Scientific Understanding of Consciousness
Neuron Axon Myelin Distribution
Science 18 April 2014: Vol. 344 no. 6181 pp. 319-324
Distinct Profiles of Myelin Distribution Along Single Axons of Pyramidal Neurons in the Neocortex
Giulio Srubek Tomassy, et.al.
Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, MA 02139, USA.
Neuroscience Institute Cavalieri Ottolenghi, Neuroscience Institute of Turin, Corso M. d'Azeglio 52, 10126 Turin, Italy.
Myelin is a defining feature of the vertebrate nervous system. Variability in the thickness of the myelin envelope is a structural feature affecting the conduction of neuronal signals. Conversely, the distribution of myelinated tracts along the length of axons has been assumed to be uniform. Here, we traced high-throughput electron microscopy reconstructions of single axons of pyramidal neurons in the mouse neocortex and built high-resolution maps of myelination. We find that individual neurons have distinct longitudinal distribution of myelin. Neurons in the superficial layers displayed the most diversified profiles, including a new pattern where myelinated segments are interspersed with long, unmyelinated tracts. Our data indicate that the profile of longitudinal distribution of myelin is an integral feature of neuronal identity and may have evolved as a strategy to modulate long-distance communication in the neocortex.
Myelin plays critical roles in enabling complex neuronal function, including learning and cognition, and abnormal myelination is associated with neurological disorders and mental illnesses. Given the importance of myelin for network behavior, realistic models of structure-function relations in the central nervous system (CNS) must be built in consideration of myelin structure and distribution as fundamental elements. Among all myelinated axons, the thickness of the myelin sheath varies greatly, and it is a major determinant of the speed of impulse propagation. However, structural features other than myelin thickness have the potential to contribute to establishing and modulating conduction velocity and network behavior. In particular, the alternating sequence of nodes and internodes along each axon could affect conduction speed.
High-resolution maps of myelin distribution along individual axons are not currently available. Furthermore, it is not known whether different neurons are endowed with signature patterns of longitudinal myelination. This analysis has been hampered by the technical difficulty of tracing single, long, winding axons through the complex milieu of the CNS, a task that requires electron microscopy (EM) serial reconstructions of large volumes of tissue. Fortunately, however, large EM data sets that allow analysis of myelin are beginning to be available. Here, using the neocortex as a prominent model of neuronal diversity, we traced the distribution of myelin along a large set of individual pyramidal neuron axons to understand whether myelin properties differ among different types of neurons. Pyramidal neurons occupy different cortical layers; have distinct molecular and long-distance connectivity properties; and compute the highest-level cognitive, sensory, and motor functions of the mammalian CNS.
The research suggests that intermittent myelination is a signature of layer II/III pyramidal neurons and that not all neurons display the same longitudinal profiles of myelination. Layer II/III pyramidal neurons are involved in elaborate cortical activities and exhibit a higher degree of molecular and electrophysiological heterogeneity than layer V and VI neurons. The observed structural heterogeneity might contribute to the functional diversity of this complex neuronal population and be important when modeling neuronal function and network behavior in the neocortex.
To determine whether defined structural features are present along the unmyelinated segments of the layer II/III neurons that we traced, we examined them for the presence of synapses. We found that both afferent and efferent synapses exist on these unmyelinated tracts, including those of neurons with intermittent myelin. Together, these features may provide a structural template for enhanced cortical plasticity.
In the peripheral nervous system, myelination is correlated with axon caliber. Although in the CNS this correlation is less stringent, because diameters of myelinated and unmyelinated axons overlap; nevertheless, axonal caliber may affect the myelin patterns that we observed. To investigate this possibility, we reconstructed the volumes of 283 cell bodies of pyramidal neurons across all layers of the S1 data set. We used these volumetric measurements as the most reliable indicator of average axon caliber, which is correlated with soma size. All pyramidal neurons in layers II/III, IV, and VI had comparable sizes. Layer V contained pyramidal neurons of different sizes, including large neurons likely representing subcerebral projection neurons. Despite different soma volumes, all neurons traced in layer V had comparable profiles of myelination and PMAS lengths. We also performed volumetric measurements of all neurons reconstructed in the V1 data set and found that they were all comparable in volume regardless of their myelination profiles. Thus, we observed no correlation between neuronal soma size (and thus axon caliber) and profile of myelination.
Another possible determinant of myelin distribution may relate to availability of mature oligodendrocytes (OLs) and oligodendrocyte progenitors (OPCs) around different neurons. We quantified the radial distribution of OPCs and OLs in the cortex. Our results indicate that the observed layer-specific differences in myelination are not due to the absence of OPCs in the upper layers but rather to their lamina-specific capacity to generate mature Ols.
Both OL development and myelin biogenesis are influenced by neuron-derived signals. Thus, the observed laminar differences in OPCs ability to give rise to OLs suggest influence of different neurons on OL development and point to a role of neuronal diversity in modulating myelin distribution in different layers. Results suggest that different classes of pyramidal neurons are endowed with different abilities to affect OL distribution and myelination.
