A role of oligodendrocytes in information processing

Myelinating oligodendrocytes enable fast propagation of action potentials along the ensheathed axons. In addition, oligodendrocytes play diverse non-canonical roles including axonal metabolic support and activity-dependent myelination. An open question remains whether myelination also contributes to information processing in addition to speeding up conduction velocity. Here, we analyze the role of myelin in auditory information processing using paradigms that are also good predictors of speech understanding in humans. We compare mice with different degrees of dysmyelination using acute multiunit recordings in the auditory cortex, in combination with behavioral readouts. We find complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. We observe partially discriminable but similar deficits in well myelinated mice in which glial cells cannot fully support axons metabolically. We suggest a model in which myelination contributes to sus- tained stimulus perception in temporally complex paradigms, with a role of metabolically active oligodendrocytes in cortical information processing

White matter integrity in mice requires continuous myelin synthesis at the inner tongue

Myelin, the electrically insulating sheath on axons, undergoes dynamic changes over time. However, it is composed of proteins with long lifetimes. This raises the question how such a stable structure is renewed. Here, we study the integrity of myelinated tracts after experi- mentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survive recombination, continue to express myelin genes, but they fail to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualize myelin-like membranes failing to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicates degradation of existing myelin at the abaxonal side and the inner tongue of the sheath. Thinning of compact myelin and shortening of internodes result in the loss of about 50% of myelin and axonal pathology within 20 weeks post recombination. In summary, our data suggest that functional axon-myelin units require the continuous incorporation of new myelin membranes

Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5

Oligodendrocytes facilitate rapid impulse propagation along the axons they myelinate and support their long-term integrity. However, the functional relevance of many myelin proteins has remained unknown. Here, we find that expression of the tetraspan-transmembrane protein CMTM5 (chemokine-like factor-like MARVEL-transmembrane domain containing protein 5) is highly enriched in oligodendrocytes and central nervous system (CNS) myelin. Genetic disruption of the Cmtm5 gene in oligodendrocytes of mice does not impair the development or ultrastructure of CNS myelin. However, oligodendroglial Cmtm5 deficiency causes an early-onset progressive axonopathy, which we also observe in global and tamoxifen-induced oligodendroglial Cmtm5 mutants. Presence of the WldS mutation ameliorates the axonopathy, implying a Wallerian degeneration-like pathomechanism. These results indicate that CMTM5 is involved in the function of oligodendrocytes to maintain axonal integrity rather than myelin biogenesis

Investigation of myelin maintenance and turnover by inducible MPB knock-out in adult mice

The turnover and maintenance of myelin in the adult CNS Myelin is a multilayered membrane structure generated by oligodendrocytes in the CNS that insulates and supports axons. While most of the oligodendrocyte population differentiates early in life and persist for most of the lifetime, myelin proteins are slowly turned over and replaced within weeks to months. However, the mechanisms of this turnover and replacement processes within the myelin sheath are largely unknown. One reason is the absence of a suitable model system. To study myelin turnover in the adult animal a model system is required that allows to investigate myelin maintenance under conditions of ongoing turnover, survival of oligodendrocytes and the avoidance of acute inflammation. In this thesis a new model system was established that meets these requirements and was used to study turnover within the individual myelin sheath. This model system is based on a strategy for the visualization of myelin renewal by the application of an inducible deletion of myelin basic protein (Mbp) expression in the adult. For this purpose, ablation of MBP was induced in young adult mice after completion of developmental myelination at the age of 8 weeks. After the knock-out was induced, any newly synthetized myelin membrane lacked MBP and therefore the essential component for myelin compaction. The absence of compaction served as a marker for newly made myelin and was studied by electron microscopy. Using volume imaging by focused ion beam scanning electron microscopy (FIB-SEM) we observed the emergence of non-compact myelin membranes at the inner tongue of the juxta-paranodal region. The localized emergence of these membranes suggests the juxta-paranode as a site of MBP integration within the myelin sheath. Furthermore, the progressive loss of compact myelin after ablation of MBP synthesis was quantified and a shortening of internodes in the optic nerve was observed. We performed proteome analysis of the optic nerve eight, 16 and 40 weeks after Mbp knock-out induction to investigate systemic responses after loss of de novo MBP synthesis and found reduced abundance for proteins associated to the myelin sheath and cell adhesion molecules while many cytoskeleton-associated proteins were increased in abundance. These results are in accordance with the detected loss of the compact myelin compartment. To identify potential mechanisms for oligodendrocyte intrinsic or extrinsic recycling of myelin we analyzed individual axons in 3D FIB-SEM volumes and detected an increased number of myelin spheres at the inner tongue of the oligodendrocytes. We suggest that these myelin spheres are very likely involved in disposal of aged myelin. Visualization of the observed processes of membrane integration and removal were made possible by combination of high-quality structural preservation, 3D FIB-SEM microscopy and the novel mouse model system. In conclusion, this study introduced and characterized a powerful tool to study myelin maintenance and turnover and used this to shed light on the process of myelin turnover and the half-life of a myelin sheath in CNS of adult mice.2021-06-1

