Organisms exhibit ~24-hour (circadian) rhythms in behavioral and physiological processes that depend on the presence of dedicated clock cells in the brain that keep time through a molecular clock that maintains daily rhythms of gene expression. In addition, molecular clocks are present in most peripheral tissues, where they serve tissue-specific functions. Together, these make up an extended clock network that synchronizes behavioral and physiological processes with the external environment and organizes them with respect to one another. For example, the circadian system generates rhythms in feeding behaviors such that feeding occurs at optimal times of day, and concurrently upregulates metabolic pathways in anticipation of increased food intake. Proper circadian organization is essential for organismal fitness, but the cellular and molecular mechanisms through which circadian rhythms are generated and integrated across multiple clock-containing tissues are unknown. To that end, experiments outlined in this project will use the powerful model organism of the fruit fly, Drosophila melanogaster, to identify neuronal pathways through which clock cells establish circadian rhythms of feeding behavior and to further delineate how feeding rhythms are coordinated with peripheral metabolic rhythms. These experiments will be conducted in collaboration with postdoctoral and undergraduate researchers in the lab who will also serve as mentors for a summer high school internship program that will expand participation to groups traditionally underrepresented in the sciences.
An understanding of the manner through which the circadian system modulates behavioral outputs and coordinates these with physiological rhythms requires analysis of novel circadian endpoints in addition to rest and activity, which has thus far been the focus of most circadian research. Objective 1 will use a newly-developed feeding monitor to determine the cellular logic through which the central clock regulates feeding rhythms. To determine whether distinct central clock mechanisms control feeding and locomotor activity rhythms, period and strength of feeding rhythms will be measured following genetic manipulations that alter molecular clock function or neuronal activity in discrete clock cell populations. Objective 2 will investigate downstream output pathways through which feeding rhythms are produced. To enact behavioral rhythms, circadian information must be transmitted across output pathways to brain areas that regulate behaviors. The Cavanaugh laboratory recently implicated SIFa peptide-expressing neurons as a component of the circadian output pathway controlling feeding. To continue to trace the circadian feeding circuit, an RNA interference-based behavioral screen will be conducted to identify cells in which the SIFa receptor must be present for normal feeding rhythms. Finally, Objective 3 will investigate how feeding and metabolic rhythms are coordinated by the clock network. The fat body is a peripheral clock tissue that serves metabolic functions. A combined transcriptomic and metabolomic approach will be employed to determine how loss of SIFa signaling or selective molecular clock abrogation in the brain or fat body affects fat body gene oscillations and whole-animal metabolite abundance.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
