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dc.contributor.authorMedlock, Laura
dc.contributor.authorSekiguchi, Kazutaka
dc.contributor.authorHong, Sungho
dc.contributor.authorDura-Bernal, Salvador
dc.contributor.authorLytton, William W
dc.contributor.authorPrescott, Steven A
dc.date.accessioned2023-04-10T15:38:05Z
dc.date.available2023-04-10T15:38:05Z
dc.date.issued2022-03-01
dc.identifier.citationMedlock L, Sekiguchi K, Hong S, Dura-Bernal S, Lytton WW, Prescott SA. Multiscale Computer Model of the Spinal Dorsal Horn Reveals Changes in Network Processing Associated with Chronic Pain. J Neurosci. 2022 Apr 13;42(15):3133-3149. doi: 10.1523/JNEUROSCI.1199-21.2022. Epub 2022 Mar 1. PMID: 35232767; PMCID: PMC8996343.en_US
dc.identifier.eissn1529-2401
dc.identifier.doi10.1523/JNEUROSCI.1199-21.2022
dc.identifier.pmid35232767
dc.identifier.urihttp://hdl.handle.net/20.500.12648/8559
dc.description.abstractPain-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 pathologic insults. To validate our model, we verified that it responded to the 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 to plan experiments for examining normal and pathologic SDH circuit function. We developed a multiscale computer model of the posterior part of spinal cord gray matter (spinal dorsal horn), which is involved in perceiving 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.
dc.language.isoenen_US
dc.relation.urlhttps://www.jneurosci.org/content/42/15/3133.longen_US
dc.rightsCopyright © 2022 the authors.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectcomputer modelingen_US
dc.subjectdegeneracyen_US
dc.subjectdorsal hornen_US
dc.subjectpainen_US
dc.subjectsomatosensationen_US
dc.subjectspinal corden_US
dc.titleMultiscale Computer Model of the Spinal Dorsal Horn Reveals Changes in Network Processing Associated with Chronic Pain.en_US
dc.typeArticle/Reviewen_US
dc.source.journaltitleThe Journal of neuroscience : the official journal of the Society for Neuroscienceen_US
dc.source.volume42
dc.source.issue15
dc.source.beginpage3133
dc.source.endpage3149
dc.source.countryUnited States
dc.source.countryCanada
dc.source.countryUnited States
dc.description.versionVoRen_US
refterms.dateFOA2023-04-10T15:38:05Z
html.description.abstractPain-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 pathologic insults. To validate our model, we verified that it responded to the 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 to plan experiments for examining normal and pathologic SDH circuit function. We developed a multiscale computer model of the posterior part of spinal cord gray matter (spinal dorsal horn), which is involved in perceiving 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.
dc.description.institutionSUNY Downstateen_US
dc.description.departmentPhysiology and Pharmacologyen_US
dc.description.departmentNathan Kline Institute for Psychiatric Researchen_US
dc.description.degreelevelN/Aen_US
dc.identifier.journalThe Journal of neuroscience : the official journal of the Society for Neuroscience


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