First results of the high resolution wire scanners for beam profile and absolute beam position measurement at the TTF

In the TESLA Test Facility, wire scanners are used to measure the electron beam profile and position. The intended use of the wire scanners (to center the electron beam in the Free Electron Laser undulator) requires an especially precise alignment of the wire scanners with respect to the undulator axis. The wire scanners should define a reference axis with respect to the external reference system of the undulator with an accuracy better than 30 μm. The wire scanners allow a beam profile measurement, which will be used to optimize and match the beam optics for the undulator. First experimental results of beam position and profile will be presented and discussed

First results of the high resolution wire scanners for beam profile and absolute beam position measurement at the TTF

In the TESLA Test Facility, wire scanners are used to measure the electron beam profile and position. The intended use of the wire scanners (to center the electron beam in the Free Electron Laser undulator) requires an especially precise alignment of the wire scanners with respect to the undulator axis. The wire scanners should define a reference axis with respect to the external reference system of the undulator with an accuracy better than 30 μm. The wire scanners allow a beam profile measurement, which will be used to optimize and match the beam optics for the undulator. First experimental results of beam position and profile will be presented and discussed

The Role of Lamins in the Nucleoplasmic Reticulum, a Pleiomorphic Organelle That Enhances Nucleo-Cytoplasmic Interplay

Invaginations of the nuclear membrane occur in different shapes, sizes, and compositions. Part of these pleiomorphic invaginations make up the nucleoplasmic reticulum (NR), while others are merely nuclear folds. We define the NR as tubular invaginations consisting of either both the inner and outer nuclear membrane, or only the inner nuclear membrane. Specifically, invaginations of both the inner and outer nuclear membrane are also called type II NR, while those of only the inner nuclear membrane are defined as type I NR. The formation and structure of the NR is determined by proteins associated to the nuclear membrane, which induce a high membrane curvature leading to tubular invaginations. Here we review and discuss the current knowledge of nuclear invaginations and the NR in particular. An increase in tubular invaginations of the nuclear envelope is associated with several pathologies, such as laminopathies, cancer, (reversible) heart failure, and Alzheimer’s disease. Furthermore, viruses can induce both type I and II NR. In laminopathies, the amount of A-type lamins throughout the nucleus is generally decreased or the organization of lamins or lamin-associated proteins is disturbed. Also, lamin overexpression or modulation of lamin farnesylation status impacts NR formation, confirming the importance of lamin processing in NR formation. Virus infections reorganize the nuclear lamina via (de)phosphorylation of lamins, leading to an uneven thickness of the nuclear lamina and in turn lobulation of the nuclear membrane and the formation of invaginations of the inner nuclear membrane. Since most studies on the NR have been performed with cell cultures, we present additional proof for the existence of these structures in vivo, focusing on a variety of differentiated cardiovascular and hematopoietic cells. Furthermore, we substantiate the knowledge of the lamin composition of the NR by super-resolution images of the lamin A/C and B1 organization. Finally, we further highlight the essential role of lamins in NR formation by demonstrating that (over)expression of lamins can induce aberrant NR structures

The Role of Lamins in the Nucleoplasmic Reticulum, a Pleiomorphic Organelle That Enhances Nucleo-Cytoplasmic Interplay

Invaginations of the nuclear membrane occur in different shapes, sizes, and compositions. Part of these pleiomorphic invaginations make up the nucleoplasmic reticulum (NR), while others are merely nuclear folds. We define the NR as tubular invaginations consisting of either both the inner and outer nuclear membrane, or only the inner nuclear membrane. Specifically, invaginations of both the inner and outer nuclear membrane are also called type II NR, while those of only the inner nuclear membrane are defined as type I NR. The formation and structure of the NR is determined by proteins associated to the nuclear membrane, which induce a high membrane curvature leading to tubular invaginations. Here we review and discuss the current knowledge of nuclear invaginations and the NR in particular. An increase in tubular invaginations of the nuclear envelope is associated with several pathologies, such as laminopathies, cancer, (reversible) heart failure, and Alzheimer's disease. Furthermore, viruses can induce both type I and II NR. In laminopathies, the amount of A-type lamins throughout the nucleus is generally decreased or the organization of lamins or lamin-associated proteins is disturbed. Also, lamin overexpression or modulation of lamin farnesylation status impacts NR formation, confirming the importance of lamin processing in NR formation. Virus infections reorganize the nuclear lamina via (de)phosphorylation of lamins, leading to an uneven thickness of the nuclear lamina and in turn lobulation of the nuclear membrane and the formation of invaginations of the inner nuclear membrane. Since most studies on the NR have been performed with cell cultures, we present additional proof for the existence of these structures in vivo, focusing on a variety of differentiated cardiovascular and hematopoietic cells. Furthermore, we substantiate the knowledge of the lamin composition of the NR by super-resolution images of the lamin A/C and B1 organization. Finally, we further highlight the essential role of lamins in NR formation by demonstrating that (over)expression of lamins can induce aberrant NR structures