Which axon is myelinated

The next step is to try to show experimentally that this happens during learning in animals. During development or learning, an adjustment of myelin thickness or internode length may be used to tune the conduction speed of myelinated axons Fields, ; Tomassy et al. This can promote synchronous neuronal firing Lang and Rosenbluth, ; Sugihara et al.

Magnetic resonance imaging of humans and cellular studies of rodents suggest that myelination can increase while learning motor tasks such as piano playing Bengtsson et al. Although most interest has focussed on the effect of changes of myelin thickness or internode length, the node of Ranvier is another potential determinant of action potential conduction speed.

Increasing the length of the node will increase the node capacitance and the axial resistance for current flow into the internode, which will both decrease conduction speed. Given the potential influence of node length on conduction speed, we quantified heterogeneity of the length of the node of Ranvier in the white matter of the rat optic nerve and corpus callosum, and in the grey matter of rat cerebral cortex.

Computer modelling was then used to explore the effects on conduction speed of the range of node lengths observed. We first measured the length of nodes of Ranvier and axon diameter in adult rat optic nerve using both confocal and serial electron microscopy Figure 1 , Figure 1—figure supplement 1. Using electron microscopy EM we found the mean node length was 1. Node lengths varied 2-fold, from 0. Node lengths were not significantly correlated with axon diameter at the node, which had a mean value of 0.

Thus, the different node lengths observed did not simply reflect axons being of different sizes. A Confocal image of a single optic nerve node of Ranvier showing the node labelled with antibody to Na V 1. B Intensity profile of Caspr staining for the node in A. Node length was measured as the distance between the half maximum intensity for each paranode.

C, D Confocal images of nodes in the optic nerve C and layer V of the cortex D highlighting the different range of node of Ranvier sizes in these areas. H Node diameter as a function of node length in the optic nerve red and in grey matter of the cerebral cortex blue. In contrast to EM, confocal microscopy allowed us to measure a greater number of nodes in different parts of the CNS.

In addition, given that oligodendrogenesis and myelination continues well into adulthood Dimou et al. Mature nodes of Ranvier were identified from their Na V 1. We first assessed whether, using confocal microscopy Figure 1C , we could observe variability of node lengths in the rat optic nerve similar to that found when using EM.

However, the node length range was slightly broader, covering a 4. In the grey matter of the adult cerebral cortex layer V of motor cortex an even larger, 8. Thus, variability of node length is a general feature of myelinated axons. The greater variability of node length observed in the cortex than in the optic nerve has parallels with the far greater variability of myelination seen in the adult cortex Tomassy et al.

To investigate whether this node length variability was accompanied by a similar variability in sodium channel number, we summed the intensity of Na V 1.

We found that there is a linear correlation between summed Na V 1. Rios et al. However, at any given sodium channel labelling intensity there was still a large variation in node lengths, suggesting that sodium channel density is not absolutely constant, and that it may be possible to vary node length in a manner independent of sodium channel number. If adjustment of node length is used to tune conduction speed, one might expect all the nodes along one axon to have similar lengths e.

To assess whether the variability in node lengths mainly occurs along axons or between axons we iontophoretically injected a fluorescent dye into the cortex of adult rats see Materials and methods. This was taken up into axons and diffused along them, allowing us to measure the lengths of up to 13 successive nodes mean 6. Remarkably, along individual axons Figure 2B,C , the distribution of node lengths was much narrower than that observed over all callosal axons examined Figure 2C , with a A Composite confocal image of a single axon in the corpus callosum iontophoretically labelled with tetramethylrhodamine dextran red.

Three consecutive nodes of Ranvier are highlighted and shown in high resolution images. Nodes of Ranvier are identified as Na V 1. B Successive node lengths along three example axons with different mean node lengths. The mean node length for each axon is plotted as a dashed line. C Distributions of node lengths of 18 individual axons in 0. D Mean coefficient of variation for node lengths along 18 individual axons and the overall coefficient of variation for all axons examined.

