Mini-Symposium: Understanding Biological Timekeeping Abstracts

Multi-scale and multi-compartment approaches to understand host-pathogen dynamics: TB as a case study

Jihwan Myung, Hiroshima University
Heterogeneity of intrinsic period as a basis of coding in the suprachiasmatic nucleus

Single neurons in the suprachiasmatic nucleus (SCN) autonomously generate circadian (~24 h) oscillations by molecular feedback loops. As a tissue, about 10,000 neurons in the SCN collectively code for seasonal rhythms in addition to maintaining circadian rhythms. Using two strains of mice, one carrying the bioluminescence reporter for Bmal1 expression (Bmal1-ELuc) and the other for Per2 expression (PER2::LUC), we found that the Bmal1 oscillations in the SCN neurons synchronize only partially such that: 1) clusters of slow and fast oscillators emerge with a characteristic topography regardless of pharmacological or physical isolations, 2) the oscillators in intact SCN slices have shorter oscillatory periods than under pharmacological and physical isolations, and 3) the periods in different SCN regions vary depending on the patterns of light duration. Together with computer simulations using a phase oscillator model, we interpret that the intrinsic periods of single oscillators play the most dominant role in forming the tissue-level dynamics while the intercellular coupling does not strongly influence the Bmal1 oscillation or the nature of the coupling is more complex than is previously assumed. Direct estimation of coupling based on the phase oscillator model indicates the existence of an unusual coupling component among clusters of oscillators. These findings reveal previously unexpected complexities in the phylogenetically ancient network structure and suggest a possibility that intrinsic periods can be used to store a particular mode of coding.

A molecular network design to maintain a fixed period in circadian clocks

Jae Kyoung Kim, University of Michigan
Circadian clocks persist with a constant period (~24-hour) even after a significant change of the expression level of clock genes. Although much is known about cellular circadian timekeeping, little is known about how these rhythms are sustained with a constant period. Here, we show how a universal motif of circadian timekeeping, where repressors bind activators rather than directly binding to DNA, can generate oscillations when activators and repressors are in stoichiometric balance. Furthermore, we find that, even in the presence of large changes in gene expression levels, an additional slow negative feedback loop keeps this stoichiometry in balance and maintains oscillations with a fixed period. To study these biochemical mechanisms of timekeeping, we develop the most accurate mathematical model of mammalian intracellular timekeeping, as well as a simplified model. These results explain why the network structure found naturally in circadian clocks can generate ~24-hour oscillations in many conditions. Furthermore, our study provides a novel design for the biological oscillators where maintaining a fixed period is crucial.

Optimized Schedules for Reentrianment in Minimum Time

Kirill Serkh, University of Michigan and Yale University
Jet-lag and circadian misalignment remain a major challenge for society. A key approach in treating circadian misalignment is properly timed light exposure. He develop a mathematically methodology to determine lighting schedules which are predicted to reentrain in minimal time. Using two models of the central circadian pacemaker in humans, we find schedules that have predicted reentrainment in a remarkably short amount of time. For example, we predict that a 12-hour schedule shift, using bright light, could have a corrected circadian phase within 2 days as well as a corrected circadian amplitude within 4 days. These schedules are mathematically optimal in that no other schedule can cause the models to re-entrain quicker. While our methodology imposes only one constraint, a maximum light level, the predicted optimal schedules nonetheless match aspects of many previously proposed schedules including: 1) rough adherence to the light-dark schedules in the new time zone, 2) avoidance of light particularly in the morning and 3) optimal combinations of phase shifting and partial amplitude suppression. The schedules are also quite easy to following and include just two regions, one were light should be avoided, and another where one should seek as much light as possible. If verified experimentally, these schedules could present a paradigm shift in the treatment of circadian misalignment.