Experiments are proposed to delve into the cellular neurobiology of Drosophila's rhythm system--the cells, molecules, and systems that underlie the animal's rest-activity cycles. One focus will involve certain adult-brain neurons, within which actions of and interactions among clock-gene products are hypothesized to form the molecular and cellular substrates of circadian behavioral rhythms: How do these proteins physically interact in vivo? To this end, FRET-based analyses will be performed to assess such biologically meaningful interactions. This will complement and may even modify the conventional view of clockwork protein-protein interactions, because the latter stems largely from characterizations of the protein interactions in tissue extracts or cultured non-neuronal cells. In experiments to be carried out at more of a systems level, THE FUNCTIONS [sic] of the brain neurons in question will be dissected by manipulations of transgenes derived from in-hand clock genes, and from the identification of others by virtue of their presumed specification of pacemaker-output factors. Which subsets of these neurons carry out functions that are output into rhythmic behavior per se, and which are involved in communication among cells within the pacemaking system? Do the presumed neurochemical outputs (alluded to above) function in that manner only, or do they also mediate feedback functions back into the pacemakers (considered both cellularly and molecularly)? With regard to the known rhythmic oscillations of certain clock-gene products and putative clock-output molecules--which of these systematic fluctuations are important for the behavioral rhythmicity that can be sustained in constant environmental conditions, and is such molecular maintenance in part a systems property (involving interactions among certain neurons, cellular feedback phenomena, or both)? Daily oscillations of behavior in Drosophila represent a feature of circadian rhythmicity that is among the most prominent and widespread among metazoan organisms. Moreover, the kinds of gene products and the ways they form the clockworks are analogous across a broad array of species. Therefore, brain-behavior studies of chronobiology in this model system may provide insights into the nature of certain rhythm-related disorders of humans, some of which are associated with genetic variations of Drosophila clock gene orthologs ? ?
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