E Mean internode length for each axon plotted against the mean node length for that axon. Each axon is represented by a different colour, and that colour is maintained for panels B , C and E. Thus, node lengths are similar along axons but differ significantly between axons. This raises the possibility that individual axons consistently adjust their node length to tune conduction speed. To examine the consequences of nodes of Ranvier having different lengths, we simulated action potential propagation in optic nerve and cortical grey matter myelinated axons, as described in the Materials and methods.

The differential equations of the model were derived and solved as in Halter and Clark Details of the parameters used are summarised in Table 1. The conduction speeds predicted for the mean node lengths observed 2.

There are two membranes per myelin lamella. Our data suggest a positive correlation between the number of Na V 1. We therefore modelled two extreme situations, for both the optic nerve and the cortical axons studied: either the density of nodal ion channels was assumed to be constant so the number of ion channels increases in proportion to node length , or the number of ion channels at the node was held constant at the values assumed for the mean node length observed so the density of channels varies inversely with node length.

Figure 3A and B show that, when the number of channels was held constant at each node, the predicted conduction speed falls with increasing node length dashed curves. This occurs for two reasons: the increase in node length increases the nodal capacitance so each node takes longer to charge , and the intracellular axial resistance to current flow from the node into the internode is increased.

The changes in conduction speed for the optic nerve are shown in Figure 3A the range of measured node lengths is shown for comparison. Increasing the node length from its mean value of 1. For cortical axons Figure 3B the predicted changes are larger, partly because, with a 1.

The node length variation observed in rat cortex Figure 1G—H and 0. Thus, altering node length from 3. A—F Calculated conduction speed as a function of node length for axons in A the optic nerve and B—F the cortical grey matter. For panels A—F , simulations were carried out assuming either that the density of ion channels at the node is constant as the node length is changed solid lines , or that the number of ion channels is kept constant dashed lines at the value assumed for the mean node length.

E—F Calculated dependence of conduction speed of cortical axons on internode length for different assumed node lengths NL. The observed range of each abscissa parameter is indicated on the graphs. Change in membrane area needed, in the myelin sheath myelin wrap or node of Ranvier node length, NL , to change the conduction speed by 8. When the nodal ion channel density is kept constant another factor affects the predicted conduction speed, in addition to the change of capacitance and axial resistance at the node: as the node length is decreased the reduction in the number of ion channels present leads to a decrease of conduction speed.

Consequently, the plot of speed against node length shows a maximum solid curves in Figure 3A—B : note that, above this maximum, increasing node length decreases speed for the reasons stated above, despite the increase in number of sodium channels at the node. Decreasing the optic nerve node length from its mean value of 1. Similarly, for the cortex, decreasing the node length from the mean value of 1.

Although the node length is similar at successive nodes along individual axons Figure 2B , some variation does exist with a mean standard deviation of 0. For example, for a mean node length of 1. When the number of channels was held constant at each node, the approximately linear relationship between conduction velocity and node length Figure 3A,B resulted in a slightly faster propagation through shorter nodes and a slightly slower propagation through longer nodes, the effects of which cancel out with no overall effect on conduction velocity.

It has recently been reported that internode lengths may vary significantly in the cortex Tomassy et al. We measured internode lengths in dye-filled axons in rat layer V cortex by measuring the distance between Na V 1. Given this large variation, we examined how internode length assumed, for simplicity, to be the same for all internodes along an axon affects the tuning of conduction speed by changes of node length Figure 3C—F.

Changes of node length also affect the predicted dependence of conduction speed on internode length Figure 3E,F. This relationship rises with internode length at low values of internode length, because more of the axon is myelinated, but decreases at large internode lengths as the spread of depolarization between nodes becomes less efficient.

This relationship shows a sharper peak for shorter node lengths Figure 3E,F. We assessed how powerful node length changes can be for tuning conduction speed, compared to altering the amount of myelin around the axon.

With the node length and internode length set at the mean values observed and the nodal conductances constant, if the number of wraps of myelin is decreased by 1 from the normal 7 to 6 for the optic nerve and from the normal 5 to 4 for the cortex , the conduction speed is predicted to decrease by 8.

