Myelin

The human body has approximately 1 trillion neurons, each of which has a cell body with a nucleus that contains the genetic material that determines how the cell functions (Feldman, 2008).  By thinking of the nervous system as the highway and the neurons as the vehicles on that highway, we can see how “the nervous system is (considered to be) the pathway for the instructions that permit our bodies to carry out such precise activities” (p. 61). In this paper, we discover why neurons are called “the basic elements of behavior” by examining them as the nerve cells that allow our brains to transport and coordinate the messages of our thoughts, actions, and deeds.

Multiple sclerosis is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. Trigeminal neuralgia involves loss of the myelin around the trigeminal nerve. Myelin is a phospholipid membrane that wraps around axons to provide them with insulation. It is produced by Schwann cells in the PNS, and by oligodendrocytes in the CNS. Intralipid treatment is first suggested in the medical literature as a way for myelin sheath repair in multiple sclerosis and trigeminal neuralgia.

Age-related hearing loss is the most common type of hearing impairment, and is typically characterized by the loss of spiral ganglion neurons (SGNs). The two Liver X receptors (LXRs) are oxysterol-activated nuclear receptors which in adults, regulate genes involved in cholesterol homeostasis and modulation of macrophage activity. LXR β plays a key role in maintenance of health of dopaminergic neurons in the substantia nigra, large motor neurons in the spinal cord, and retinal ganglion cells in adult mice. We now report that LXR β is expressed in the SGNs of the cochlea and that loss of LXR β leads to age-related cochlea degeneration. We found that in the cochlea of LXR β-/- mice, there is loss of SGNs, activation of macrophages, demyelination in the spiral ganglion, decrease in glutamine synthetase (GS) expression and increase in glutamate accumulation in the cochlea. Part of the cause of damage to the SGNs might be glutamate toxicity which is known to be very toxic to these cells. Our study provides a so far unreported role of LXR β in maintenance of SGNs whose loss is a very common cause of hearing impairment.

The mechanism by which oligodendrocytes are depleted from active lesions in multiple sclerosis (MS) is not clear but many reports implicate a cytolytic process. The most applied animal model for MS, chronic relapsing experimental autoimmune encephalomyelitis (EAE), has been established in inbred strains of mice, especially SJL and PL. Studies on oligodendrocytes from these strains in vitro have been hampered to date by an inability to grow these cells from mouse CNS tissue. We report here a successful method to culture SJL mouse oligodendrocytes and have analyzed lysis of these cells in vitro mediated by the pore-forming protein, perforin, a candidate effector molecule in inflammatory demyelination. Cultures were exposed to murine perforin, 36–72 hemolytic U, for up to 2.5 hr and examined using the oligodendrocyte phenotypic markers O4, galactocerebroside and myelin basic protein (MBP), in addition to a membrane dye (DiI) and a marker of necrosis, propidium iodide, (PI). Cultures were imaged chronologically by phase contrast, immunofluorescence, digital, light and electron microscopy. Findings showed that the majority of oligodendrocytes were killed within 60–90 min via pore expansion and ultimately, membrane disruption. The structural features of the cellular damage comprised swelling of the cell body, fenestration and fragmentation of membranes and processes, cytoplasmic vacuolation and breakdown of the nuclear envelope. Astrocytes in the same system were relatively resistant to cell lysis. The above patterns of oligodendrocyte damage in SJL oligodendrocytes were reminiscent of patterns in the MS lesion, leaving us to conclude that perforin may play an important role in the human disease.

Intracortical myelin is a key determinant of neuronal synchrony and plasticity that underpin optimal brain function. Magnetic resonance imanging (MRI) facilitiates the examination of intracortical myelin but presents with methodological challenges. Here we describe a whole-brain approach for the in vivo investigation of intracortical myelin in the human brain using ultra-high field MRI. Twenty-five healthy adults were imaged in a 7 Tesla MRI scanner using diffusion-weighted imaging and a T-weighted sequence optimized for intracortical myelin contrast. Using an automated pipeline, T values were extracted at 20 depth-levels from each of 148 cortical regions. In each cortical region, T values were used to infer myelin concentration and to construct a non-linearity index as a measure the spatial distribution of myelin across the cortical ribbon. The relationship of the myelin concertation and non-linearity index with other neuroanatomical properties were investigated. Five patients with...

Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 w...

TO THE EDITOR: We read the Pictures & Perspectives by Heindl et al 1 regarding the eyes of Oetzi, the celebrated Tyrolean Iceman dating back to the 4th millennium BCE. Building on previous studies, the authors mention a "unique view" onto this ancient corpse's anatomy, thanks to the "natural mummification in the glacier ice," 1 which has allowed many important discoveries, including the determination of this prehistoric individual's violent cause of death. Specifically, addressing the issue of the preservation of ocular structures, 2,3 it is interesting to examine the actual role played by environmental and climate conditions as opposed to purely anatomic characteristics of the tissues themselves. The available literature shows a consistent presence of ocular structures in mummified remains, 2 either natural or artificial. 3-6 Twenty-one of 52 Third Intermediate Period (1064e656 BCE) to Graeco-Roman (332 BCEe395 CE) period in Egyptian mummies 7 revealed preservation of ocular structures exclusively through desiccation in 40.4%. 4 Similarly, the globes of the eyes with optic nerves and orbital muscles could be identified in the mummified remains of 2 remarkable 18 th Dynasty Egyptian dignitaries: Nebiri and the Royal Architect Kha. 8 The Korean Mummy Project, assessing 7 computed tomography scanned mummies, indicates eye structures were likely to have preserved in 4 of 7 (57.1 %) of naturally mummified Joseon Dynasty individuals from the 17 th e19 th centuries (Shin DH, unpublished data), which approximately equals the number of preserved eye structures in 18 th /19 th century German crypt mummies (5/10 [50%] individuals) [Nerlich AG, personal communication]. In a series of 23 naturally and 23 artificially mummified Capuchin mummies from Palermo, Sicily, Panzer et al 5 reported a higher prevalence for the preservation of the bulbs and optic nerves bilaterally, namely in 21 of 23 mummies (6 natural and 17 artificial mummies), yielding a 91.3% figure. Apparently, this preservative phenomenon has little to do with climate since ocular structures are a common feature of both cold (Alpine glaciers 1), hot and sultry (Atacama desert of Northern Chile, 2 Peru, 3 Northern African desert 4), hot summer subtropical Mediterranean climate (Sicily 5), and humid continental regions of the world (South Korea, Germany). In Oetzi's case, as in all others, the most likely reason for the preservation of intact ocular globes is to be searched in the eye's anatomy. The sclera is a tough connective tissue extremely resistant to destruction. Scleral collagen is, in composition and arrangement, more similar to that seen in skin, with wider fibrils and a much more interwoven structure than the cornea. 6 Dehydration leads to a collapse of the vitreous body and a retraction of the sclera, resulting in a shrunken but compact eye globe. As to the optic nerve, the narrow and compact optic canal and the myelin sheath, whose dry mass is characterized by a high proportion of lipids 9 act as a protective shield. In summary, the preservation of eye structures in mummies is independent of region, time period and cause of mummification, but depends on the overall preservation of a mummified human body.

Tubulinopathies are a group of recently described diseases characterized by mutations in the tubulin genes. Mutations in TUBB4A produce diseases such as dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), which are clinically diagnosed by magnetic resonance imaging (MRI). We propose the taiep rat as the first animal model for tubulinopathies. The spontaneous mutant suffers from a syndrome related to a central leukodystrophy and characterized by tremor, ataxia, immobility, epilepsy, and paralysis. The pathological signs presented by these rats and the morphological changes we found by our longitudinal MRI study are similar to those of patients with mutations in TUBB4A. The diffuse atrophy we found in brain, cerebellum and spinal cord is related to the changes detectable in many human tubulinopathies and in particular in H-ABC patients, where myelin degeneration at the level of putamen and cerebellum is a clinical trademark of the disea...

