Elucidating Axonal Injuries Through Molecular Modelling of Myelin Sheaths and Nodes of Ranvier

Around half of the traumatic brain injuries are thought to be axonal damage. Disruption of the cellular membranes, or alternatively cytoskeletal damage has been suggested as possible injury trigger. Here, we have used molecular models to have a better insight on the structural and mechanical properties of axon sub-cellular components. We modelled myelin sheath and node of Ranvier as lipid bilayers at a coarse grained level. We built ex-novo a model for the myelin. Lipid composition and lipid saturation were based on the available experimental data. The model contains 17 different types of lipids, distributed asymmetrically between two leaflets. Molecular dynamics simulations were performed to characterize the myelin and node-of-Ranvier bilayers at equilibrium and under deformation and compared to previous axolemma simulations. We found that the myelin bilayer has a slightly higher area compressibility modulus and higher rupture strain than node of Ranvier. Compared to the axolemma in unmyelinated axon, mechanoporation occurs at 50% higher strain in the myelin and at 23% lower strain in the node of Ranvier in myelinated axon. Combining the results with finite element simulations of the axon, we hypothesizes that myelin does not rupture at the thresholds proposed in the literature for axonal injury while rupture may occur at the node of Ranvier. The findings contribute to increases our knowledge of axonal sub-cellular components and help to understand better the mechanism behind axonal brain injury.

New plasmon-polariton model of the saltatory conduction

ABSTRACTWe propose a new model of the saltatory conduction in myelinated axons. This conduction of the action potential in myelinated axons does not agree with the conventional cable theory, though the latter has satisfactorily explained the electrosignaling in dendrites and in unmyelinated axons. By the development of the wave-type concept of ionic plasmon-polariton kinetics in axon cytosol we have achieved an agreement of the model with observed properties of the saltatory conduction. Some resulting consequences of the different electricity model in the white and the gray matter for nervous system organization have been also outlined.SIGNIFICANCEMost of axons in peripheral nervous system and in white matter of brain and spinal cord are myelinated with the action potential kinetics speed two orders greater than in dendrites and in unmyelinated axons. A decrease of the saltatory conduction velocity by only 10% ceases body functioning. Conventional cable theory, useful for dendrites and unmyelinated axon, does not explain the saltatory conduction (discrepancy between the speed assessed and the observed one is of one order of the magnitude). We propose a new nonlocal collective mechanism of ion density oscillations synchronized in the chain of myelinated segments of plasmon-polariton type, which is consistent with observations. This model explains the role of the myelin in other way than was previously thought.

Localized axolemma deformations suggest mechanoporation as axonal injury trigger

Traumatic brain injuries are a leading cause of morbidity and mortality worldwide. With almost 50% of traumatic brain injuries being related to axonal damage, understanding the nature of cellular level impairment is crucial. Experimental observations have so far led to the formulation of conflicting theories regarding the cellular primary injury mechanism. Disruption of the axolemma, or alternatively cytoskeletal damage has been suggested mainly as injury trigger. However, mechanoporation thresholds of generic membranes seem not to overlap with the axonal injury deformation range and microtubules appear too stiff and too weakly connected to undergo mechanical breaking. Here, we aim to shed a light on the mechanism of primary axonal injury, bridging finite element and molecular dynamics simulations. Despite the necessary level of approximation, our models can accurately describe the mechanical behavior of the unmyelinated axon and its membrane. More importantly, they give access to quantities that would be inaccessible with an experimental approach. We show that in a typical injury scenario, the axonal cortex sustains deformations large enough to entail pore formation in the adjoining lipid bilayer. The observed axonal deformation of 10-12% agree well with the thresholds proposed in the literature for axonal injury and, above all, allow us to provide quantitative evidences that do not exclude pore formation in the membrane as a result of trauma. Our findings bring to an increased knowledge of axonal injury mechanism that will have positive implications for the prevention and treatment of brain injuries.

Shielding effects of myelin sheath on axolemma depolarization under transverse electric field stimulation

Axonal stimulation with electric currents is an effective method for controlling neural activity. An electric field parallel to the axon is widely accepted as the predominant component in the activation of an axon. However, recent studies indicate that the transverse component to the axolemma is also effective in depolarizing the axon. To quantitatively investigate the amount of axolemma polarization induced by a transverse electric field, we computed the transmembrane potential (Vm) for a conductive body that represents an unmyelinated axon (or the bare axon between the myelin sheath in a myelinated axon). We also computed the transmembrane potential of the sheath-covered axonal segment in a myelinated axon. We then systematically analyzed the biophysical factors that affect axonal polarization under transverse electric stimulation for both the bare and sheath-covered axons. Geometrical patterns of polarization of both axon types were dependent on field properties (magnitude and field orientation to the axon). Polarization of both axons was also dependent on their axolemma radii and electrical conductivities. The myelin provided a significant “shielding effect” against the transverse electric fields, preventing excessive axolemma depolarization. Demyelination could allow for prominent axolemma depolarization in the transverse electric field, via a significant increase in myelin conductivity. This shifts the voltage drop of the myelin sheath to the axolemma. Pathological changes at a cellular level should be considered when electric fields are used for the treatment of demyelination diseases. The calculated term for membrane polarization (Vm) could be used to modify the current cable equation that describes axon excitation by an external electric field to account for the activating effects of both parallel and transverse fields surrounding the target axon.

