Grant: Discovery Grants Program - Individual

One of primary goals in neuroscience is to understand how the brain can collect, store, and use information from the environment. These processes are generally referred to as learning and memory. But what is memory, and how are memories formed at the cellular and molecular levels? Recent studies show that epigenetic mechanisms play an important role. Epigenetics was first discussed in the context of developmental biology and was proposed to be the mechanism that allows for cellular differentiation by determining and maintaining the ""correct"" gene expression profile for a given cell type. Later, factors were identified that mediate epigenetic regulation; these include DNA methylation, histone modification, non-coding RNAs, and ATP-dependent chromatin remodelling. In addition to their role in cell type determination, these factors are also involved in dynamic regulation of gene expression in the response of neurons to external cues. The long-term goal of my research program is to understand how these epigenetic factors contribute to the cellular and molecular processes underlying learning and memory in Drosophila. In the short term, I will focus on the evolutionarily conserved SWI/SNF chromatin remodelling complex. This large 15-subunit complex regulates nucleosome positioning around gene promoters. This seems like a general ""housekeeping"" function, however we actually have very little knowledge about the importance of SWI/SNF-mediated nucleosome regulation in context of a whole organism, and studies that have been done suggest a more subtle or specific role than may be expected. For example, selected members of this complex have been implicated in specialized processes like dendrite development and long-term memory. The proposed experiments will reveal the true biological importance of chromatin remodelling in the context of learning and memory, and will expand our knowledge of epigenetic processes underlying brain function in a simple, yet sufficiently complex organism, Drosophila melanogaster. Importantly, I will examine these topics at the systems level by taking advantage of the extensive genetic resources and high-throughput methodology available with flies. Using a highly efficient learning and memory assay I will execute a comprehensive analysis of all SWI/SNF components in memory, and will systematically investigate the role of SWI/SNF-mediated nucleosome regulation in the underlying cellular and molecular processes. Neuronal phenotypes will be linked to genomic mechanisms using targeted gene knockdown followed by isolation and genomic interrogation of specific neurons that are essential for memory formation. This research will enhance our fundamental understanding epigenetic processes in the nervous system and will have a multidisciplinary impact in the fields of neuroscience, developmental biology, chromatin biology, and epigenetics.