Modeling the emergence of circadian rhythms in a clock network

L. DIAMBRA

Santiago

Congreso; ISCB-Latin America 2012; 2012

International society of computational biology

Background Most living organisms present circadian rhythm. Several recent observations have suggested that this rhythm at the molecular level results from a gene regulatory network [1]. Circadian rhythms in pacemaker cells persist for weeks in constant darkness, while in other types of cells the molecular oscillations that underlie circadian rhythms damp rapidly under the same conditions [2]. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms leading to damped or self- sustained oscillations under constant condition remain largely unknown. Methods In this work we have implemented a model for a network of interacting clock neu- rons to describe the emergence (or damping) of circadian rhythms in Drosophila, in the absence of external clues. Our model consists of an array of pacemakers that interact through the modulation of some parameters by a network feedback. The individual pacemakers are described by a well-known biochemical model for circadian oscillation [3], to which we have added degradation of PER protein by light and noise. Each clock neuron has some of its parameters modulated by the PER protein level of all the other clock neurons. This corresponds to a fully connected network, without self-interactions. In particular we have investigated the effect of modulation of the parameters associated with (i) the control of net entrance of PER into the nucleus; and (ii) the non-photic degradation of PER. Results Our results indicate that the modulation of PER entrance into the nucleus allows the synchronization of clock neurons, leading to coherent circadian oscillations under constant dark condition. On the other hand, the modulation of non-photic degradation cannot reset the phases of individual clocks subjected to intrinsic biochemical noise. This means that mechanisms based on a positive feedback acting over the rate of entrance of the phosphorylated PER into the nucleus could be essential for maintaining the circadian oscillation under free-running condition. This fact suggests a putative way of action for the neuropeptide PDF [4], which could be acting as an agent that promotes the entrance of the phosphorylated PER into the nucleus.