On the existence of mechanoreceptors within the neurovascular unit of the rodent and rabbit brain

We describe a set of perivascular interneurons (PINs) originating a series of fibro-vesicular complexes (FVCs) throughout the gray matter of the adult rabbit and rat brain. PINs-FVCs are ubiquitous throughout the brain vasculature as defined in Golgi-impregnated specimens. Most PINs consist of small, aspiny cells with local or long (> 1 millimeter) axons that split running with arterial blood vessels. Upon ramification, axons originate FVCs around the roots of the arising vascular branches. Distally, FVCs form paired axons that run parallel to the vessel’s wall until another ramification ensues and a new FVC is formed. This alternating pattern ceases when the capillary diameter narrows (i.e., <8 µm) and axons resolve. FVCs, as visualized by electron microscopy, consist of clusters of anastomotic perivascular bulbs (PVBs) arising from the PIN’s unmyelinated axon. PVBs lie alongside the pre- or -capillary wall, surrounded by end-feet and the extracellular matrix of endothelial cells and pericytes. A PVB contains mitochondria, multivesicular bodies, and granules with a membranous core similar to those observed in Meissner corpuscles and other mechanoreceptors. Some PVBs form asymmetrical, axo-spinous synapses with presumptive adjacent neurons. Antisera to sensory fiber-terminals co-label putative FVCs that are embedded by astrocytic end-feet. Because of the strategic location, ubiquity, and cytological organization of the PIN-FVC, it is suggested that: 1. PIN-FVCs are distributed throughout the mammalian brain vasculature. 2. The PIN-FVC is a putative sensory receptor intrinsic of the neurovascular unit. 3. The PIN-FVC may correspond to an afferent limb of the sensory-motor feed-back controlling local blood flow.

Ionic mechanisms underlying history-dependence of conduction delay in an unmyelinated axon

Axonal conduction velocity can change substantially during ongoing activity, thus modifying spike interval structures and, potentially, temporal coding. We used a biophysical model to unmask mechanisms underlying the history-dependence of conduction. The model replicates activity in the unmyelinated axon of the crustacean stomatogastric pyloric dilator neuron. At the timescale of a single burst, conduction delay has a non-monotonic relationship with instantaneous frequency, which depends on the gating rates of the fast voltage-gated Na+ current. At the slower timescale of minutes, the mean value and variability of conduction delay increase. These effects are because of hyperpolarization of the baseline membrane potential by the Na+/K+ pump, balanced by an h-current, both of which affect the gating of the Na+ current. We explore the mechanisms of history-dependence of conduction delay in axons and develop an empirical equation that accurately predicts this history-dependence, both in the model and in experimental measurements.

Neurons define non-myelinated axon segments by the regulation of galectin-4-containing axon membrane domains

The mechanism underlying selective myelination of axons versus dendrites or neuronal somata relies on the expression of somatodendritic membrane myelination inhibitors (i.e. JAM2). However, axons still present long unmyelinated segments proposed to contribute to axonal plasticity and higher order brain functions. Why these segments remain unmyelinated is still an unresolved issue. The bifunctional lectin galectin-4 (Gal-4) organizes the transport of axon glycoproteins by binding to N-acetyllactosamine (LacNac) termini of N-glycans. We have shown that Gal-4 is sorted to segmental domains (G4Ds) along the axon surface, reminiscent of these long unmyelinated axon segments in cortical neurons. We report here that oligodendrocytes (OLGs) do not deposit myelin on Gal-4 covered surfaces or myelinate axonal G4Ds. In addition, Gal-4 interacts and co-localizes in G4Ds with contactin-1, a marker of non-myelinated nodes of Ranvier. Neither Gal-4 expression nor G4D dimensions are affected by myelin extracts or myelinating OLGs, but are reduced with neuron maturation. As in vitro, Gal-4 is consistently segregated from myelinated structures in the brain. Our data shape the novel concept that neurons establish and regulate axon membrane domains expressing Gal-4, the first inhibitor of myelination identified in axons, whose boundaries delineate myelination-incompetent axon segments along neuron development.