust behavioral paradigms and viral-mediated manipulation of gene activity in the adult brain.