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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067122-10
Application #
8206720
Study Section
Special Emphasis Panel (ZRG1-IFCN-D (02))
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2003-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
10
Fiscal Year
2012
Total Cost
$389,708
Indirect Cost
$133,321
Name
Washington University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
Im, Seol Hee; Taghert, Paul H (2011) Neuroscience. A CRY to rise. Science 331:1394-5
Im, Seol Hee; Taghert, Paul H (2010) PDF receptor expression reveals direct interactions between circadian oscillators in Drosophila. J Comp Neurol 518:1925-45
Shafer, Orie T; Taghert, Paul H (2009) RNA-interference knockdown of Drosophila pigment dispersing factor in neuronal subsets: the anatomical basis of a neuropeptide's circadian functions. PLoS One 4:e8298
Park, Dongkook; Taghert, Paul H (2009) Peptidergic neurosecretory cells in insects: organization and control by the bHLH protein DIMMED. Gen Comp Endocrinol 162:2-7
Shafer, Orie T; Kim, Dong Jo; Dunbar-Yaffe, Richard et al. (2008) Widespread receptivity to neuropeptide PDF throughout the neuronal circadian clock network of Drosophila revealed by real-time cyclic AMP imaging. Neuron 58:223-37
Nitabach, Michael N; Taghert, Paul H (2008) Organization of the Drosophila circadian control circuit. Curr Biol 18:R84-93
Shafer, Orie Thomas; Helfrich-Forster, Charlotte; Renn, Susan Christine Portia et al. (2006) Reevaluation of Drosophila melanogaster's neuronal circadian pacemakers reveals new neuronal classes. J Comp Neurol 498:180-93

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