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Multiscale computer model of the spinal dorsal horn reveals changes in network processing associated with chronic pain

View ORCID ProfileLaura Medlock, View ORCID ProfileKazutaka Sekiguchi, View ORCID ProfileSungho Hong, View ORCID ProfileSalvador Dura-Bernal, View ORCID ProfileWilliam W Lytton, View ORCID ProfileSteven A. Prescott
doi: https://doi.org/10.1101/2021.06.09.447785
Laura Medlock
aNeurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
bInstitute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada
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Kazutaka Sekiguchi
cDrug Developmental Research Laboratory, Shionogi Pharmaceutical Research Center, Toyonaka, Osaka 561-0825, Japan
dState University of New York Downstate Health Science University, Brooklyn, NY 11203, US
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Sungho Hong
eComputational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa 904-0495, Japan
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Salvador Dura-Bernal
dState University of New York Downstate Health Science University, Brooklyn, NY 11203, US
fNathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, US
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William W Lytton
dState University of New York Downstate Health Science University, Brooklyn, NY 11203, US
gKings County Hospital, Brooklyn, NY 11207, US
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  • For correspondence: steve.prescott@sickkids.ca billl@neurosim.downstate.edu
Steven A. Prescott
aNeurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada
bInstitute of Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada
hDepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
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  • For correspondence: steve.prescott@sickkids.ca billl@neurosim.downstate.edu
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Abstract

Pain-related sensory input is processed in the spinal dorsal horn (SDH) before being relayed to the brain. That processing profoundly influences whether stimuli are correctly or incorrectly perceived as painful. Significant advances have been made in identifying the types of excitatory and inhibitory neurons that comprise the SDH, and there is some information about how neuron types are connected, but it remains unclear how the overall circuit processes sensory input or how that processing is disrupted under chronic pain conditions. To explore SDH function, we developed a computational model of the circuit that is tightly constrained by experimental data. Our model comprises conductance-based neuron models that reproduce the characteristic firing patterns of spinal neurons. Excitatory and inhibitory neuron populations, defined by their expression of genetic markers, spiking pattern, or morphology, were synaptically connected according to available qualitative data. Using a genetic algorithm, synaptic weights were tuned to reproduce projection neuron firing rates (model output) based on primary afferent firing rates (model input) across a range of mechanical stimulus intensities. Disparate synaptic weight combinations could produce equivalent circuit function, revealing degeneracy that may underlie heterogeneous responses of different circuits to perturbations or pathological insults. To validate our model, we verified that it responded to reduction of inhibition (i.e. disinhibition) and ablation of specific neuron types in a manner consistent with experiments. Thus validated, our model offers a valuable resource for interpreting experimental results and testing hypotheses in silico to plan experiments for examining normal and pathological SDH circuit function.

Significance Statement We developed a multiscale computer model of the posterior part of spinal cord gray matter (spinal dorsal horn), involved in perception of touch and pain. The model reproduces several experimental observations and makes predictions about how specific types of spinal neurons and synapses influence projection neurons that send information to the brain. Misfiring of these projection neurons can produce anomalous sensations associated with chronic pain. Our computer model will not only assist in planning future experiments, but will also be useful for developing new pharmacotherapy for chronic pain disorders, connecting the effect of drugs acting at the molecular scale with emergent properties of neurons and circuits that shape the pain experience.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 15, 2022.
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Multiscale computer model of the spinal dorsal horn reveals changes in network processing associated with chronic pain
Laura Medlock, Kazutaka Sekiguchi, Sungho Hong, Salvador Dura-Bernal, William W Lytton, Steven A. Prescott
bioRxiv 2021.06.09.447785; doi: https://doi.org/10.1101/2021.06.09.447785
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Multiscale computer model of the spinal dorsal horn reveals changes in network processing associated with chronic pain
Laura Medlock, Kazutaka Sekiguchi, Sungho Hong, Salvador Dura-Bernal, William W Lytton, Steven A. Prescott
bioRxiv 2021.06.09.447785; doi: https://doi.org/10.1101/2021.06.09.447785

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