Written by Shrey Mehta ‘26
Edited by Yuliya Velhan ‘25
Introduction
Imagine that you’re at a party with at least a hundred people in a stuffy room.
Through the corner of your eye, you detect some smoke – something has caught on fire and everyone needs to evacuate.
You frantically run to alert your friends, call 911, and exit the party. All these reflexes and fast-paced actions are the result of the harmonized effort of your nervous system: a network of different cell types processing information and executing complicated tasks.
Neurons are these fundamental units of the nervous system that orchestrate exactly what you did in response to the fire at the party. But in reality, neurons cannot do this all alone. Here, the role of myelin becomes known.
Glia: An Overview
To really understand the detrimental effects of maladaptive myelin, it is first important to dive into the various roles of glial cells in the nervous system. Their main job is to support the primary functional units of the brain, the neurons. Without these supportive cells, the nervous system essentially loses the “glue” that keeps the neuronal network connecting and working at optimal efficiency. Some examples of their functions include: regulating neurotransmitters, forming the blood-brain barrier, cleaning up cell debris, synchronizing neuronal communication. In this article, I’ll specifically focus on the function of oligodendrocytes – which form the myelin sheaths around the axons of neurons. [4]
The most significant function of myelin is insulation – keeping the electrochemical charges within the neurons so that communication is not disrupted but rather, fastened! In the healthy brain, myelin is actually very adaptive (plastic) and these changes are thought to refine neural circuit dynamics to promote coordinated circuit function and overall healthy cognitive behavior. What’s been noticed recently, however, is that myelin may actually have the exact opposite effect in certain diseases. Instead of supporting the function of the neurons, myelin seems to actually promote the pathological patterns that manifest in neurological disorders. [4]
Problems with Myelin & Resulting Pathology
It is evident that adaptive myelin and myelin plasticity is critical to several cognitive and neurophysiological activities. Hence, it is reasonable to believe that the dysregulation of myelination can also have very negative effects. The following evidence indicated that impaired myelination or maladaptive myelination can instead tune neuronal networks towards unhealthy activity. [1] [2]
One such implication of problems with myelin is cancer therapy-related cognitive impairment (CRCI), which may also be referred to as chemo brain fog. Due to structural changes in myelin and white matter in the brain, this condition presents as significant deficits in attention, concentration, and memory. This segways into the next major implication: neurodegeneration as seen in aging and diseases like Alzheimer disease. Researchers have shown that loss of homeostatic myelination contributes to further cognitive dysfunction and neuron dysfunction in Alzheimer’s. [1] [3]
While the issues above involve defective myelin, there is also a wide range of issues that arise from myelin that has no apparent issue but has, simply put, gone rogue. Maladaptive myelin describes the scenario in which myelin is not impaired but leads to abnormal patterns of neuronal activity and subsequent system-wide dysfunction. Such pathological systems were first observed in generalized epilepsy, seizures that involve both hemispheres of the brain. Interestingly, researchers found hallmarks (in rodent models) such as increased myelin thickness and myelinated axons especially in brain regions that are known to promote epilepsy. Because of this, it is impossible that maladaptive or aberrant patterns of myelination can reinforce deleterious patterns of neuronal activity, like seizures. [3] [5]
Therapeutic Considerations
In order to combat this variety of neurological disorders, there are currently two therapeutic approaches being considered: (1) promotion of remyelination and (2) restoring adaptive myelination. The key to accomplishing these approaches is to tackle the homeostatic signaling pathways of the nervous system and reprogram them to promote healthy myelination. Ultimately, the root of this issue is in the disruption of homeostasis, or normalcy in the system. Once that balance can be restored, the body can fight against these challenging neurological pathologies. [1] [5]
References
[1] Knowles, J. K., Batra, A., Xu, H., & Monje, M. (2022, November 14). Adaptive and maladaptive myelination in health and disease. Nature News. Retrieved March 23, 2023, from https://www.nature.com/articles/s41582-022-00737-3
[2] Knowles, J. K., Xu, H., Soane, C., Batra, A., Saucedo, T., Frost, E., Tam, L. T., Fraga, D., Ni, L., Villar, K., Talmi, S., Huguenard, J. R., & Monje, M. (2022, May 2). Maladaptive myelination promotes generalized epilepsy progression. Nature News. Retrieved March 23, 2023, from https://www.nature.com/articles/s41593-022-01052-2
[3] Duncan, I. D., & Radcliff, A. B. (2016, September). Inherited and acquired disorders of myelin: The underlying myelin pathology. Experimental neurology. Retrieved March 23, 2023, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010953/
[4] Nasrabady, S. E., Rizvi, B., Goldman, J. E., & Brickman, A. M. (2018, March 2). White matter changes in Alzheimer's disease: A focus on myelin and oligodendrocytes - acta neuropathological communications. BioMed Central. Retrieved March 23, 2023, from https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-018-0515-3
[5] Can myelin repair lead to the reversal of multiple sclerosis? Brain and Life Magazine - Trusted by Neurologists. (n.d.). Retrieved March 23, 2023, from https://www.brainandlife.org/articles/research-myelin-repair-reverse-ms
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