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.
By identifying and characterizing the molecular mechanisms that influence the acquisition and extinction of fear-related memories, the findings of the experiments outlined in this application may have broad reaching translational implications by establishing RNA modifications as targets for therapeutic intervention in fear- related anxiety disorders.
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