Why myelination is important

Carbon-dating analysis of human tissue has identified adult-born oligodendrocytes within the cortex, although the same analyses indicated that the majority of oligodendrocytes in the corpus callosum originate in early childhood Yeung et al.

However, the neuroimaging studies in humans that correlate white matter structural alterations with task learning suggest that new myelin can be formed throughout life. Such protracted myelination would in principle require lifelong oligodendrocyte production, given that individual myelinating oligodendrocytes have a restricted time window of just a few hours to initiate formation of new sheaths Watkins et al.

This is important given evidence that OPCs can directly differentiate into oligodendrocytes without cell division, at least in rodents Hughes et al.

OPCs in the corpus callosum could directly differentiate into oligodendrocytes many years after their terminal cell division; thus the time of differentiation of these new oligodendrocytes cannot be determined by carbon-dating, and so Yeung et al. We still have much to learn about the relative contributions of oligodendrocyte generation and myelin remodelling to CNS development throughout life. To fully understand the precise dynamics of oligodendrogenesis, myelin formation and myelin remodelling throughout various stages of life, longitudinal imaging at high-resolution represents the gold-standard approach.

Here we provide an overview of recent in vivo imaging studies that are beginning to clarify the dynamics of myelination, which will also allow us to begin to understand how such dynamics might impact neural circuit function. To begin to definitively address how oligodendrocytes are generated and how myelin is made and dynamically remodelled in vivo , two recent studies utilised repeated two-photon imaging of the mouse somatosensory cortex over extended periods of time.

Hughes et al. They found that the oligodendrocyte population continues to expand and that cortical oligodendrocyte density nearly doubles between young adult and middle-aged stages Figure 1A. This was accompanied by an over twofold increase in the number of cortical myelin sheaths.

But how does oligodendrocyte number increase? In early post-natal development many oligodendrocytes are produced but only a subset survive and go on to myelinate axons Barres et al. This appears to be similar in adulthood — by following individual cortical OPCs in the adult cortex for up to 50 days, Hughes et al. It remains unknown what proportion of newly differentiated oligodendrocytes are generated following OPC division versus direct differentiation.

However, once oligodendrocytes commit to myelination they remain stable, with no evidence of myelinating oligodendrocytes undergoing cell death during a day imaging period. Oligodendrocyte and myelin dynamics in the mammalian cortex throughout life.

A Oligodendrocyte precursor cells OPCs continuously generate new myelinating oligodendrocytes OLs in the somatosensory cortex from birth up to middle age. The OL population then declines in old age, accompanied by a reduction in myelin coverage. Most myelin sheaths, once formed, are stable in length over prolonged period of time, indicating that there is normally very little remodelling of existing myelin.

Summary of data from Hill et al. Similarly, Hill et al. They also found that the oligodendrocyte number continues to expand in adulthood up to P, and that oligodendrocytes are stable in middle age for up to 80 days of imaging. They found that myelination of the cortex also peaks in middle age at P, and that oligodendrocyte density significantly falls from its peak at P through very old age P Figure 1A.

This was reflected in a reduction of myelin coverage of layer I cortical axons between P and P Long-term oligodendrocyte survival may vary between different parts of the CNS.

Tripathi et al. The reduction in oligodendrocyte number and myelination in certain CNS regions with age raises intriguing questions concerning the role of myelin loss in age-associated cognitive decline. MRI analysis shows that white matter microstructure correlates with fluid intelligence Ritchie et al. Subsequent age-associated myelin loss could lead to reduced cognitive function due to dysregulation of myelinated circuits.

Could the generation of new oligodendrocytes and subsequently new myelin in the adult cortex be responsive to circuit activity? Previous research has shown that reducing sensory input by removing whiskers from mice leads to reduced oligodendrogenesis in the somatosensory cortex Hill et al. To investigate this further, Hughes et al. By imaging the somatosensory cortex before and after the 3 weeks, they demonstrated that sensory stimulation increases oligodendrocyte number, potentially due to the increased survival of newly differentiated cells.

Kougioumtzidou et al. This suggests that de novo myelination could be modulated by cortical circuit activity throughout life, perhaps to fine-tune the function of those same circuits. Many questions remain to be addressed: what is the effect of oligodendrogenesis and new myelination on actual circuit function? Does neuronal activity enhance the long-term survival of myelinating oligodendrocytes? It is possible that the loss of oligodendrocytes in old age is due to age-associated reduction in neuronal activity, which might, in turn, affect overall oligodendrocyte survival.

