Multiscale Modeling: A Valuable Asset for Therapeutics Development

Center for Neural EngineeringJean-Marie C. Bouteiller

Theodore W. Berger

Sept. 9, 2015

Multiscale Nature of the Nervous System

Temporal Scale

Spati

al S

cale

mse

c

min yrs

nm

mm

m

Electrophysiology

Neurodegenerative diseases

Behavior Imaging

Experimental ParadigmObservable

Long Term Potentiation

Isolated characterization

Modeling of the Nervous System

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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.

Modeling of the Nervous SystemElementary Objects of the Nervous System (EONS):

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:

… From Synapse…

6

… From Synapse… to Neuron Level

7

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

Subcellularcompartment

Cell

Inhibitory receptor

IPSPEPSP

EPSC IPSC

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

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

Example of Application (2)Study of the effects of Glutamatergic and Gabaergic Molecular Dynamics Modulation on Neuron Spiking ActivitySynaptic Level

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Neuronal Integration

*: New spikes with respect to control -: Spikes removed with respect to control

Time (ms)

… From Neuron…

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… From Neuron… to Network

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Summary

Multiscale In-Silico Models can provide insights on nervous system function and dysfunctions

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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

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

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

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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.

End.

Acknowledgments

Theodore W. Berger, PhDDong Song, PhD

Eric Hu Sushmita Allam, PhD

Mike Huang

Endre T. Somogyi, PhD (IU, Bloomington)Herbert Sauro, PhD (UW, Seattle)

Serge Bischoff, PhDMichel Baudry, PhD

Funding:P41 EB001978-24

U01 GM104604