Traumatic injury of the central nervous system (CNS) has severe impact on the patients' quality of life and initiates many molecular and cellular changes at the site of insult. Traumatic CNS injury results in direct damage of the axons of CNS neurons, loss of myelin sheaths, destruction of the surrounding vascular architecture and initiation of an immune response. Class III semaphorins (SEMA3s) are present in the neural scar and influence a wide range of molecules and cell types in and surrounding the injured tissue. SEMA3s and their receptors, neuropilins (NRPs) and plexins (PLXNs) were initially studied because of their involvement in repulsive axon guidance. To date, SEMA3 signaling is recognized to be of crucial importance for re-vascularization, the immune response and remyelination. The purpose of this review is to summarize and discuss how SEMA3s modulate these processes that are all crucial components of the tissue response to injury. Most of the functions for SEMA3s are achieved through their binding partners NRPs, which are also co-receptors for a variety of other molecules implicated in the above processes. The most notable ligands are members of the vascular endothelial growth factor (VEGF) family and the transforming growth factor family. Therefore, a second aim is to highlight the overlapping or competing signaling pathways that are mediated through NRPs in the same processes. In conclusion, we show that the role of SEMA3s goes beyond inhibiting axonal regeneration, since they are also critical modulators of re-vascularization, the immune response and re-myelination.

We present an approach for combining high resolution MRI-based myelin mapping with functional information from electroencephalography (EEG) or magnetoencephalography (MEG). The main contribution to the primary currents detectable with EEG and MEG comes from ionic currents in the apical dendrites of cortical pyramidal cells, aligned perpendicularly to the local cortical surface. We provide evidence from an in-vivo experiment that the variation in MRI-based myeloarchitecture measures across the cortex predicts the variation of the cur- rent density over individuals and thus is of functional relevance. Equivalent current dipole locations and mo- ments due to pitch onset evoked response fields (ERFs) were estimated by means of a variational Bayesian algorithm. The myeloarchitecture was estimated indirectly from individual high resolution quantitative multi- parameter maps (MPMs) acquired at 800 μm isotropic resolution. Myelin estimates across cortical areas correlat- ed positively with dipole magnitude. This correlation was spatially specific: regions of interest in the auditory cor- tex provided significantly better models than those covering whole hemispheres. Based on the MPM data we identified the auditory cortical area TE1.2 as the most likely origin of the pitch ERFs measured by MEG. We can now proceed to exploit the higher spatial resolution of quantitative MPMs to identify the cortical origin of M/EEG signals, inform M/EEG source reconstruction and explore structure–function relationships at a fine structural level in the living human brain.

Introduction: Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary. Development: We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models. Conclusions: Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study.

Bipolar disorder (BD) is a major psychiatric illness that affects 1% of the population and has its onset during adolescence or early adulthood (1, 2). It significantly decreases the quality of life of patients and caregivers and increases the burden of health and social care services (3). Since 90s, a growing interest on the neurobiological underpinnings of BD has been object of several magnetic resonance imaging (MRI) studies that, so far, have repeatedly reported diffuse white matter

