A single baroreceptor unit consists of multiple sensors

Arterial baroreceptors (BRs) play a vital role in the regulation of the cardiopulmonary system. What is known about how these sensors operate at the subcellular level is limited, however. Until recently, one afferent axon was considered to be connected to a single baroreceptor (one-sensor theory). However, in the lung, a single airway mechanosensory unit is now known to house many sensors (multiple-sensor theory). Here we tested the hypothesis that multiple-sensor theory also operates in BR units, using both morphological and electrophysiological approaches in rabbit aortic arch (in whole mount) labeled with Na+/K+-ATPase, as well as myelin basic protein antibodies, and examined microscopically. Sensory structures presented in compact clusters, similar to bunches of grapes. Sensory terminals, like those in the airways, formed leaf-like or knob-like expansions. That is, a single myelinated axon connected with multiple sensors forming a network. We also recorded single-unit activities from aortic baroreceptors in the depressor nerve in anesthetized rabbits and examined the unit response to a bolus intravenous injection of phenylephrine. Unit activity increased progressively as blood pressure (BP) increased. Five of eleven units abruptly changed their discharge pattern to a lower activity level after BP attained a plateau for a minute or two (when BP was maintained at the high level). These findings clearly show that the high discharge baroreceptor deactivates after over-excitation and unit activity falls to a low discharge sensor. In conclusion, our morphological and physiological data support the hypothesis that multiple-sensory theory can be applied to BR units.

Information theoretic modeling of paranodal regions in myelinated axons

As a natural form of nanoscale communication, neuro-spike communication inspires the deployment of nanomachines inside the human body for healthcare. To this end, the identification of failure mechanisms in normal and diseased connections of nervous nano-networks is crucial. Thus, in this paper, we investigate the information transmission through a single myelinated axon segment. We introduce a realistic multi-compartmental model for a single myelinated segment by incorporating the axon's paranodal regions to the model. Next, we characterize the myelinated segment communication channel in terms of attenuation over the range of frequencies. Based on this, we derive the rate per channel use and upper bound on the information capacity. The performance evaluations reveal that our approach provides dramatic correction regarding frequency response. We believe that this result could have a significant effect on the characterization of demyelinated axons from the information and communication technology (ICT) perspective.

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.

A possible mechanism for neurofilament slowing down in myelinated axon: Phosphorylation-induced variation of NF kinetics

Neurofilaments(NFs) are the most abundant intermediate filaments that make up the inner volume of axon, with possible phosphorylation on their side arms, and their slow axonal transport by molecular motors along microtubule tracks in a “stop-and-go” manner with rapid, intermittent and bidirectional motion. The kinetics of NFs and morphology of axon are dramatically different between myelinate internode and unmyelinated node of Ranvier. The NFs in the node transport as 7.6 times faster as in the internode, and the distribution of NFs population in the internode is 7.6 folds as much as in the node of Ranvier. We hypothesize that the phosphorylation of NFs could reduce the on-track rate and slow down their transport velocity in the internode. By modifying the ‘6-state’ model with (a) an extra phosphorylation kinetics to each six state and (b) construction a new ‘8-state’ model in which NFs at off-track can be phosphorylated and have smaller on-track rate, our model and simulation demonstrate that the phosphorylation-induced decrease of on-track rate could slow down the NFs average velocity and increase the axonal caliber. The degree of phosphorylation may indicate the extent of velocity reduction. The Continuity equation used in our paper predicts that the ratio of NFs population is inverse proportional to the ratios of average velocity of NFs between node of Ranvier and internode. We speculate that the myelination of axon could increase the level of phosphorylation of NF side arms, and decrease the possibility of NFs to get on-track of microtubules, therefore slow down their transport velocity. In summary, our work provides a potential mechanism for understanding the phosphorylation kinetics of NFs in regulating their transport and morphology of axon in myelinated axons, and the different kinetics of NFs between node and internode.

Implication of Contactins in Demyelinating Pathologies

Demyelinating pathologies comprise of a variety of conditions where either central or peripheral myelin is attacked, resulting in white matter lesions and neurodegeneration. Myelinated axons are organized into molecularly distinct domains, and this segregation is crucial for their proper function. These defined domains are differentially affected at the different stages of demyelination as well as at the lesion and perilesion sites. Among the main players in myelinated axon organization are proteins of the contactin (CNTN) group of the immunoglobulin superfamily (IgSF) of cell adhesion molecules, namely Contactin-1 and Contactin-2 (CNTN1, CNTN2). The two contactins perform their functions through intermolecular interactions, which are crucial for myelinated axon integrity and functionality. In this review, we focus on the implication of these two molecules as well as their interactors in demyelinating pathologies in humans. At first, we describe the organization and function of myelinated axons in the central (CNS) and the peripheral (PNS) nervous system, further analyzing the role of CNTN1 and CNTN2 as well as their interactors in myelination. In the last section, studies showing the correlation of the two contactins with demyelinating pathologies are reviewed, highlighting the importance of these recognition molecules in shaping the function of the nervous system in multiple ways.

Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b

Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl− (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon–myelin interface. Cell-type–specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity–related solute homeostasis at the axon–myelin interface, and the integrity of myelinated axons.

MR g-ratio-weighted connectome analysis in patients with multiple sclerosis

Multiple sclerosis (MS) is a brain network disconnection syndrome. Although the brain network topology in MS has been evaluated using diffusion MRI tractography, the mechanism underlying disconnection in the disorder remains unclear. In this study, we evaluated the brain network topology in MS using connectomes with connectivity strengths based on the ratio of the inner to outer myelinated axon diameter (i.e., g-ratio), thereby providing enhanced sensitivity to demyelination compared with the conventional measures of connectivity. We mapped g-ratio-based connectomes in 14 patients with MS and compared them with those of 14 age- and sex-matched healthy controls. For comparison, probabilistic tractography was also used to map connectomes based on the number of streamlines (NOS). We found that g-ratio- and NOS-based connectomes comprised significant connectivity reductions in patients with MS, predominantly in the motor, somatosensory, visual, and limbic regions. However, only the g-ratio-based connectome enabled detection of significant increases in nodal strength in patients with MS. Finally, we found that the g-ratio-weighted nodal strength in motor, visual, and limbic regions significantly correlated with inter-individual variation in measures of disease severity. The g-ratio-based connectome can serve as a sensitive biomarker for diagnosing and monitoring disease progression.