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Epitranscriptomic mechanisms of fear-related learning and memory

恐惧相关学习和记忆的表观转录组机制

基本信息

批准号：
9081413
负责人：
Timothy W Bredy
金额：
$ 37.7万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9081413
关键词：
Address Adult Affect Automobile Driving Behavioral Behavioral Paradigm Binding Proteins Biological Assay Biology Brain Cells Characteristics DNA Sequence Data Ensure Epigenetic Process Extinction (Psychology)Fright Gene Expression Gene Expression Profiling Gene Expression Regulation Genes Goals High-Throughput Nucleotide Sequencing Impairment Laboratories Lead Learning Light Longevity Maintenance Mediating Medicine Memory Metabolism Modification Molecular Nature Neurons Pathway interactions Pattern Positioning Attribute Post-Transcriptional Regulation Pre-Clinical Model Process Protocols documentation RNA RNA Stability RNA methylation RNA-Binding Proteins Recording of previous events Research Research Proposals Role Structure Therapeutic Intervention Thinking Time Training Variant Viral anxiety-related disorders classical conditioning cognitive function demethylation design educational atmosphere effective therapy epigenetic regulation experience in vivo innovation insight knock-down lentiviral-mediated neuropsychiatric disorder novel programs public health relevance research study targeted treatment transcriptome

项目摘要

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.

描述（由申请人提供）：RNA修饰，特别是N6甲基腺苷（m6A），是在成人大脑中新发现的表观遗传机制，其最近被证明是高度动态的，并且如我们的初步证据所示，似乎涉及与恐惧相关的学习和记忆。该研究计划的首要目标是首次建立表观转录调节之间的因果关系。恐惧相关焦虑症临床前模型中的基因表达和记忆的形成与维持。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疾病的方法。这些实验的成功完成也有可能极大地改变我们对适应性可塑性机制的看法，因为它揭示了RNA的定性性质，而不是其总体丰度，如何参与一个关键的学习过程，这对我们理解以异常强烈的记忆为特征的神经精神疾病具有重要意义。这将通过先进的高通量测序方法、强大的行为范式和病毒介导的成人大脑基因活性操纵的有效结合来实现。