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Myelin Plasticity and Age-related Degeneration
Dr. Terri Wood
Rutgers School of Graduate Studies
December 15, 2021
The central nervous system (CNS) is comprised of neurons, vascular cells, and glial cells. Oligodendrocytes exist as unique glial cells within the CNS that produce myelin. Myelin serves as an extended membrane that covers and tightly wraps the axons of neurons (Kuhn et al., 2019). The myelin sheath serves as an electric insulator within the CNS, facilitating rapid propagation of electrical impulses along the axonal length by saltatory conduction (Simons & Nave, 2016). Oligodendrocytes are metabolically active and thus facilitate the movement of macromolecules under the myelin sheath. Oligodendrocytes also serve to preserve the axonal integrity of neurons within the CNS.
Oligodendrocytes are produced from oligodendrocyte precursor cells (OPCs) which undergo various stages of development to differentiate into myelinating oligodendrocytes ultimately. (Kuhn et al., 2019). Different stages of the oligodendrocyte differentiation cycle can be identified by expressing distinct transcription factors and surface antigens. In essence, oligodendroglia lineage markers help recognize the development and differentiation from neural progenitor cells (NPC) to myelinating oligodendrocytes (OL). The A2B5 antibody recognizes the neural progenitor cells and oligodendrocyte precursor cells (OPC). On the opposite hand, pre-oligodendrocytes are recognized by demonstrating three myelin markers, namely 2′, 3′-cyclic-nucleotide 3′ -phosphodiesterase (CNPase) and the cell surface markers O4 and O1. The O1 antibody may identify mature oligodendrocytes because of their membrane lipid composition change when they begin expressing galactocerebroside (Galc) protein (Goldman & Kuypers, 2015). Apart from galactocerebroside, mature oligodendrocytes produce other myelin proteins such as myelin basic protein (MBP), the transmembrane proteolipid protein (PLP), myelin associated glycoprotein (MAG), and myelin-oligodendrocyte glycoprotein (MOG) (Kuhn et al., 2019). The distinct developmental stages and identification markers are demonstrated in Appendix 1.
Oligodendrocytes’ primary function is to produce myelin, which facilitates efficient saltatory conduction of electrical impulses along the nerve cell axons in the CNS (Goldman & Kuypers, 2015). Myelination is a highly regulated process that involves differentiation of OPCs to mature oligodendrocytes. Mature oligodendrocytes extend their processes to neurons in the vicinity, establish contact with the axons and sheathe them with myelin. During myelination, oligodendrocytes sense the proximity of the neighboring neuron cells to ascertain the uniform spacing of myelin segments along their respective axons. After the successful connection of the oligodendrocyte to the axon, the architecture of the oligodendrocyte plasma membrane changes rapidly. The plasma membrane extends down the axon, forming paranodal loops that form a compact myelin sheath. Myelin facilitates the rapid transduction of electric signals within the neurons in the CNS (Simons & Nave, 2016). Therefore, the primary importance of myelin in the CNS is to facilitate fast and efficient communication within the cell bodies of individual neurons within the CNS. Myelin facilitates the movement of electric signals from one end of the neuron cell to the axon. Therefore, oligodendrocytes have a critical role in facilitating sustainable myelination to facilitate the efficient movement of electric signals and messages within the nerve cells in the CNS.
Myelin Damage and Remyelination:
Demyelination is a continuous process that occurs when the myelin sheath surrounding the axons is lost and disintegrated, leading to axonal degeneration. The process occurs due to inflammatory and immune mediated attacks on the myelin and the oligodendrocytes. Myelinated axons lose their myelin sheath due to insults that may include trauma, ischemia, and immune-mediated attacks (Kuhn et al., 2019). Considering that the myelin sheath is damaged, impulses and transmissions may be slowed or stopped resulting in neurological problems. Ultimately, the demyelinated axons can become damaged and die.
The process of remyelination functions to repair and reinstate the demyelinated axons. The process occurs when newly distinguished oligodendrocytes from the adult OPC pool move to exchange the lost oligodendrocytes. Furthermore, the process may be induced by infiltrating Schwann cells (Franklin & ffrench-Constant 2017). The process of remyelination may be fostered through an artificial injection of M2-type macrophages and regulatory T cells in the body (Kuhn et al., 2019). M2 macrophages and regulatory T cells promote remyelination through activin-A secretion. The primary importance of remyelination is to ascertain the continuity of learning and plasticity.
Understanding Myelin plasticity:
What is Myelin plasticity?