Myelin oligodendrocyte glycoprotein (MOG) is an integral membrane protein expressed in CNS oligodendrocytes and outermost myelin lamellae. Anti-MOG Abs cause myelin destruction (demy-elination) in animal models of multiple sclerosis (MS); however, such pathogenic Abs have not yet been characterized in humans. Here, a method that specifically detects IgG binding to human MOG in its native, membrane-embedded conformation on MOG-trans-fected mammalian cells was used to evaluate the significance of these auto Abs. Compared with healthy controls, native MOG-specific IgGs were most frequently found in serum of clinically isolated syndromes (P < 0.001) and relapsing-remitting MS (P < 0.01), only marginally in secondary progressive MS (P < 0.05), and not at all in primary progressive MS. We demonstrate that epitopes exposed in this cell-based assay are different from those exposed on the refolded, extracellular domain of human recombinant MOG tested by solid-phase ELISA. In marmoset monkeys induced to develop MS-like CNS inflammatory demyelination, IgG reactivity against the native membrane-bound MOG is always detected before clinical onset of disease (P < 0.0001), unlike that against other myelin constituents. We conclude that (i) epitopes displayed on native, glycosylated MOG expressed in vivo are early targets for pathogenic Abs; (ii) these Abs, which are not detected in solid-phase assays, might be the ones to play a pathogenic role in early MS with predominant inflammatory activity; and (iii) the cell-based assay provides a practical serologic marker for early detection of CNS autoimmune demyelination including its preclinical stage at least in the primate MS model. allergic encephalomyelitis autoimmunity clinically isolated syndrome demyelination M ultiple sclerosis (MS) is an immune-mediated, chronic demyelinating disorder of CNS white matter mediated by CD4 myelin-reactive T helper 1 cells (1). Humoral immunity may play a role in MS pathogenesis, as suggested by intrathecal Ab synthesis and oligoclonal B cell expansion, observations of Ab deposition associated with myelin vacuolization in MS plaques (2), and involvement of IgG and complement deposition (3). Myelin oligodendrocyte glycoprotein (MOG) is a target myelin antigen for both humoral and cellular CNS-directed immune responses. The full-length protein contains 218 aa and two predicted transmembrane domains, is posttranscriptionally processed as suggested by apparent electrophoretic mobility, and is a potential site for glycosylation, phosphorylation, isopreny-lation, and myristoylation (4). The encephalitogenic properties of MOG are believed to result from the extracellular location of its IgV-like domain on the outermost myelin lamellae, which makes it an exposed target accessible to initial autoimmune attack on compact myelinated axons (5). In both rodent and primate MS models of experimental allergic encephalomyelitis (EAE), Abs against MOG directly induce demyelination (6, 7). Moreover, certain Abs against MOG have been proposed as predictors of early conversion to clinically definite MS in the context of a first demyelinating event (8). A common problem encountered in human studies of humoral immunity against MOG is that accurate detection of Ab depends highly on the conformation of the antigens used for detection. Previous studies, either in MS or EAE, have not fully characterized the structural features of the proteins used as Ab targets in vitro and have reported conflicting findings, in part because of the different folded forms of this poorly water-soluble antigen. The existing assays detecting anti-MOG Abs use various MOG preparations, recombinant, native-purified, or in vitro-translated proteins of variable length including short peptides (4, 8–11). None of these methods takes into account the specific tertiary structure of the folded MOG as it is presented to the immune system in vivo, e.g., in association with a hydrophobic, lipid-rich bilayer membrane environment. Therefore, these techniques may fail to detect reactivity against epitopes displayed by native MOG expressed in situ on myelin sheaths, as it would be upon an initial immune response. Here, we describe a cell-based assay that specifically measures Abs directed against conformationally folded, cell membrane-expressed human MOG (designated hMOG cme), and evaluate the relative incidence of these antinative MOG Abs in serum of humans and Callithrix jacchus marmosets with MS-like EAE. We find that hMOG cme Abs predominate during clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) and can be detected during the preclinical stage of EAE. These findings underscore the potential value of antinative MOG Abs as a practical candidate biomarker for detecting MS at its early, inflammatory stage.

We present an approach for combining high resolution MRI-based myelin mapping with functional information from electroencephalography (EEG) or magnetoencephalography (MEG). The main contribution to the primary currents detectable with EEG and MEG comes from ionic currents in the apical dendrites of cortical pyramidal cells, aligned perpendicularly to the local cortical surface. We provide evidence from an in-vivo experiment that the variation in MRI-based myeloarchitecture measures across the cortex predicts the variation of the current density over individuals and thus is of functional relevance. Equivalent current dipole locations and moments due to pitch onset evoked response fields (ERFs) were estimated by means of a variational Bayesian algorithm. The myeloarchitecture was estimated indirectly from individual high resolution quantitative multi-parameter maps (MPMs) acquired at 800μm isotropic resolution. Myelin estimates across cortical areas correlated positively with dipole m...

