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1. Regulation of oligodendrocyte exploratory behavior and sampling of axons by neural activity

   Gronseth, JR ; Mallon, TA ; Martell, MR ; Duxbury, BB ; Treichel, AJ ; Menges, ES ; Nelson, HN ; Hines, JH ( January 2019 , Annual meeting of the Society for Neuroscience)

   Oligodendrocytes (OLs), the myelinating cell type of the CNS, interact with a plethora of diverse neuronal subtypes but only wrap a select subset with myelin sheaths. Prior to initiating axon wrapping, OLs dynamically extend and retract membrane processes in order to contact and sample numerous axons. Whether neural activity-dependent mechanisms regulate exploratory axon sampling, target axon recognition, and stabilization of OL-axon interactions prior to initial axon wrapping is unknown. To test this, we directly observed interactions between pre-myelinating OL processes and individually labeled target axons in larval zebrafish using time-lapse confocal microscopy. In control larvae anesthetized with the neuromuscular blockermore »pancuronium bromide, we observed dynamic axon sampling characterized by frequent formation and turnover of OL-axon interactions. In contrast, treatment with the neural activity blocker tricaine methanesulfonate (MS-222) caused reduced frequency of new interaction formation, increased interaction duration, and reduced frequency of interaction retraction. Time-lapse imaging revealed differential effects on OL-axon interactions at axon varicosities and thin, intervening segments. Specifically, the destabilizing effects of neural activity on OL-axon interactions were heightened at axon varicosities. MS-222 increased contact durations at varicosities but not at neighboring intervening segments. Neural activity manipulations also influenced the dynamics of axon varicosity formation, lifetime, and turnover, raising the possibility that changes to axon morphology or local properties could direct OL-axon interactions and subsequent myelination. Taken together, we conclude that neural activity negatively regulates the duration of OL-axon interactions prior to initial axon wrapping and myelination. These findings support a mechanism whereby neural activity plays opposing roles on OL-axon interactions before and after initial myelin ensheathment. Prior to ensheathment, neural activity destabilizes interactions, which may serve to facilitate increased overall sampling of potential wrapping sites. After successful ensheathment, neural activity stabilizes OL-axon adhesion in order to promote continued growth and maturation of the myelin sheath. Current and future studies aim to understand the reciprocal effects between OL processes and axon morphology, and the effects of synaptic vesicle release during initial OL-axon interactions.« less
2. Axon determination of subtype specific myelin ensheathment and pruning

   Nelson, HN ; Treichel, AJ ; Eggum, EN ; Martell, MR ; Kaiser, AJ ; Trudel, AG ; Gronseth, JR ; Maas, ST ; Bergen, S ; Hines, JH ( January 2019 , Annual meeting of the Society for Neuroscience)

   In the developing central nervous system, pre-myelinating oligodendrocytes contact and sample candidate nerve axons by extending and retracting process extensions. Some contacts stabilize and mature, leading to the initiation of axon wrapping, myelin sheath formation, and sheath elongation by oligodendrocytes. Although axonal signals influence the overall process of myelination, which precise steps and oligodendrocyte cell behaviors require signaling from axons is incompletely understood. In this study, we investigated whether cell behaviors during the early events of myelination involve input from axons or are mediated by an oligodendrocyte-autonomous myelination program. To address this, we utilized in vivo time-lapse imaging in embryonicmore »and larval zebrafish during the initial hours and days of axon wrapping and myelination. Transgenic reporter lines marked individual axon subtypes or oligodendrocyte membranes. In the larval zebrafish spinal cord, individual axon subtypes supported distinct nascent sheath growth rates and pruning frequencies. Oligodendrocytes ensheathed individual axon subtypes at different rates during a two-day period after initial axon wrapping. When the ratio of oligodendrocytes to target axons was increased by ablating spinal projection axons, local spinal neuron axons supported a constant ensheathment rate despite the increased ratio of oligodendrocytes to target axons. We conclude that properties of individual axon subtypes instruct oligodendrocyte behaviors during initial stages of myelination by differentially controlling nascent sheath growth and stabilization.« less
3. Individual neuronal subtypes control initial myelin sheath growth and stabilization

