Multiscale Computer Model of the Spinal Dorsal Horn Reveals Changes in Network Processing Associated with Chronic Pain

Abstract

Pain-related sensory input is processed in the spinal cord 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 spinal dorsal horn (SDH), and there is some information about how neuron types are connected, but it remains unclear how the overall circuit processes sensory input. To explore SDH circuit 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 excitatory and inhibitory neurons. Excitatory neuron subtypes defined by calretinin, somatostatin, delta opioid receptor, protein kinase C gamma, or vesicular glutamate transporter 3 expression or by transient/central spiking/morphology, and inhibitory neuron subtypes defined by parvalbumin or dynorphin expression or by islet morphology were synaptically connected according to available qualitative data. Synaptic weights were adjusted to produce firing in projection neurons, defined by neurokinin-1 expression, matching experimentally measured responses to a range of mechanical stimulus intensities. Input to the circuit was provided by three types of afferents whose firing rates were also matched to experimental data. To validate our model, we ablated specific neuron types or applied other changes and compared model output with experimental data after equivalent manipulations. The resulting model provides a valuable tool for testing hypotheses in silico to plan novel experiments on SDH circuit dynamics and function.

Modernizing the NEURON Simulator for Sustainability, Portability, and Performance

“…NetPyNE (Dura-Bernal et al, 2019 ) is a high-level declarative NEURON wrapper used to develop a wide range of neural circuit models (Metzner et al, 2020 ; Anwar et al, 2021 ; Bryson et al, 2021 ; Pimentel et al, 2021 ; Ranieri et al, 2021 ; Romaro et al, 2021 ; Volk et al, 2021 ; Borges et al, 2022 ; Dura-Bernal et al, 2022a , b ; Medlock et al, 2022 ) 4 , and also as a resource for teaching neurobiology and computational neuroscience.…”

Degeneracy in epilepsy: Multiple Routes to Hyperexcitable Brain Circuits and their Repair

“…Degeneracy can be found not only at the single cell level but also at the network level of synaptically connected neurons. Analogous to multiple configurations of intrinsic ion channels leading to indistinguishable electrical behavior of single neurons (Taylor et al, 2009), multiple configurations of synaptic properties can support indistinguishable electrical behavior of neuronal networks (Prinz et al, 2004;Marder and Goaillard, 2006;Medlock et al, 2022;Narayanan, 2019, 2021b). Moreover, the circuit degeneracy is also enhanced by the fact that intrinsic and synaptic channels can (not only in isolation but also) jointly con-tribute to indistinguishable network activity (Prinz et al, 2004;Marder and Goaillard, 2006;Grashow et al, 2010).…”

“…A simulation study of the thalamo-cortical network in childhood absence epilepsy (Knox et al, 2018) Another recent multiscale simulation study, although not focusing on epilepsy, has provided novel insights on degeneracy in the context of pathological perturbations linked to hyperexcitability associated with chronic pain (Medlock et al, 2022). In network simulations of spinal dorsal horn, the authors have demonstrated that, under physiological conditions, similar circuit activity can emerge in different models with disparate configurations of synaptic properties.…”

Modelling the contributions to hyperexcitability in a mouse model of Alzheimer’s disease

“…Our findings are in agreement with a general and increasingly accepted concept of degeneracy (Edelman and Gally, 2001). In complex degenerate systems, such as the nervous system, multiple distinct mechanisms can be sufficient, but typically not necessary, to account for a given function or malfunction, such as normal excitability or hyperexcitability (Kamaleddin, 2022; see also Neymotin et al ., 2016; Ratté and Prescott, 2016; O’Leary, 2018; Medlock et al ., 2022). Consistent with the degeneracy framework, our results suggest that multiple extrinsic and intrinsic mechanisms are sufficient but not necessary to increase neuronal excitability in AD.…”