La contaminacion por campos electromagneticos causa daño celular depende de intensidad, frecuencia, tipo de ondas y tiempo de exposición. Relación entre campos E/M altos y actividad tumoral ha sido confirmada por diferentes estudios clínicos.

Isolated CNS myelin membranes were extracted with Triton X-100 under conditions previously established for the isolation of cytoskeletal proteins. Treated myelin retained much of its characteristic lamellar structure despite the removal of most of the major myelin basic protein (18.5 kDa) and the proteolipid protein, which together normally constitute 60% of the total myelin protein. The SDS-PAGE profile of this extract residue demonstrated an enrichment in proteins of Mr 30 to 60 kilodaltons (the Wolfgram group). The major myelin proteins were identified by antibodies on Western immunoblots, as were the 2′3′-cyclic nucleotide 3′-phosphodiesterase (CNP), actin, tubulin, myelin-associated glycoprotein (MGP) and the 21.5 kDa MBP. The overall behavior of CNP, the 21.5 kDa MBP, MGP and tubulin towards Triton extraction is reminiscent of the behavior of other membrane-skeletal complexes, supporting the idea that these and other minor myelin proteins might be part of heteromolecular complexes with interactions spanning several lamellae of the myelin sheath.

Axon-to-myelin transfer of lipids and lipid precursors have been studied in the rabbit optic system by intraocular injection of [32p]ortho p hos p hate , [tac]glycerol and [3 H]glycerol. Choline and ethanolamine_ p host4 p ho g ly cerides and m y elin showed increasing [32 P]-radioactivity between 7 and 21 days following injection, while [5 H]-and [ C]-radioactivities remained relatively constant. The latter radioactivities decreased, however, in all the axon-and axolemma-enriched fractions during the same period. These findings supported the concept that a portion of substances undergoing axonal transport enters the pool of myelin lipids by two mechanisms: transcellular transfer of intact lipid and axon-myelin transfer of precursors which are re-utilized for lipid biosynthesis by myelin-localized enzymes. The present study shows that inorganic phosphate, possibly generated by catabolic activity within the axon, is able to enter myelin and participate in the re-utilization mechanism as previously described for serine, choline and acyl chains. The relative invariance of the 3H:14C ratio suggested that the majority of glycerol is not re-utilized in this manner but probably enters myelin through transfer of intact lipid. These and earlier results suggest a possible form of metabolic dependence of myelin on trophic substances from the axon.

The ultrastructure fluctuations and complex dynamics of the multi-layered membrane structure of myelin are fundamental for understanding and control its formation process and the processes associated with degeneration and repair in neurological diseases such as multiple sclerosis (MS). Myelin is considered a quasi-crystalline material due to limitations of the available standard techniques that do not allow to solve heterogeneity and fluctuations in matter at nanoscale and mesoscale. To overcome this limitation in this work we used Scanning micro X-ray Diffraction (S{\mu}XRD), which is a unique non-invasive probe of both k-space and real space allowing to visualize statistical fluctuations of myelin order with high spatial resolution in real space. We have used this method to examine the myelin sheath in the sciatic nerve of Xenopus laevis. We have found that the stable periodic arrangement of myelin is ensured by large and anti-correlated fluctuations at nanoscale, between hydropho...

