How Circadian Rhythms and Sleep Interact with Basic Physiology

We seek to determine how physiological processes are integrated with the regulation of circadian rhythms and sleep. We recently identified a circadian rhythm of permeability in the blood brain barrier (BBB) of flies and mammals. In Drosophila, efflux transporters pump small lipophilic molecules, including xenobiotics, out of the brain during the daytime. Transporter activity is regulated by daily cycles of magnesium, which in turn are driven by rhythmic gap junction expression between two cell layers of the BBB. This mechanism confers circadian permeability onto many molecules, including the anti-epileptic phenytoin, which has time-of-day specific effects in a fly seizure model. I will discuss mechanisms underlying the rhythmic permeability of the mammalian BBB.
A recent screen of >12,000 lines that inducibly over-expressed random genes across the Drosophila genome in the nervous system identified a single sleep-promoting molecule: nemuri, an anti-microbial peptide. nemuri is induced by stress, which includes sleep deprivation and bacterial infection, and is capable of killing bacteria and driving sleep. Ongoing work examines the mechanisms that account for nemuri induction by stress.