Brains anticipate and respond to daily changes in the environment. Disruption of 24-hour rhythms in neural function correlates with and may contribute to many disorders, including insomnia, epilepsy, and neurodegenerative diseases. Anticipation of environmental changes, reflecting the well-studied circadian clock, interacts with the direct effects of the environment on behavior and physiology, termed masking, to generate widespread time-of-day dependent functions. Relatively little is known about the molecular and neural substrates of masking and their regulation by circadian clocks. This proposal focuses on the function of a highly conserved, widely expressed, but little studied, ion channel NARROW ABDOMEN (NA) in Drosophila. na mutants exhibit disrupted behavioral responses to light as well as poor circadian rhythms, providing an in vivo genetic model to study this novel ion channel family. Using na, we have identified a central brain locus (~20 neurons) important for masking behavior. Here we will analyze the role of circadian and photoreceptive pathways in regulating this locus. Studies of the highly conserved mammalian ortholog of NA, NALCN, suggest regulation by neuropeptide receptor activation. Here we will examine whether NA mediates the effects of the key circadian neuropeptide PDF. Our preliminary data also suggest that NA overexpression can partially rescue weakly rhythmic clock mutants. We will assess the molecular mechanisms by which NA strengthens rhythms in flies with genetically disabled clocks. These results highlight the possibility that NA activation may be a therapeutic target to improve rhythms in various brain disorders. Preliminary results suggest that both NA and the genetic bases of masking and circadian behavior are conserved, indicating our findings will be applicable to humans.
