Abstract

Demyelination of neurons can compromise the communication performance between the cells as the absence of myelin attenuates the action potential propagated through the axonal pathway. In this work, we propose a hybrid experimental and simulation model for analyzing the demyelination effects on neuron communication. The experiment involves locally induced demyelination using Lysolecithin and from this, a myelination index is empirically estimated from analysis of cell images. This index is then coupled with a modified Hodgkin-Huxley computational model to simulate the resulting impact that the de/myelination processes has on the signal propagation along the axon. The effects of signal degradation and transfer of neuronal information are simulated and quantified at multiple levels, and this includes (1) compartment per compartment of a single neuron, (2) bipartite synapse and the effects on the excitatory post-synaptic potential, and (3) a small network of neurons to understand how the impact of de/myelination has on the whole network. By using the myelination index in the simulation model, we can determine the level of attenuation of the action potential concerning the myelin quantity, as well as the analysis of internal signalling functions of the neurons and their impact on the overall spike firing rate. We believe that this hybrid experimental and in silico simulation model can result in a new analysis tool that can predict the gravity of the degeneration through the estimation of the spiking activity and vice-versa, which can minimize the need for specialised laboratory equipment needed for single-cell communication analysis.

Highlights

  • With the ever-growing knowledge of the biological processes involved in the regeneration of nerve tissues, a better understanding of these events is crucial for the creation of more robust models that could accelerate the development of targeted therapeutics against neurodegeneration [1]

  • We have proposed a new hybrid computational simulation and experimental model to analyze signal propagation along neurons as they undergo demyelination and remyelination

  • We have analysed the effects of demyelination for three different levels and this includes (1) a single compartment within an axon, (2) bipartite synapse to understand how signal propagation changes as they propagate to the post-synaptic neuron and, (3) the impact of de/remyelination on a neuronal network

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Summary

Introduction

With the ever-growing knowledge of the biological processes involved in the regeneration of nerve tissues, a better understanding of these events is crucial for the creation of more robust models that could accelerate the development of targeted therapeutics against neurodegeneration [1]. In relapse-remitting MS (RRMS), demyelination is caused by abnormal peripheral immune invasion of the CNS and inflammatory attack against the myelin sheath, most notably from activated T-cells [2]. This form of the disease is characterised by “attacks” (relapse), followed by periods of recovery (remitting), where innate repair mechanisms of the CNS restore damaged myelin in a process known as remyelination. MS can manifest in the form of primary progressive MS (PPMS), where demyelination is continuous and remyelination mechanisms appear to be dysfunctional [3] It is, of considerable interest to develop therapies that can promote or restore remyelination, with current research approaches including stem cell therapeutics, biomaterial construct implants and nanoparticle or extracellular vesicle treatment formulations, among others [4]–[7]

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