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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
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.
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
11
Neuronal Integration
*: New spikes with respect to control -: Spikes removed with respect to control
Time (ms)
… From Neuron…
12
… From Neuron… to Network
13
Summary
Multiscale In-Silico Models can provide insights on nervous system function and dysfunctions
14
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
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.
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