Alternatively, it may be that oligodendrocytes have a limited lifespan independent of neuronal activity either intrinsically programmed or influenced by other extrinsic signals associated with aging. In either case, circuit stimulation could help alleviate age-associated myelin loss by either promoting survival of existing oligodendrocytes or stimulating the production of new oligodendrocytes.

This in turn could have significant implications in the treatment and prevention of age-associated cognitive decline. Activity-mediated oligodendrogenesis is not restricted to the somatosensory cortex — young adult mice undergoing motor learning also show an increase in the number of newly differentiated oligodendrocytes in the motor cortex Xiao et al.

What about other areas of the CNS? Many cortical axons project via the corpus callosum, and therefore, stimulation of cortical circuits could signal to both cortical and callosal OPCs. Two rodent studies have demonstrated that stimulation of cortical neurons induces oligodendrogenesis within the corpus callosum.

Gibson et al. This led to an increase in oligodendrocyte number and sheath thickness 4 weeks post-stimulation. More recently, Mitew et al. They also demonstrated that new oligodendrocytes preferentially form myelin sheaths on the active axons.

It remains unknown how long-lasting changes to myelin in response to neuronal activity might be. The long-term survival of myelinating cells noted by Tripathi et al. Whether the myelin sheaths themselves change once neuronal activity returns to normal levels requires more investigation of individual sheath dynamics, which is discussed below.

Thus, it is possible that lifelong de novo myelination may occur in many CNS regions, where axons suitable for myelination have sufficient unmyelinated space. However, it remains unclear to what extent oligodendrogenesis continues in different areas of the adult human brain. Carbon-dating analysis suggests that most oligodendrocytes in the corpus callosum tract are generated in early childhood Yeung et al.

Immunohistochemical analysis of human brain tissue using a novel marker for newly differentiated oligodendrocytes BCAS1 shows new oligodendrocytes in the frontal cortex even beyond middle-age, but very few new oligodendrocytes in white matter after the third decade of life Fard et al. This difference in oligodendrogenesis between species could be a result of scale. Given the energy cost of such a process, is this mechanism sustainable throughout life in an organ the size of the human brain?

Perhaps in the human brain there is limited oligodendrocyte overproduction, because of a need for more protracted myelination of the larger CNS, or because signals such as neuronal activity stimulate OPCs to differentiate into oligodendrocytes as and when required. The remodelling of existing myelin sheaths could alter conduction properties without the need for generating new oligodendrocytes or myelin.

Changing the lengths of existing myelin sheaths could change the myelin coverage along an axon and the distance between nodes of Ranvier which would both impact conduction speeds. In addition, even very subtle myelin remodelling could alter the lengths of the nodes themselves.

Whether changes to node of Ranvier are primarily driven by myelination or reorganisation of the axon itself remains to be determined. Both Hill et al. Hill et al. More sheaths may become stable in length with age; Hughes et al. Similar sheath length stability has also been described elsewhere; Auer et al. They found that individual sheaths undergo rapid but variable growth in the first few days after formation, before stabilising their sheath lengths.

Once stabilised, sheaths only continue to grow to accommodate the overall growth of the animal. Why do some sheaths in the cortex change in length, whilst others do not? This may reflect diversity in the demands of distinct neural circuits.

Axonal diversity has been observed during initial myelination in the zebrafish spinal cord, where some axons use synaptic vesicle release to regulate myelin sheath number and length while others do not Koudelka et al. This raises the intriguing hypothesis that only some axons are capable of regulating myelin via activity-related signals. However, more detailed analysis of axon subtype diversity coupled with longitudinal study of sheath length dynamics could confirm if sheath length remodelling is specific to certain circuits.

Does sheath length stability reflect an inability of sheaths to remodel? Experiments in the zebrafish suggest that sheath length remodelling can be induced when the myelination profile of an axon is disrupted. Auer et al. They found that when a single myelin sheath is lost on a fully myelinated axon, the neighbouring sheaths could reinitiate rapid growth to cover the unmyelinated gap.

