Model-based Inference of a Directed Network of Circadian Neurons

The suprachiasmatic nucleus (SCN) is the master clock of the brain. It is a network of neurons that behave like biological oscillators, capable of synchronizing and maintaining daily rhythms. The detailed structure of this network is still unknown, and the role that the connectivity pattern plays in the network’s ability to generate robust oscillations has yet to be fully elucidated. In recent work, we used an information theory–based technique to infer the structure of the functional network for synchronization, from bioluminescence reporter data. Here, we propose a computational method to determine the directionality of the connections between the neurons. We find that most SCN neurons have a similar number of incoming connections, but the number of outgoing connections per neuron varies widely, with the most highly connected neurons residing preferentially in the core.

[1]  Francis J. Doyle,et al.  Weakly Circadian Cells Improve Resynchrony , 2012, PLoS Comput. Biol..

[2]  F. Davis,et al.  Transplanted suprachiasmatic nucleus determines circadian period. , 1990, Science.

[3]  Markus Meister,et al.  Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms , 1995, Neuron.

[4]  Linda R Petzold,et al.  Functional network inference of the suprachiasmatic nucleus , 2016, Proceedings of the National Academy of Sciences.

[5]  Kwoon Y. Wong,et al.  Multiplexing Visual Signals in the Suprachiasmatic Nuclei. , 2017, Cell reports.

[6]  S. Bernard,et al.  Spontaneous synchronization of coupled circadian oscillators. , 2005, Biophysical journal.

[7]  R. Leak,et al.  Suprachiasmatic pacemaker organization analyzed by viral transynaptic transport , 1999, Brain Research.

[8]  Linda R Petzold,et al.  Velocity Response Curves Support the Role of Continuous Entrainment in Circadian Clocks , 2010, Journal of biological rhythms.

[9]  Alexis B. Webb,et al.  Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons , 2009, Proceedings of the National Academy of Sciences.

[10]  Hanspeter Herzel,et al.  Measuring Relative Coupling Strength in Circadian Systems , 2018, Journal of biological rhythms.

[11]  Jihwan Myung,et al.  Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping , 2015, Proceedings of the National Academy of Sciences.

[12]  A. Harmar,et al.  Circadian changes in the expression of vasoactive intestinal peptide 2 receptor mRNA in the rat suprachiasmatic nuclei. , 1998, Brain research. Molecular brain research.

[13]  A. Goldbeter,et al.  Toward a detailed computational model for the mammalian circadian clock , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Erik D Herzog,et al.  Small-World Network Models of Intercellular Coupling Predict Enhanced Synchronization in the Suprachiasmatic Nucleus , 2009, Journal of biological rhythms.

[15]  Mingzhou Ding,et al.  Evaluating causal relations in neural systems: Granger causality, directed transfer function and statistical assessment of significance , 2001, Biological Cybernetics.

[16]  Erik D Herzog,et al.  Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons , 2005, Nature Neuroscience.

[17]  Stephanie R. Taylor,et al.  Resynchronization Dynamics Reveal that the Ventral Entrains the Dorsal Suprachiasmatic Nucleus , 2017, Journal of biological rhythms.

[18]  J. Dunlap Molecular Bases for Circadian Clocks , 1999, Cell.

[19]  Sergio Martinoia,et al.  Evaluation of the Performance of Information Theory-Based Methods and Cross-Correlation to Estimate the Functional Connectivity in Cortical Networks , 2009, PloS one.

[20]  M. A. Henson,et al.  A molecular model for intercellular synchronization in the mammalian circadian clock. , 2007, Biophysical journal.

[21]  Linda R. Petzold,et al.  On the Inference of Functional Circadian Networks Using Granger Causality , 2015, PloS one.

[22]  Michael I. Ham,et al.  Functional structure of cortical neuronal networks grown in vitro. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[23]  Joseph S. Takahashi,et al.  Circadian Integration of Metabolism and Energetics , 2010, Science.

[24]  J. Stelling,et al.  Robustness properties of circadian clock architectures. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Hanspeter Herzel,et al.  Coupling governs entrainment range of circadian clocks , 2010, Molecular systems biology.

[26]  Hiroyuki Kubota,et al.  Decoupling of Receptor and Downstream Signals in the Akt Pathway by Its Low-Pass Filter Characteristics , 2010, Science Signaling.

[27]  Imre Kalló,et al.  Expression of VIP and/or PACAP receptor mRNA in peptide synthesizing cells within the suprachiasmatic nucleus of the rat and in its efferent target sites , 2004, The Journal of comparative neurology.

[28]  R. Moore,et al.  Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections , 2001, Brain Research.

[29]  Francis J. Doyle,et al.  Intercellular Coupling Confers Robustness against Mutations in the SCN Circadian Clock Network , 2007, Cell.

[30]  Sanbing Shen,et al.  The mouse VPAC2 receptor confers suprachiasmatic nuclei cellular rhythmicity and responsiveness to vasoactive intestinal polypeptide in vitro , 2003, The European journal of neuroscience.