During their lifetime, the mammalian central nervous system (CNS) usually produces new oligodendrocytes and myelin to facilitate learning acquisition and preservation of remote memory. Adaptive myelination serves to maximize the timing in particular circuits by tuning conduction in individual axons. Adaptive myelination enables humans to continue learning and to respond to new experiences in their later phases and stages of life.
Myelin plasticity can cause a wide range of structural and functional alterations in myelin. Myelin plasticity can occur from production of new OPCs, changes in OPC differentiation, or experience-induced OPC proliferation. This can cause remodeling of the myelin sheath, changes in the sheath thickness and length of myelin internodes, trophic and metabolic support to the axons and variation in the distribution of OPCs in the CNS. Experience derived learning can be custom-tailored to each neural circuit altering the neuronal function in specific areas of the brain contributing to altered human behavior and learning.
What is Adaptive myelination?
Adaptive myelination is a powerful mechanism that controls circuit functioning (Williamson & Lyon, 2018). The primary importance of adaptive myelination is to enable continuous learning because the secretion of new myelin is adjustable in response to circuit activity. The process is relevant as it facilitates the production of new myelinating oligodendrocytes, which is necessary for efficient motor learning. Research has shown that learning a new task leads to a simultaneous white matter alteration in the relevant regions of the brain. On the other hand, studies show that the primary importance of myelin plasticity is to enable the consistent alteration of a circuit functioning in different stages of the life process. Myelin plasticity has been shown to be fundamental in enhancing cognitive processes such as learning acquisition, mastering and refinement of motor skills. This can be conducive to enhance spatial and temporal memory and may also be involved in fear conditioning responses.
In their article entitled “Myelin plasticity: sculpting circuits in learning and memory,” Xin & Chan (2020) define adaptive myelination as the secretion of new myelin instigated by new experiences and learning. The authors suggest that in their lifetime, humans’ CNS usually produces new oligodendrocytes and myelin to facilitate learning acquisition and preservation of remote memory. According to the authors, the CNS undergoes the conditional deletion of mature oligodendrocytes during adulthood, resulting in demyelination. Therefore, CNS produces new myelin to avoid behavioral deficits. Adaptive myelination occurs as individuals respond to new learning activities and experiences. According to Xin & Chan (2020), the chief function of adaptive myelination is to facilitate optimization rate of conduction in individual axons. The authors affirm that adaptive myelination enables humans to continue learning and respond to new experiences in their later phases and stages of life.
Xin & Chan (2020) define myelin plasticity as the wide range of structural and functional changes in myelin. The authors reveal that myelin plasticity occurs due to three primary reasons: production of new oligodendrocytes, changes in oligodendrocyte lineage, and dissociations between experience-induced oligodendrocyte progenitor cells. The authors further assert that myelin plasticity also occurs due to the remodeling of the myelin sheath, change in the thickness and length of myelin, change in the density of myelin, change in function, and variation the distribution of OPCs in the CNS. The authors affirm that myelin plasticity is custom-tailored to each circuit and behavior. Apart from changing axonal conductance, myelin plasticity plays a crucial part in the neuronal functioning of human behavior and learning.
Williamson & Lyons (2018) assert that adaptive myelination is a powerful mechanism that regulates circuit functioning throughout life. The authors reveal that the primary importance of adaptive myelination is to enable continuous learning because the secretion of new myelin is adaptable in response to circuit activity. The process is relevant because it facilitates the production of new oligodendrocytes, which are very essential in motor learning. The authors also reveal that learning a new task leads to a simultaneous white matter alteration in the relevant regions of the brain. On the other hand, the authors reveal that the primary importance of myelin plasticity is to enable the consistent alteration of the circuit functioning in different stages of the life process. Scholars also reveal that myelin plasticity is fundamental to enhancing cognitive processes such as learning acquisition. According to Xin & Chan (2020), myelin plasticity is relevant to motor learning, enhancing spatial memory and fear memory in the CNS.
Although, the field of myelin plasticity and remodeling have garnered immense attention over the last decade, there are still many scientific questions regarding its mechanism that are unanswered. For instance, it is still unclear the implication of newly formed oligodendrocytes in learning acquisition, recent memory, and remote memory. However, biologists and systems neuroscientists have successfully agreed on the role of neuronal plasticity in influencing learning and memory. Furthermore, the possibility of separating the influence of passive experience from that of experience-induced myelination has also been answered. New studies suggest that in the developmental and adulthood stages of human life, the progression of myelination is directly modulated by experiences. Rather than framing passive experience as distinct from experience-induced myelination, we should consider cell-autonomous and environmental cues as factors that engage freely in normal human processes Xin & Chan, 2020). The integration of the cell-autonomous and environmental cues determines the functioning of oligodendrocyte lineage cells.
