Heterogeneity of the Suprachiasmatic Nucleus: Quantification, Simulation, and Functional Analysis

• Applicant: Dr. Grigory Bordyugov
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235843329

• Final Report Year: 2017

Final Report Abstract

The main project aims were to understand the generation and coordination of circadian rhythms in the mammalian SCN on different scales which can range from the single cell periodicity to the coordination of oscillations on the level of the whole organ. We are glad to be able to report advances on at least three different levels of this hierarchy. On a single cell level, we present a computational framework for mechanism-focused modeling of gene regulatory networks. Using a very simple and intuitive description of the interaction between genes together with their regulatory elements, the framework allows to define interactions between the chosen genes and automatically tune the parameters of the model, aiming at fitting a chosen set of experimental data. Whereas we have achieved a remarkable degree of agreement between the simulated oscillations and their experimental counterpart, the question of the uniqueness of the parameter values in the model is still open and requires further investigations. If one chooses to abstract away the details of how rhythms generated, be it on the single cell or the organism level, and is only interested in few fundamental oscillation properties such as amplitude, period and the phase of the oscillations, the simplest mathematical oscillator models turn out to be a great predictor for a substantial variety of observed phenomena. In this project, we continued our previous efforts to understand and describe the behaviour of entrainment phase under different conditions. Our main contribution here is a new conceptual treatment of photoperiod and its influence on entrainment phase. We have discovered the “entrainment onion” – the counterpart of the Arnold tongue under varying photoperiod (instead of Zeitgeber strength) and showed that changes in photoperiod can effectuate significantly larger deviations of entrainment phase. Considering the SCN as an ensemble of interacting circadian neurons, we proposed to use a new measure for its synchronization property - the Moran’s I statistics, previously nearly unknown in the field of chronobiology. This statistics complements the more traditional Kuramoto’s order parameter in being sensitive not only to the global distribution of the phases, but rather to how well neighbouring oscillators are correlated. With the help of Moran’s I, it became possible to automatically classify between regimes in the SCN that would have remained undistinguishable using Kuramoto’s order parameter only. In conclusion, we report on the discovery of the extremely strong rhythmicity in the choroid plexus (CP) (experiments performed in the lab of Prof Toru Takumi). CP seems to be at least as robust an oscillator as the SCN, having a higher amplitude of circadian oscillations and a slightly shorter period. We proposed that the remarkable rhythmic properties of the CP can be modelled by oscillators with the so-called “twist”, i.e. dependence of the instantaneous period on the amplitude. Co-culture experiments with the SCN and CP additionally suggest that the CP can tune the oscillations in the SCN.

Publications

• (2017) Moran's I quantifies spatio-temporal pattern formation in neural imaging data. Bioinformatics (Oxford, England) 33 (19) 3072–3079
  Schmal, Christoph; Myung, Jihwan; Herzel, Hanspeter; Bordyugov, Grigory
  
• (2018) Measuring Relative Coupling Strength in Circadian Systems. Journal of biological rhythms 33 (1) 84–98
  Schmal, Christoph; Herzog, Erik D.; Herzel, Hanspeter
  
• (2018) The choroid plexus is an important circadian clock component. Nature communications 9 (1) 1062
  Myung, Jihwan; Schmal, Christoph; Hong, Sungho; Tsukizawa, Yoshiaki; Rose, Pia; Zhang, Yong; Holtzman, Michael J.; Schutter, Erik de; Herzel, Hanspeter; Bordyugov, Grigory; Takumi, Toru
  
• A theoretical study on seasonality. Frontiers in neurology. 2015;6
  Schmal C, Myung J, Herzel H, Bordyugov G
  
• Tuning the phase of circadian entrainment. Journal of The Royal Society Interface. 2015;12(108):20150282
  Bordyugov G, Abraham U, Granada A, Rose P, Imkeller K, Kramer A, et al.
  
• The plant leaf movement analyzer (PALMA): a simple tool for the analysis of periodic cotyledon and leaf movement in Arabidopsis thaliana. Plant methods. 2017;13(1):2
  Wagner L, Schmal C, Staiger D, Danisman S