Anorexia nervosa (AN) is a serious eating disorder that typically emerges during adolescence and occurs most frequently in females. To date, very few studies have investigated the possible impact of AN on white matter tissue properties during adolescence, when white matter is still developing. The present study evaluated white matter tissue properties in adolescent girls with AN using diffusion MRI with tractography and T1 relaxometry to measure R1 (1/T1), an index of myelin content. Fifteen adolescent girls with AN (mean age = 16.6 years ± 1.4) were compared to fifteen age-matched girls with normal weight and eating behaviors (mean age = 17.1 years ± 1.3). We identified and segmented 9 bilateral cerebral tracts (18) and 8 callosal fiber tracts in each participant's brain (26 total). Tract profiles were generated by computing measures for fractional anisotropy (FA) and R1 along the trajectory of each tract. Compared to controls, FA in the AN group was significantly decreased in 4 of 26 white matter tracts and significantly increased in 2 of 26 white matter tracts. R1 was significantly decreased in the AN group compared to controls in 11 of 26 white matter tracts. Reduced FA in combination with reduced R1 suggests that the observed white matter differences in AN are likely due to reductions in myelin content. For the majority of tracts, group differences in FA and R1 did not occur within the same tract. The present findings have important implications for understanding the neurobiological factors underlying white matter changes associated with AN and invite further investigations examining associations between white matter properties and specific physiological, cognitive, social, or emotional functions affected in AN.

Tibetan medicine integrates diet, lifestyle, herbs, and accessory therapies to increase health and longevity. A comparison of the three humor theory of Tibetan medicine and the three thermodynamic phase properties of myelin lipids exemplifies how integrating medical systems can increase understanding of complex chronic disabling conditions. As a correlative study to microscopically better understand multiple sclerosis (MS) from the view of Tibetan medicine, the physical disruption of central nervous system myelin membranes in MS is interpreted from the theory of the three humors (vital energies) of Tibetan medicine: rLung (Wind), MKhris pa (Bile), and Bad gen (Phlegm). The three classes of myelin lipids-phospholipids, sphingolipids, and cholesterolare interpreted as one of three humors based on Langmuir isotherm thermodynamic measurements. The nature of rLung is movement or change. Myelin sphingolipids have rLung properties based on thermodynamic observations of changes in phase organization. MKhris pa is fire, energetic. Phospholipids have MKhris pa properties based on thermodynamic observations of being energetic membrane lipids with fast molecular motions and fluid-like properties. The nature of Bad gen is substance and form; it dominates body structure. Cholesterol relates to Bad gen because it dominates membrane structure. We propose a theoretical relationship whereby demyelination in MS is viewed as a continuum of imbalance of the three humors as understood in Tibetan medicine. Myelin lipid data is presented to support this theoretical relationship. Clinically, MS is, in general, a rLung-MKhrispa disorder in women and a Bad gen-MKhrispa disorder in men, with rLung-MKhrispa excess in both genders during exacerbation, inflammation, and demyelination. Studying Tibetan medicine in its traditional context will create an integrative model for the treatment of MS and other chronic conditions.

Anorexia nervosa (AN) is a serious eating disorder that typically emerges during adolescence and occurs most frequently in females. To date, very few studies have investigated the possible impact of AN on white matter tissue properties during adolescence, when white matter is still developing. The present study evaluated white matter tissue properties in adolescent girls with AN using diffusion MRI with tractography and T1 relaxometry to measure R1 (1/T1), an index of myelin content. Fifteen adolescent girls with AN (mean age = 16.6 years ± 1.4) were compared to fifteen age-matched girls with normal weight and eating behaviors (mean age = 17.1 years ± 1.3). We identified and segmented 9 bilateral cerebral tracts (18) and 8 callosal fiber tracts in each participant's brain (26 total). Tract profiles were generated by computing measures for fractional anisotropy (FA) and R1 along the trajectory of each tract. Compared to controls, FA in the AN group was significantly decreased in 4 of 26 white matter tracts and significantly increased in 2 of 26 white matter tracts. R1 was significantly decreased in the AN group compared to controls in 11 of 26 white matter tracts. Reduced FA in combination with reduced R1 suggests that the observed white matter differences in AN are likely due to reductions in myelin content. For the majority of tracts, group differences in FA and R1 did not occur within the same tract. The present findings have important implications for understanding the neurobiological factors underlying white matter changes associated with AN and invite further investigations examining associations between white matter properties and specific physiological, cognitive, social, or emotional functions affected in AN.