To further understand myelin plasticity, experiment on age-related degeneration is important. (Hill, Li and Grutzendler, 2018) the article attempts to gain insights into the patterns of myelin distribution to ascertain whether they are indeed fixed or whether myelinating oligodendrocytes generated during the adulthood result in structural remodeling. To achieve this, the authors seek to carry out an investigation by using tools such as high-resolution, intravital label-free, and the mouse cortex’s fluorescence optical imaging. The occurrence of myelin on the cellular structure provides the saltatory axonal conduction that facilitates a substantial increase in the processing speed of neurons.
The first experiment aimed to investigate the oligodendrocytes’ lifelong generation and the myelin segment plasticity at the axonal resolution of the individual at the mouse cerebral cortex. The tools used included long-term intravital myelin imaging with label-free spectral confocal reflectance microscopy. The finding presented a rise in oligodendrocyte density during adulthood and aging. Continuous oligodendrogenesis resulted in an increased myelination of the cortex in previously unmyelinated regions. Interestingly, internodes formed during development were unaffected and remained stable. This finding further suggests that unlike other forms of CNS plasticity, where both the synapse formation and synaptic pruning is essential for refinement of neuronal circuitry, myelin plasticity is distinct.
Long-term imaging analysis demonstrated that a significant portion of the internodes exhibit some form of changes in length like the extension and retraction of myelin segments. Observing the mice through imaging showed a significant decline in myelination, including the development of myelin spheroids and a notable accumulation of myelin waste within the microglia. Additionally, (Hill, Li, and Grutzendler, 2018) allude that the age-related degeneration of the myelin and the disruption of the internodal and nodal structures may contribute to a decline in cognitive function.
Another investigation sought to investigate the structural patterns of the myelin. The development of new myelin inter-nodes is as a consequence of the new oligodendrocytes. In observing the formation of the oligodendrocytes in 80 days, it was established that no cells were replaced in the process. In line with confirming the specificity of SCoRe of the myelin, the experiment performed immunohistochemistry on the tissues of the fixed brain for contacting-associated protein.
The combination of these experiments presents the realization that myelin plasticity indeed occurs through the life-span of rodents. Using the label-free imaging of the myelin and a membrane-targeted fluorescent protein, it was thus detected that the overwhelming bulk of oligodendrocytes were steady. However, a small subgroup displayed structural plasticity through prolongation and contraction over a substantial period. However, the changes were very modest compared to new oligodendrogenesis and formation of novel internodes. The authors demonstrated that by imaging some myelination patterns along the part of the single axons, it was clear that the distribution of the myelin was indeed not fixed. It was thus shown that in the aging process, there indeed exists some form of reversal of the process of plasticity in the sense that there is no evidence of the formation of newer internodes. It is evident from the experimental findings that myelin undergoes remodeling that may lead to a protracted oligodendrocyte due to a sheath retraction.
Further research understanding how age-related changes occur in myelination of the cortex is warranted as this area is easily susceptible to trauma, inflammation and demyelinating neuropathologies like multiple sclerosis. (Hill et. Al., 2018) allude that cortical demyelination may contribute to cognitive decline. Therefore, motor, spatial and cognitive memory changes compel further investigation. Ultimately, further research needs to investigate the pathogenic correlations between microglia and myelin in the aging process, given the engagement of microglia in the engulfment of myelin waste.
Franklin, R. J. (2017). Regenerating CNS myelin—from mechanisms to experimental medicines. Nature Reviews Neuroscience, 18(12), 753-769.
Goldman, S. A., & Kuypers, N. J. (2015). How to make an oligodendrocyte. Development, 142(23), 3983-3995.
Hill, R. A., Li, A. M., & Grutzendler, J. (2018). Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nature neuroscience, 21(5), 683-695.
Kuhn, S., Gritti, L., Crooks, D., & Dombrowski, Y. (2019). Oligodendrocytes in development, myelin generation and beyond. Cells, 8(11), 1424.
Simons, M., & Nave, K. A. (2016). Oligodendrocytes: myelination and axonal support. Cold Spring Harbor perspectives in biology, 8(1), a020479.
Williamson, J. M., & Lyons, D. A. (2018). Myelin dynamics throughout life: an ever-changing landscape?. Frontiers in cellular neuroscience, 12, 424.
Xin, W., & Chan, J. R. (2020). Myelin plasticity: sculpting circuits in learning and memory. Nature Reviews Neuroscience, 21(12), 682-694.