In several cases a new myelin sheath would form in place of its predecessor and could even push back against the invading neighbour sheaths to restore the original pattern of myelination Figure 2A. Therefore, sometimes a specific myelination pattern is preferentially maintained, even after myelin disruption. This may be to sustain the optimised conduction properties of the underlying axon. Interestingly, they found that upon ablation of single sheaths on such sparsely myelinated axons a new sheath formed in virtually the same place as the ablated sheath, even along an otherwise unmyelinated stretch of the axon Figure 2B.

Thus the myelination patterns along sparsely myelinated axons also appear to be stably maintained in zebrafish, as suggested by Hill et al. The function of sparse myelination profiles remains unknown.

Myelin remodelling can occur in vivo. A Ablation of single sheaths on a fully myelinated axon can induce the rapid growth of neighbouring sheaths to cover the gap. This gap can either be covered entirely by the neighbouring sheaths, or the original myelination profile can be restored by the addition of a new sheath.

B Ablation of a sheath on a sparsely myelinated axon is followed by formation of a new myelin sheath of identical size and location to the ablated predecessor sheath.

Summary of data from Auer et al. Do stable myelin sheaths in mammals also have this capacity to remodel when the myelination pattern is disrupted? Further longitudinal studies coupled with demyelination are required to answer this question.

It is possible that such remodelling is not induced by neuronal activity but is a compensatory mechanism for myelin loss. To establish new treatments for demyelinating diseases, a better understanding of myelin biology and pathology is absolutely required. How do we structure a research effort to elucidate the mechanisms involved in developmental myelination and demyelinating diseases?

We need to develop useful models to test drugs or to modify molecular expression in glial cells. One strong strategy is to use a culture system. Coculture of dorsal root ganglion neurons and Schwann cells can promote efficient myelin formation in vitro Figure 1E.

Researchers can modify the molecular expression in Schwann cells, neurons, or both by various methods, including drugs, enzymes, and introducing genes , and can observe the consequences in the culture dish. Modeling demyelinating disease in laboratory animals is commonly accomplished by treatment with toxins injurious to glial cells such as lysolecithin or cuprizone.

Autoimmune diseases such as MS or autoimmune neuropathies can be reproduced by sensitizing animals with myelin proteins or lipids Figure 3. Some mutant animals with defects in myelin proteins and lipids have been discovered or generated, providing useful disease models for hereditary demyelinating disorders.

Further research is required to understand myelin biology and pathology in detail and to establish new treatment strategies for demyelinating neurological disorders. Myelin can greatly increase the speed of electrical impulses in neurons because it insulates the axon and assembles voltage-gated sodium channel clusters at discrete nodes along its length.

Myelin damage causes several neurological diseases, such as multiple sclerosis. Future studies for myelin biology and pathology will provide important clues for establishing new treatments for demyelinating diseases. Brinkmann, B. Neuron 59 , — Franklin, R. Remyelination in the CNS: From biology to therapy. Nature Reviews Neuroscience 9 , — Nave, K. Axonal regulation of myelination by neuregulin 1. Current Opinion in Neurobiology 16 , — Poliak, S. The local differentiation of myelinated axons at nodes of Ranvier.

Nature Reviews Neuroscience 4 , — Sherman, D. Mechanisms of axon ensheathment and myelin growth. Nature Reviews Neuroscience 6 , — Siffrin, V. Multiple sclerosis — candidate mechanisms underlying CNS atrophy. Trends in Neurosciences 33 , — Susuki, K. Molecular mechanisms of node of Ranvier formation. Current Opinion in Cell Biology 20 , — Cell Signaling.

Ion Channel. Cell Adhesion and Cell Communication. Aging and Cell Division. Endosomes in Plants. Ephs, Ephrins, and Bidirectional Signaling. Ion Channels and Excitable Cells.

Signal Transduction by Adhesion Receptors. Citation: Susuki, K. Nature Education 3 9 How does our nervous system operate so quickly and efficiently? The answer lies in a membranous structure called myelin. Aa Aa Aa. Information Transmission in the Body. Figure 1. Figure Detail. Axonal Signaling Regulates Myelination. Figure 2: The fate of demyelinated axons. The case in the CNS is illustrated. Research in Myelin Biology and Pathology. Figure 3.

References and Recommended Reading Brinkmann, B. Waxman, S. The Axon: Structure, Function and Pathophysiology. New York: Oxford University Press, Article History Close. Share Cancel. Revoke Cancel. Dynamics and mechanisms of CNS myelination. Dev Cell. Ann Neurol. Inherited and acquired disorders of myelin: The underlying myelin pathology.

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