Myelination is essential for the rapid propagation of action potentials along axons in both the central (CNS) and peripheral (PNS) nervous systems. In the PNS, the myelin sheath is formed by Schwann cells (SCs) [1]. Myelinating Schwann cells wrap around axons so that the molecular machinery required to propagate action potentials is concentrated at regular sites, known as nodes of Ranvier. The scarcity of data regarding axon-glia physiology in peripheral nerves underscores the complexity of this cell-cell relationship and the relative inadequacy of the current approaches used in peripheral nerve research. Recent data have highlighted the role of subcellular organelles and molecular factors in the interaction between SC and axons [2]. This is consistent with the emerging opinion in the field that the interdependence between the axon and the myelinating glia is so deep that CNS and PNS neuropathies cannot be correctly addressed and treated without first understanding the extent and complexity of the relationship between neurons and glial cells [3]. The PNS shows a surprising capacity of regeneration compared to the CNS. This ability of peripheral nerves to recover quickly following damage is to a large extent due to the remarkable plasticity of Schwann cells [4]. SCs are derived from neural crest cells that differentiate into SC precursors and then into immature SCs between E12 and E15 in mice. Around birth, axonal sorting and myelination start in the peripheral nerves. Some SCs establish a 1:1 relationship with large-diameter axons, wrap them multiple times to form a thick and compact myelin sheath. Nerve homeostasis, trophic support and myelin maintenance are other important functions of SCs in adulthood [5]. The myelin geometry, diameter and internodal length, is therefore a critical parameter of the nerve conduction velocity and changes in this geometry underlie numerous functional properties of the brain and nerves [6]. Moreover, reduced internodal length, which strongly impairs nerve conduction velocity [6,7], is linked to human neuropathies such as multiple sclerosis in the central nervous system [8] and Charcot-Marie-Tooth (CMT) diseases [9-11] and congenital neuro-muscular dystrophy 1A [12] in the peripheral nervous system. While the molecular mechanisms responsible for the homogeneity of myelin thickness in Schwann cells along the same axon have been uncovered [13-15], the mechanisms responsible for myelin elongation and the formation of regular myelin lengths remain Abstract Myelination is essential for the rapid propagation of action potentials along axons in both the central and peripheral nervous systems, and the Schwann cells are the responsible of myelin sheath production in the peripheral nervous system. In the cochlea, sensory hair cells and neurons are in close association with several types of glial cells. Whereas hair cells are surrounded by supporting cells, spiral ganglion neuron axons are myelinated by Schwann cells. This myelin contributes to axonal protection and allows for efficient action potential transmission along the auditory nerve. Because in the last decade, myelin research has been notably focusing on the molecular and cellular mechanism of demyelination process and the associated axonal loss, in this review we summarize the role of the myelin sheath in auditory nerve and how Schwann cell demyelination results in a reduction in the velocity of action potential propagation, and an increase in nerve conduction vulnerability.

Continuous (24 h) exposure of mixed oligodendrocyte/microglial cells to peptides 45–89 derived from citrullinated C8 isoforms of myelin basic protein (MBP) induces cell death. In contrast, MBP-C8 at the same molecular concentration is not toxic to oligodendrocyte/microglial cells as detected by the MTT test and trypan blue exclusion method. The loss of oligodendrocyte/microglial cells resulted in the release of cytochrome c from mitochondria, suggesting MBP 45–89-induced apoptosis. On the other hand, peptides 45–89 stimulated the secretion of nitric oxide from microglial cells only via induction of iNOS. The addition of peptide 45–89 to the microglial cells led to a decrease of the level of the inhibitory protein IkB, indicating that activation of the transcription factor NF-kB is involved in these processes. We propose that the immunodominant peptide 45–89 induces damage of oligodendrocytes by activation of microglial cells and subsequent generation of nitric oxide, and that this may be the first step in the initiation of autoimmunity.

