Circadian rhythms are organismically ubiquitous biological cycles whose propr daily regulation is strongly connected to the well being of species ranging from microbes to mammals. The 25- year-old genetic approach toward understanding these rhythms has recently begun to reveal elements of the clock mechanisms that underlie daily rhythmicities. This sub-proposal in a Program Project application revolves around the behavioral genetic, neuro- genetics, and molecular neurobiology of circadian rhythms in Drosophila. The experiments proposed stress more of a ~systems~ approach than one that would concentrate upon the hard core of molecular pacemaking. Thus, the neural substrates of behavioral rhythms, and a periodic feature of late development, will be delved into by application of rhythm mutants and transgenic strains carrying manipulated forms of clock-genes; these studies include descriptions of anatomic output pathways from neurons that are candidate for CNS-pacemaker cells, and selectively effected perturbations of the structure and function of such cells in conjunction with bioassaying the effects of the molecularly mediated neuronal damage. Input paths to the central pacemakers, which bring in environmental cues to effect crucial daily re-sets of the clock, will be dissected both in terms of anatomy and elements of signal-transduction pathways that putatively participate in processing the resetting stimuli. Output pathways will be investigated, with respect to varying physiological parameters that are hypothesize to be the first- or second-stage targets of clock- gene functions. The latter includes cyclically varying levels of the encoded mRNAs and proteins; these molecular cyclings will be tracked in conjunction with physiological recordings and perturbations, by applying a transgene in which portions of a clock gene (called period) have been fused to DNA sequences encoding a real-time reporter; this is luciferase activity, which as recently been shown to permit non-invasive monitoring of molecular rhythms in live adult flies and in per-expressing tissues explanted from animals late in development. Genetic and molecular-genetic studies are proposed in two areas: (1) analysis of the behavioral and neurobiological consequences of manipulating a clock-controlled gene~s expression, and of effecting the same kinds of perturbations of a neuropeptide-encoding gene whose product is co-expressed with clock genes in a subset of the CNA pacemaking neurons; (2) genetic and biological studies of rhythm mutants, recently isolated on the basis of defects in circadian behavioral rhythms: these phenogenetic studies will proceed into cloning of the genes defined by mutations that appear to be the most promising candidates for disrupting important elements of Drosophila~s circadian system.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brandeis University
United States
Zip Code
Vodala, Sadanand; Pescatore, Stefan; Rodriguez, Joseph et al. (2012) The oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs. Cell Metab 16:601-12
Shang, Yuhua; Haynes, Paula; Pírez, Nicolás et al. (2011) Imaging analysis of clock neurons reveals light buffers the wake-promoting effect of dopamine. Nat Neurosci 14:889-95
Hall, Jeffrey C (2005) Systems approaches to biological rhythms in Drosophila. Methods Enzymol 393:61-185
Choi, James C; Park, Demian; Griffith, Leslie C (2004) Electrophysiological and morphological characterization of identified motor neurons in the Drosophila third instar larva central nervous system. J Neurophysiol 91:2353-65
Busza, Ania; Emery-Le, Myai; Rosbash, Michael et al. (2004) Roles of the two Drosophila CRYPTOCHROME structural domains in circadian photoreception. Science 304:1503-6
Park, Demian; Coleman, Melissa J; Hodge, James J L et al. (2002) Regulation of neuronal excitability in Drosophila by constitutively active CaMKII. J Neurobiol 52:24-42
McDonald, M J; Rosbash, M; Emery, P (2001) Wild-type circadian rhythmicity is dependent on closely spaced E boxes in the Drosophila timeless promoter. Mol Cell Biol 21:1207-17
Joiner, M A; Griffith, L C (2000) Visual input regulates circuit configuration in courtship conditioning of Drosophila melanogaster. Learn Mem 7:32-42
Joiner, M A; Griffith, L C (1999) Mapping of the anatomical circuit of CaM kinase-dependent courtship conditioning in Drosophila. Learn Mem 6:177-92
DeSimone, S; Coelho, C; Roy, S et al. (1996) ERECT WING, the Drosophila member of a family of DNA binding proteins is required in imaginal myoblasts for flight muscle development. Development 122:31-9

Showing the most recent 10 out of 79 publications