PROJECT SUMMARY Olfaction plays a critical role in animal survival, enabling the detection of food sources, dangers, and potential mates. The remarkable plasticity of the olfactory system allows for the modification of responses to cues based on various internal states. However, the precise mechanisms underlying olfactory plasticity, particularly at the level of peripheral sensory neuronal activity, remain poorly understood. In this research proposal, we aim to investigate the contribution of long non-coding RNAs (lncRNAs) and lncRNA-encoded micropeptides in modulating olfactory receptor neurons (ORNs) and other olfactory functions. LncRNAs are transcripts longer than 200 nucleotides that lack an open reading frame longer than 100 codons. Various lncRNAs have been implicated in neural development, function, and diseases. While lncRNAs are traditionally considered non-coding, certain lncRNAs encode micropeptides, which contribute to diverse biological processes. Despite their abundance and potential importance, the functions of lncRNAs and their encoded micropeptides in the nervous system, particularly in olfaction, remain largely unexplored. To address this knowledge gap, we will capitalize on the well-characterized olfactory system of the fruit fly. This system offers several advantages, including numerical simplicity, well-defined neurons that drive complex behaviors, and the availability of powerful genetic tools. We recently generated a comprehensive survey of lncRNAs in the main fly olfactory organ that demonstrated the diversity and expression patterns of lncRNAs in the olfactory system and set the stage for investigating their functional roles and their impact on sensory behaviors. Through a multidisciplinary approach that includes genetic, electrophysiological, behavioral, and molecular assays, we will test the hypothesis that lncRNAs and their micropeptides contribute to olfactory modulation and function. Our initial focus will be on the lncRNA ANRUS (Antennal RNA Upregulated by Starvation) and its encoded micropeptide. We will functionally characterize ANRUS and test whether it contributes to olfactory modulation. During the R00 phase, we will investigate the unexpected regulation of ANRUS levels by a food odor, ethyl acetate. Finally, we propose to expand our investigation by characterizing the micropeptidome of the antenna, a first step toward exploring the regulatory roles of these micropeptides in olfaction and gaining a deeper understanding of the mechanisms governing olfactory plasticity and function. Dr. Talross will benefit from outstanding support from her mentoring team at Yale University, which will facilitate her journey towards independence. The proposed objectives in this proposal are carefully designed to equip Dr. Talross with the necessary skills and experience to secure an Assistant Professor position and pursue R01 funding as an independent investigator.