Introduction
Myelin maintains the precise timing and coordination of neural signalling by regulating action potential conduction. Maladaptive myelination disrupts this process and underlies many neurological disorders [1]. We recently showed that cortical demyelination induced by cuprizone, a central nervous system demyelinating drug, shifts cortical excitability and synchrony, leading to motor deficits [2]. However, cuprizone impacts myelinated fibres across the brain, including thalamocortical projections of the internal capsule, an essential yet understudied motor pathway. We propose that demyelination of these pathways impedes thalamic control of cortical states [3] and may contribute more to motor impairments than intracortical dynamics.
Methods
We built a sparsely connected spiking neural network comprising four populations: cortical excitatory and inhibitory neurons, the ventral lateral thalamic nucleus, and the thalamic reticular nucleus. Parameters were fitted to Neuropixels data to generate biophysically realistic yet computationally tractable neuronal responses. Demyelination was simulated by either decreasing axonal conduction velocity or increasing spike propagation failure rate, each scaled to the putative severity of cuprizone-induced damage. Key metrics such as firing rate, firing patterns, and spike correlations were analyzed under both conditions and compared to assess how thalamocortical demyelination alters network excitability and synchrony.
Results
Simulations reveal that decreasing conduction velocity or increasing propagation failure rate significantly impacts thalamocortical network dynamics. That is, demyelination impairs the ability of the thalamus to control cortical dynamics and generates network-wide hypoexcitability and decorrelates spiking activity. These results support our hypothesis that demyelination of thalamocortical pathways contributes to network dysfunction.
Discussion
Our preliminary results suggest that thalamocortical demyelination alters action potential conduction, triggering shifts in network excitability and synchrony that may underlie the motor deficits observed in demyelinating disorders. Investigating demyelination also provides an effective framework for exploring the fundamental role of myelin in neural circuits. Future work will assess how these changes in neural dynamics contribute to motor control impairments, which may provide insight on conditions such multiple sclerosis. These findings highlight the importance of axonal pathways that extend beyond the cortex in understanding how demyelination disrupts neural communication.
References
1. Knowles, J. K., Batra, A., Xu, H., & Monje, M. (2022). Adaptive and maladaptive myelination in health and disease. Nature Reviews Neurology, 18, 735–746. https://doi.org/10.1038/s41582-022-00737-3
2. Gagnon, K., Flora Nunes, G. D., Nettles, D., Nguyen, T., Carter, E. R., Lins, A., Williamson, R., Lefebvre, J., Denman, D., Hughes, E. G., & Welle, C. G. (2025). Myelin supports cortical circuit function underlying skilled movement. bioRxiv. https://doi.org/10.64898/2025.12.23.696289
3. Poulet, J. F., Fernandez, L. M., Crochet, S., & Petersen, C. C. (2012). Thalamic control of cortical states. Nature Neuroscience, 15, 370–372. https://doi.org/10.1038/nn.3035
Acknowledgement
We would like to thank the National Research Council of Canada (NSERC GRANT RGPIN-2017-06662), the Canadian Institute of Health Research (CIHR GRANT NO PJT-156164) and National Institutes of Health (NIH GRANT NS115975) for funding.
