We are interested in signaling mechanisms used by circadian pacemaker neurons to organize daily locomotor behavior. There has been tremendous progress in recent years to define the molecular basis of the cell autonomous clockwork mechanism. That definition has permitted the identification of the primary pacemaker clock neurons within the brain, and in turn presented the opportunity to re-examine fundamental issues concerning the neural basis of behavior. In the previous grant cycle, we identified the receptor for PDF, which is a primary transmitter in the Drosophila circadian neural circuit. That finding establishes a basis for the current grant application. We now propose to describe PDF receptor expression by several independent means. This information will be critical to help interpret PDF signaling that underlies daily locomotor rhythms. Second we will establish an in vitro cell culture model to explore how PDF synchronizes pacemaker neurons by regulating the circadian molecular oscillator mechanism. There is in vivo evidence that PDF delays the entry of PERIOD protein into the nucleus and that frames an explicit hypothesis to be tested. In the past year, we have adapted a novel genetic FRET reporter to measure cAMP levels in vivo real-time. Thus our third aims it to use this method to study PDF signaling dynamics in the living brain. Finally, we will expand our research focus beyond PDF by pursuing the candidacy of several additional neurotransmitters/ neuropeptides for their potential contributions to the operations of the Drosophila circadian neural circuit. The normal functioning of the circadian pacemaker mechanism is essential for proper daily coordination of body and cognitive functions. When the body's timekeeping mechanisms go awry, as in seasonal adaptive disorders or as a consequence of shift work schedules, clinical complications can result. The work we undertake will directly address the fundamental mechanisms that help synchronize the body's clockwork of neurons. The principles we help establish will be useful to develop therapies that can reverse these chronobiological disorders.

Public Health Relevance

We study signaling mechanisms used by circadian pacemaker neurons to organize daily locomotor behavior. We face numerous challenges to the body?s normal timekeeping functions, including travel-related jet-lag, shift work schedules, and seasonal disorders. The major focus for our work concerns transmitter signaling by pacemaker neurons to help learn more about the processes that could help reverse such time-related disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-D (02))
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Beckel-Mitchener, Andrea C
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Washington University
Schools of Medicine
Saint Louis
United States
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Liang, Xitong; Holy, Timothy E; Taghert, Paul H (2017) A Series of Suppressive Signals within the Drosophila Circadian Neural Circuit Generates Sequential Daily Outputs. Neuron 94:1173-1189.e4
Diao, Feici; Mena, Wilson; Shi, Jonathan et al. (2016) The Splice Isoforms of the Drosophila Ecdysis Triggering Hormone Receptor Have Developmentally Distinct Roles. Genetics 202:175-89
Liang, Xitong; Holy, Timothy E; Taghert, Paul H (2016) Synchronous Drosophila circadian pacemakers display nonsynchronous Ca²? rhythms in vivo. Science 351:976-81
Klose, Markus; Duvall, Laura; Li, Weihua et al. (2016) Functional PDF Signaling in the Drosophila Circadian Neural Circuit Is Gated by Ral A-Dependent Modulation. Neuron 90:781-794
Langenhan, Tobias; Barr, Maureen M; Bruchas, Michael R et al. (2015) Model Organisms in G Protein-Coupled Receptor Research. Mol Pharmacol 88:596-603
Duvall, Laura B; Taghert, Paul H (2013) E and M circadian pacemaker neurons use different PDF receptor signalosome components in drosophila. J Biol Rhythms 28:239-48
Duvall, Laura B; Taghert, Paul H (2012) The circadian neuropeptide PDF signals preferentially through a specific adenylate cyclase isoform AC3 in M pacemakers of Drosophila. PLoS Biol 10:e1001337
Taghert, Paul H; Nitabach, Michael N (2012) Peptide neuromodulation in invertebrate model systems. Neuron 76:82-97
Im, Seol Hee; Li, Weihua; Taghert, Paul H (2011) PDFR and CRY signaling converge in a subset of clock neurons to modulate the amplitude and phase of circadian behavior in Drosophila. PLoS One 6:e18974
Duvall, Laura B; Taghert, Paul H (2011) Circadian rhythms: biological clocks work in phospho-time. Curr Biol 21:R305-7

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