Phase response curves of a molecular model oscillator: Implications for mutual coupling of paired oscillators

Increasing evidence indicates that the accessory medulla is the circadian p acemaker controlling locomotor activity rhythms in insects. A prominent gro up of neurons of this neuropil shows immunoreactivity to the peptide pigmen t-dispersing hormone (PDH). In Drosophila melanogaster, the PDH-immunoreact ive (PDH-ir) lateral neurons, which also express the clock genes period and timeless, are assumed to be circadian pacemaker cells themselves. In other insects, such as Leucophaea maderae, a subset of apparently homologue PDH- ir cells is a candidate for the circadian coupling pathway of the bilateral ly symmetric clocks. Although knowledge about molecular mechanisms of the c ircadian clockwork is increasing rapidly, very little is known about mechan isms of circadian coupling. The authors used a computer model, based on the molecular feedback loop of the clock genes in D. melanogaster, to test the hypothesis that release of PDH is involved in the coupling between bilater ally paired oscillators. They can show that a combination of all-delay- and all-advance-type interactions between two model oscillators matches best t he experimental findings on mutual pacemaker coupling in L. maderae. The mo del predicts that PDH affects the phosphorylation rate of clock genes and t hat in addition to PDH, another neuroactive substance is involved in the co upling pathway, via an all-advance type of interaction. The model suggests that PDH and light pulses, represented by two distinct classes of phase res ponse curves, have different targets in the oscillatory feedback loop and a re, therefore, likely to act in separate input pathways to the clock.