1. Multiscale Modeling: A Valuable Asset for Therapeutics Development Center for Neural Engineering Jean-Marie C. Bouteiller Theodore W. Berger Sept. 9, 2015

2. Multiscale Nature of the Nervous System Temporal Scale Spatial Scale msec min yrs nm mm m Electrophysiology Neurodegenerative diseases Behavior Imaging Experimental Paradigm Observable Long Term Potentiation Isolated characterization

3. Modeling of the Nervous System 3 Elementary Objects of the Nervous System (EONS): EONS is a detailed parametric (mechanistic) model of the biomolecular mechanisms that take place at the synaptic scale.

4. Modeling of the Nervous System Elementary Objects of the Nervous System (EONS):

5. Example of Application (1) Combinations: Given X compounds, identify a combination of 2 potential synergistic compounds, and their optimal concentrations 5 In-Vitro Validation: In-Silico Prediction:

6. … From Synapse… 6

7. … From Synapse… to Neuron Level 7

8. Example of Application (2) Study of the effects of Glutamatergic and Gabaergic Molecular Dynamics Modulation on Neuronal Spiking Excitatory synapse Inhibitory synapse Excitatory Receptor CA1 pyramidal Cell Compound Target Subcellular compartment Cell Inhibitory receptor IPSPEPSP EPSC IPSC

9. Example of Application (2) Study of the effects of Glutamatergic and Gabaergic Molecular Dynamics Modulation on Neuron Spiking Activity NMDA receptor inhibition (AP5): (Ambert et al. Open Access Bioinformatics 2010) Binding

10. Example of Application (2) GABA A receptor inhibition (bicuculline): GABA A dynamic response Study of the effects of Glutamatergic and Gabaergic Molecular Dynamics Modulation on Neuron Spiking Activity

11. Example of Application (2) Study of the effects of Glutamatergic and Gabaergic Molecular Dynamics Modulation on Neuron Spiking Activity Synaptic Level 11 Neuronal Integration *: New spikes with respect to control - : Spikes removed with respect to control Time (ms)

12. … From Neuron… 12

13. … From Neuron… to Network 13

14. Summary  Multiscale In-Silico Models can provide insights on nervous system function and dysfunctions 14

15. Summary  Multiscale In-Silico Models can provide insights on nervous system function and dysfunctions  They can guide development of potential therapeutics  Study of combinations  Therapeutics efficacy  Side Effects, toxicity 15

16. Summary  Multiscale In-Silico Models can provide insights on nervous system function and dysfunctions  They can guide development of potential therapeutics  Study of combinations  Therapeutics efficacy  Side Effects, toxicity  Challenges preventing adoption of this technology 16

17. Summary  Multiscale In-Silico Models can provide insights on nervous system function and dysfunctions  They can guide development of potential therapeutics  Study of combinations  Therapeutics efficacy  Side Effects, toxicity  Challenges preventing adoption of this technology 17 Our brain: (i) To structure complexity (ii) Address actual needs (problem driven) Non-believers’ brain: After many other fields, biology and medicine are next… … It is just a matter of when.

18. End. Acknowledgments Theodore W. Berger, PhD Dong Song, PhD Eric Hu Sushmita Allam, PhD Mike Huang Endre T. Somogyi, PhD (IU, Bloomington) Herbert Sauro, PhD (UW, Seattle) Serge Bischoff, PhD Michel Baudry, PhD Funding: P41 EB001978-24 U01 GM104604

19. Methodologies: Parametric Modeling Elementary Objects of the Nervous System (EONS):

20. Methodologies: Parametric Modeling Elementary Objects of the Nervous System (EONS):

21. Methodologies: Parametric Modeling Elementary Objects of the Nervous System (EONS):

22. Example of Application (3) Defense & Ecotoxicity: 22 Discovery of protective drugs against neurotoxic agents (Defense) Determination of neurotoxic effects of nanoparticles (Ecotoxicity) Anti-epileptic / pro-convulsant simulator

23. Example of Application (3) Defense & Ecotoxicity: 23 Discovery of protective drugs against neurotoxic agents (Defense) Determination of neurotoxic effects of nanoparticles (Ecotoxicity) Anti-epileptic / pro-convulsant simulator In-silico study of anti-epileptic effects of drugs: 86% of results were reproduced in-vitro