Uncovering the Origin and Mechanisms of Ultradian Rhythms in the Drosophila Brain

项目总结

PROJECT SUMMARY Both inputs to the brain and outputs from the brain occur over a broad range of timescales and in many cases repeat rhythmically. Rhythmic changes in gene expression have been studied in the brain only in the context of circadian rhythms. Additionally, shorter-than-a-day (ultradian) rhythms have been sparsely reported and it is unknown how these rhythms originate, particularly at the molecular level and whether they interact and/or share part of the timekeeping machinery utilized by the circadian clock. Understanding how these rhythms are generated and maintained will illuminate new aspects of brain gene expression and physiology and open unexplored areas of research. In an effort to reveal RNA oscillations at different timescales in the fly brain, we profiled fly brains by RNAseq every two hours for three days. By analyzing these data, we identified dozens of RNAs oscillating with 6-, 12-, and 24-hour rhythms in the brain. Interestingly, enrichment analysis shows that more than half of these genes are highly expressed in the glia, suggesting this cell type has oscillators operating at different timescales. The importance and novelty of these results are two-fold: a. they demonstrate, for the first time, the presence of ultradian RNA oscillations in the fly brain; b. suggest the existence of oscillators operating at different timescales (circadian and ultradian) in the glial cells. In this context, the present proposal aims to comprehensively identify the mechanisms responsible for ultradian rhythmic gene expression in the glial cells within the fly brain. Our work will shed light on new mechanisms of ultradian expression in flies for the first time. In addition, we will identify and characterize new timekeeping or timer-like mechanisms operating in glial cells that also have a circadian clock. Last, our work will provide new information and lead to developing tools to perturb and investigate these rhythms in the future. In sum, we are convinced that this project will uncover new modes of timed regulation of transcription and physiology within the brain, which might be of vast importance beyond Drosophila and uncover potential connections between ultradian and circadian oscillators within these cells. This pioneering study will set the stage for further studying the role of oscillations in the glia, a key cell type in the brain, as well as to understand the mechanism and role of ultradian rhythms in general. As circadian rhythms have been linked to numerous diseases including depression and sleep disorders, the present proposal has obvious implications for human health.