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Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling

This study explores the role of GABA signaling in the mammalian circadian clock through in vitro and in vivo experiments, as well as multiscale simulations. It also investigates optimal dosing strategies for shift work adjustment using benzodiazepine sleep medications.

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Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling

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  1. Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling Michael A. Henson, UMass Amherst Erik D. Herzog, Washington U. Yannis Kevrekidis, Princeton NIH U01-EB021956-01

  2. Mammalian Circadian Rhythm Generation • The circadian clock generates 24 hour rhythms that regulate numerous physiological and behavioral processes. • Robustness emerges from the network behavior of many heterogeneous neurons. • Shift work creates chronic misalignment between the clock and the environment. www.bio.tamu.edu/users/bell-pedersen/index.html, http://www.bmscentral.com

  3. The Suprachiasmatic Nucleus (SCN) • The SCN of the hypothalamus is the dominant circadian pacemaker in mammals. • The SCN consists of ~20,000 neurons that produce 24 hour cycles in gene expression and firing frequency. • The mechanisms that allow large populations of SCN neurons to coordinate their rhythms are not well understood. E. D. Herzog, Nature Reviews Neuroscience, 2007

  4. SCN Pacemaker Neurons • Neural oscillations are produced by a gene regulatory network with interlocking positive and negative feedback loops. • Circadian modulation of neural firing causes several cell membrane properties to vary over the course of the day. C. S. Colwell, Nature Reviews Neuroscience, 2011.

  5. Intercellular Signaling in the SCN Vasoactive intestinal peptide (VIP) γ-aminobutyric acid (GABA) Presynaptic Neuron Core Clock Core Clock Rhythmic VIP Release Rhythmic GABA Release Postsynaptic Neuron VPAC2 Receptor Binding GABA-A Receptor Binding Calcium Activation Increased Chloride Ion Influx CREB Protein Activation Membrane Hyperpolarization Increased Per transcription Essential for SCN synchronization Role in SCN synchronization controversial Inhibited Neural Firing Wagner et al., Journal of Physiology London, 2001; Gerhold et al. Journal of Neuroscience, 2005

  6. Project Aims • GABA blockade and enhancement will be investigated through in vitro experiments and multiscale simulations based on biophysically based neural networks. • Combined GABA and VIP signaling will be studied through in vivo experiments with wild-type and VIP deficient mice and multiscale simulations. • Optimal dosing strategies of benzodiazepine sleep medications for improved adjustment to shift work will be computed with the multiscale model and tested through in vivo experiments.

  7. Taking Control of Neuronal Firing Mazuski and Hermanstyne (unpublished)

  8. Daily Activation of VIP Neurons Shifts SCN PER2 Rhythms

  9. Pattern Matters: Bursts are Better for Entrainment

  10. SCN Network Modeling Single neuron VIP intercellular signaling

  11. Experiments have shown that GABA can elicit excitatory responses in the SCN* Excitatory GABA-elicited currents are predicted to reduce synchrony GABA may actually counteract the synchronizing effect of VIP Excitatory GABA-Elicited Responses *M. A. Belenky et al., Journal of Comparative Neurology, 2008

  12. Polynomial Chaos Expansion for Heterogeneous Networks In Uncertainty Quantification (UQ)*the object of study is a family of modelsin terms of a few uncertain parameters,drawn from a distribution. For us, there is only one type of neuron, and the distribution comes from heterogeneity, not uncertainty. The model output is assumed to bea function of these heterogeneous parameters,and can be evaluated at any chosen values.The heterogeneity can be intrinsic (kinetic constants), or structural (type of connectivity). Phase θ vs. heterogeneous frequency ω  * D. Xiu. "Numerical Methods for Stochastic Computations: A Spectral Method Approach." 2010.

  13. Heterogeneous Effective Dynamics Simulation of N = 1024 single-ion-channelHodgkin-Huxley-like neuronswith heterogeneous driving current Iand heterogeneous connectivity degreeκ. Insets: membrane potential V plotted as a function of the two heterogeneities during one cycle. h is the dimensionless channel activation variable. app time The network dynamics can be thought of as an irregular discretizationof an effective PDE in 2D heterogeneity space.

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