These same speed decreases can be achieved with no change of myelin wrapping or ion channel density by decreasing the node length from 1. Whether the internode needs to be lengthened by the same amount, to maintain axon length, and the consequences of this, are considered in the Simulations section of the Materials and methods. Strikingly, to produce these speed changes, the change of membrane area needed shown in Figure 3G when altering node length is fold less in the optic nerve, and fold less in the cortex, than that needed when altering the myelin sheath.

Thus, tuning conduction speed by altering node length is far more efficient than altering myelination when considering the amount of lipid and protein synthesis or breakdown needed, and would probably also be faster. By combining anatomical measurements with computational modelling we have established a proof of principle for the idea that node of Ranvier length may be adjusted to tune axon conduction speed, and hence alter action potential arrival time.

Even at constant axon diameter, we found that node length displayed a surprising variability, both in the optic nerve and in the grey matter of the cortex Figure 1.

Remarkably, this node length variation was largely between different axons, while the nodes on any given axon tended to have similar lengths Figure 2. The range of node lengths observed is sufficient to produce large variations in action potential conduction speed Figure 3 , comparable to those produced by adding or removing a wrap of myelin.

These data suggest that axons may be able to adjust their node lengths in order to tune their conduction speed, and thus the arrival time of the information that they transmit.

There is now evidence of oligodendrogenesis and myelination in the adult CNS Dimou et al. To avoid these, we studied only nodes that expressed the mature node marker Na V 1. The node length was approximately proportional to the amount of sodium channel labelling at the node Figure 1I , suggesting that node length may mainly be adjusted by the insertion or removal of membrane containing sodium channels although conceivably it is possible to vary node length in a manner independent of sodium channel trafficking by endo- or exocytosis of vesicles lacking sodium channels in their membrane.

The fact that node lengths are similar over long distances along an axon Figure 2B raises three mechanistic questions. First, when the node length is set to a different mean value in different axons, by what mechanism is the nodal ion channel density controlled Figure 1I? Second, what signal regulates node length, in order to adjust the arrival time of action potentials at the end of the axon?

Conceivably a signal could be passed back along the axon from a postsynaptic cell by dynein-based motors, as occurs for BMP signalling from postsynaptic cells to the nuclei of presynaptic neurons Smith et al. Third, what local molecular mechanism regulates the length of each node, how accurately can this be controlled, and is the internode length shortened when the node is elongated to preserve overall axon length?

Interestingly, nodal amyloid precursor protein has been proposed as a regulator of node length Xu et al. Computer simulations of the propagation of action potentials along myelinated axons Figure 3 show that rather small changes in node length can produce quite significant changes of conduction speed. The range of node lengths seen in the optic nerve 0. The effect of altering node length is larger in cortical axons than in the optic nerve, partly because the 1.

Our data and simulations suggest that modulation of node length could be a viable strategy for adjusting the propagation time of action potentials to meet information processing needs. Such modulation has been suggested to occur during chronic stress and major depression Miyata et al.

Altering node length offers the advantage that very small changes of membrane area, which could easily be produced rapidly by exocytosis or endocytosis at the node, produce large changes of conduction speed. In comparison, to produce the same speed changes by altering the number of myelin wraps requires the energetically expensive Harris and Attwell, , and probably more time consuming, synthesis or disassembly of a membrane area that is — fold larger.

In practice, both mechanisms might be used on different time scales. For the optic nerve, 3 male 8—10 weeks old Sprague-Dawley rats were anaesthetised and perfused through the heart with fixative containing 2.

Back-scattered images were obtained on a scanning electron microscope Hitachi SU with a working distance of 2 mm, 1—1. Four male 8—10 week old rats were anaesthetized with isoflurane and killed by cervical dislocation in accordance with United Kingdom animal experimentation regulations.

After decapitation the brain was carefully dissected from the skull and 1 mm thick coronal slices containing the corpus callosum were obtained from the forebrain from 4 to 8 mm rostral of the olfactory bulb using a tissue cutter block. Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system.

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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.

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