The prefrontal cortex (PFC) is a key region implicated in a range of neuropsychiatric disorders such as depression, schizophrenia and autism. In parallel, the role of the gut microbiota in contributing to these disorders is emerging. Germ-free (GF) animals, microbiota-deficient throughout life, have been instrumental in elucidating the role of the microbiota in many aspects of physiology, especially the role of the microbiota in anxiety-related behaviours, impaired social cognition and stress responsivity. Here we aim to further elucidate the mechanisms of the microbial influence by investigating changes in the homeostatic regulation of neuronal transcription of GF mice within the PFC using a genome-wide transcriptome profiling approach. Our results reveal a marked, concerted upregulation of genes linked to myelination and myelin plasticity. This coincided with upregulation of neural activity-induced pathways, potentially driving myelin plasticity. Subsequent investigation at the ultrastructural level demonstrated the presence of hypermyelinated axons within the PFC of GF mice. Notably, these changes in myelin and activity-related gene expression could be reversed by colonization with a conventional microbiota following weaning. In summary, we believe we demonstrate for the first time that the microbiome is necessary for appropriate and dynamic regulation of myelin-related genes with clear implications for cortical myelination at an ultrastructural level. The microbiota is therefore a potential therapeutic target for psychiatric disorders involving dynamic myelination in the PFC.

Quantitative assessment of the myelin content in white matter (WM) using MRI has become a useful tool for investigating myelin-related diseases, such as multiple sclerosis (MS). Myelin water fraction (MWF) maps can be estimated pixel-by-pixel by a determination of the T 2 or T 2 ⁎ spectrum from signal decay measurements at each individual image pixel. However, detection of parameters from the measured decay curve, assuming a combination of smooth multi-exponential curves, results in a nonlinear and seriously ill-posed problem. In this paper, we propose a new method to obtain a stable MWF map robust to the presence of noise while sustaining sufficient resolution, which uses weighted combinations of measured decay signals in a spatially independent neighborhood to combine tissues with similar relaxation parameters. To determine optimal weighting factors, we define a spatially independent neighborhood for each pixel and a distance with respect to decay rates that effectively includes pixels with similar decay characteristics, and which therefore have similar relaxation parameters. We recover the MWF values by using optimally weighted decay curves. We use numerical simulations and in vitro and in vivo experimental brain data scanned with a multi-gradient-echo sequence to demonstrate the feasibility of our proposed algorithm and to highlight its advantages compared to the conventional method.

We report here the isolation of fractions enriched in components of the myelin-like membranes surrounding the giant axons of the earthworm.Lumbricus terrestris L. The composition and purity of the fractions have been assessed using SDS-protein electrophoresis, Western immunoblots, and electron microscopy. Preliminary enzyme assays indicated that the mitochondrial marker, succinate dehydrogenase, has a similar specific activity distribution in earthworm nerve cord and in mouse liver sedimentation velocity fractions, however, the distribution of the total units of activity among the fractions seems to indicate the existence of smaller mitochondria in earthworm nerve cord compared with mouse liver mitochondria. In earthworm nerve cord fractions, Na+/K+ ATPase and Ca2+/Mg2+ ATPase were found to be enriched exclusively in the fraction containing large plasma and myelin-like membranes, while in the mouse liver fractions, the total units of these two enzymes were found to be distributed broadly among fractions. 5′-Nucleotidase activity in the earthworm nerve cord seemed to be restricted to the microsomal fractions (endomembrane network), with a very low activity associated with the large plasma and myelin-like membrane fraction. We have established the presence of keratins or prekeratins in the myelin-like membranes, probably in the form of tonofilaments. However, we could not show that the desmosome-like structures, characteristic of these membranes, are composed of those proteins described for vertebrate epithelial desmosomes.