What fascinates me is the ability of the nervous system to mediate our adaptive responses to our changing environment and our changing behavioral states. As an entry point into this phenomenon, in my graduate training, I?ve used the Drosophila neuromuscular junction (NMJ) to build expertise in applying genetic and molecular analysis to understand how neural circuitry is adapted downstream of physiological input. In this context, at the cellular level, I?ve been most curious as to how neurons and their targets adapt highly specialized and complementary cellular morphologies during synaptic morphogenesis (SM). At the molecular level, neural activity initiates the deployment of calcium-dependent transcriptional and post- transcriptional programs that regulate synaptic morphology and organization. After learning about factors that control local translation within the synaptic compartment, such as the fragile X mental retardation protein (FMRP), I became very interested in post-transcriptional control of SM. Mechanistically, I am interested in how the translation of individual genes is controlled downstream of neural-activity during SM, which lead me to studying miRNAs. In my dissertation work thus far, I have identified several miRNAs as essential for activity- dependent morphogenesis of the NMJ terminal including miR-973. MiR-973 loss of function revealed a novel phenotype and suggested that it is required for activity-dependent synapse stability. Through these efforts, I have developed a sound understanding of approaches to characterize changes in synaptic architecture and plasticity. I will build upon this skill set in the F99 phase of this proposal by using optogenetics, ribosome profiling, and genetic approaches to resolve the mechanistic contribution of miR-973 in synaptic stability at the NMJ. Concurrently, I have developed a training plan with my sponsor and co- sponsor to ensure that I am actively thinking about the broader relevance of my work to synaptic plasticity in mammalian systems. Collectively, training during the F99 phase will provide a solid foundation that will enable me to construct effective experimental approaches to studying neural plasticity in a broad range of contexts. Moving forward, I will be in great position to transition into the K00 phase where I will apply my expertise in synaptic morphogenesis to exercise-mediated neural plasticity in the adult mammalian brain. My ultimate goal is to utilize this approach to identify novel molecular pathways and signaling factors that mediate neural plasticity as potential targets for therapeutic applications, which aligns with the Brain Initiative on Neurotherapeutics and Mechanisms shaping neuronal circuitry.
Behavioral intervention such as exercise has been shown to mitigate pathogenesis of neural disease such as Alzheimer's and Parkinson's disease, and other form neurodegeneration. I have developed a training plan and research project that will bridge my current training in genetic and molecular approaches of studying synaptic biology to exercise mediated models of neural plasticity. My ultimate goal is to utilize this approach to identify novel molecular pathways and signaling factors that mediate neural plasticity as potential targets for therapeutic applications, which aligns with the Brain Initiative on Neurotherapeutics and Mechanisms shaping neuronal circuitry.