Here, we describe myelin distribution along single axons in the murine brain. We demonstrate that pyramidal neurons of different neocortical layers present signature profiles of myelination, which indicates that longitudinal myelin deposition is a defining feature of each neuron. This contributes to the emergence of a myelin gradient that reflects idiosyncratic interactions between pyramidal neurons and oligodendrocytes.
Although the functional significance of these heterogeneous profiles of myelination awaits future elucidation, we propose that it may have served the evolutionary expansion and diversification of the neocortex by enabling the generation of different arrays of communication mechanisms and the emergence of highly complex neuronal behaviors.
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Science 18 April 2014: Vol. 344 no. 6181 pp. 264-266
Myelin—More than Insulation
R. Douglas Fields
National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Building 35, Room 2A211, MSC 3713, Bethesda, MD 20892, USA.
Myelin is a coating of compacted cell membrane that is wrapped around the axon by non-neuronal cells called oligodendrocytes. These multipolar cells extend slender cellular processes to grip axons and spin up to dozens of layers of membrane around it like electrical tape. Many oligodendrocytes grasp a single axon to span its full length. The tiny space exposed between each grasping “hand” corresponds to a node of Ranvier, where voltage-gated sodium channels are concentrated. When the electrical potential across the axon membrane depolarizes by about 20 mV, these channels allow rapid influx of sodium ions that discharges the transmembrane potential, creating a voltage transient of ∼0.1 V—the action potential. Myelin forces the action potential to be generated only at these 1-µm-long nodes of Ranvier and to leap rapidly in sequence over tens or hundreds of micrometers to excite an action potential in the next node. Rather than spreading down an unmyelinated axon as a slow wave of depolarization, the nodes of Ranvier act as repeaters. The speed at which signals are transmitted is limited by the distance between nodes, the thickness of the myelin wrapping, and the length of the exposed axon in the node.
Variation in myelination along an axon could adjust transmission speed to optimize the time of arrival of signals from multiple axons at a relay point in a neural circuit. Unusually long nodes of Ranvier (50 µm) may even delay action potential propagation, as they increase the electrical capacitance of the axon membrane and consequently increase the time required to charge and discharge it. The as yet unknown ion channel properties in these unmyelinated regions of cortical neurons will also influence conduction velocity. However, the total transmission time across the relatively short distance of the cerebral cortex (about 0.5 mm in a mouse and 2 to 4 mm in humans) may present a negligible delay, suggesting additional reasons for the intermittent myelin. Perhaps unmyelinated axon segments can permit more complex forms of network integration.
The “neuron doctrine” states that information flows through synaptic inputs on dendrites and passes out of the axon as an action potential to excite dendrites of the next neuron in the circuit. However, other modes of communication are becoming apparent. Synapses can form on unmyelinated segments of axons, and bare axons can release neurotransmitters, signaling by nonsynaptic communication. Action potentials also propagate backward into the cell body, affecting neural integration and synaptic plasticity. Oscillations and waves of electrical activity at different frequencies couple neurons into functional assemblies that coordinate and gate information, and the frequency of oscillation differs in layers II/III and V. Myelin also can constrain where axons sprout and form synapses with dendrites or with other axons. Indeed, proteins in the myelin sheath, such as Nogo, block axon sprouting, indicating that the myelin wrapping stabilizes axon structure and the pattern of connectivity in neural circuits.
The most critical segment of unmyelinated axon is the axon initial segment. The 5- to 80-µm-long unmyelinated section between the cell body and first myelin segment is the decision point where action potentials are triggered. The morphological features of this segment, and types of ion channels present in it, regulate excitability of the neuron. This region also controls the shape of the action potential, which affects the amount of neurotransmitter released from the synapse, the frequency of action potential firing, and other aspects of action potential signaling. Action potentials are initiated at the distal end of the axon initial segment, and the distance to this trigger point has important functional consequences. Tomassy et al. found that this region of the axon was longer in layers III/IV than V/VI.
The length and membrane properties of the axon initial segment influence the capacity of action potentials to propagate back into the cell body and dendrites. Back-propagating action potentials in hippocampal neurons develop during slow-wave sleep and quiet periods of wakefulness and are important in memory formation.
The length of the myelinated axon between nodes may be determined by neuronal signals, intrinsic properties of the oligodendrocytes, and region-specific factors. Tomassy et al. report that the layer-specific pattern of myelination on axons is disrupted in genetically modified mice that have abnormal cortical layering, pointing to a role for neurons in specifying myelination properties. The age of oligodendrocytes can also determine the length of internodal segments, with oligodendrocytes generated later in life producing shorter internodes. Internodal length and other properties of myelin differ in different brain regions, with corresponding effects on conduction velocity.
There are countless axons in the nervous system that are unmyelinated and they do not “short out.” Myelin organizes the very structure of network connectivity, facilitates modes of nervous system function beyond the neuron doctrine, and regulates the timing of information flow through individual circuits. It is certainly time to set aside the frayed metaphor of myelin as insulation and appreciate the more fascinating reality.
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