   https://doi.org/10.1186/s13064-020-00149-3  

   Nelson, Heather N. ; Treichel, Anthony J. ; Eggum, Erin N. ; Martell, Madeline R. ; Kaiser, Amanda J. ; Trudel, Allie G. ; Gronseth, James R. ; Maas, Samantha T. ; Bergen, Silas ; Hines, Jacob H. ( December 2020 , Neural Development)

   Abstract Background In the developing central nervous system, pre-myelinating oligodendrocytes sample candidate nerve axons by extending and retracting process extensions. Some contacts stabilize, leading to the initiation of axon wrapping, nascent myelin sheath formation, concentric wrapping and sheath elongation, and sheath stabilization or pruning by oligodendrocytes. Although axonal signals influence the overall process of myelination, the precise oligodendrocyte behaviors that require signaling from axons are not completely understood. In this study, we investigated whether oligodendrocyte behaviors during the early events of myelination are mediated by an oligodendrocyte-intrinsic myelination program or are over-ridden by axonal factors. Methods To address this, wemore »utilized in vivo time-lapse imaging in embryonic and larval zebrafish spinal cord during the initial hours and days of axon wrapping and myelination. Transgenic reporter lines marked individual axon subtypes or oligodendrocyte membranes. Results In the larval zebrafish spinal cord, individual axon subtypes supported distinct nascent sheath growth rates and stabilization frequencies. Oligodendrocytes ensheathed individual axon subtypes at different rates during a two-day period after initial axon wrapping. When descending reticulospinal axons were ablated, local spinal axons supported a constant ensheathment rate despite the increased ratio of oligodendrocytes to target axons. Conclusion We conclude that properties of individual axon subtypes instruct oligodendrocyte behaviors during initial stages of myelination by differentially controlling nascent sheath growth and stabilization.« less
4. Numerical Simulation of Stress States in White Matter via a Continuum Model of 3D Axons Tethered to Glia

   https://doi.org/10.1115/IMECE2020-24667  

   Pasupathy, Parameshwaran ; De Simone, Robert ; Pelegri, Assimina A. ( November 2020 , International Mechanical Engineering Congress and Exposition, IMECE 2020)

   A new finite element approach is proposed to study the propagation of stress in axons in the central nervous system (CNS) white matter. The axons are embedded in an extra cellular matrix (ECM) and are subjected to tensile loads under purely non-affine kinematic boundary conditions. The axons and the ECM are described by the Ogden hyperelastic material model. The effect of tethering of the axons by oligodendrocytes is investigated using the finite element model. Glial cells are often thought of as the “glue” that hold the axons together. More specifically, oligodendrocytes bond multiple axons to each other and create amore »myelin sheath that insulates and supports axons in the brainstem. The glial cells create a scaffold that supports the axons and can potentially bind 80 axons to a single oligodendrocyte.

   In this study, the microstructure of the oligodendrocyte connections to axons is modeled using a spring-dashpot approximation. The model allows for the oligodendrocytes to wrap around the outer diameter of the axons at various locations, parameterizing the number of connections, distance between connection points, and the stiffness of the connection hubs. The parameterization followed the distribution of axon-oligodendrocyte connections provided by literature data in which the values were acquired through microtome of CNS white matter. We develop two models: 1) multiple oligodendrocytes arbitrarily tethered to the nearest axons, and 2) a single oligodendrocyte tethered to all the axons at various locations. The results depict stiffening of the axons, which indicates that the oligodendrocytes do aid in the redistribution of stress. We also observe the appearance of bending stresses at inflections points along the tortuous path of the axons when subjected to tensile loading. The bending stresses appear to exhibit a cyclic variation along the length of the undulated axons. This makes the axons more susceptible to damage accumulation and fatigue. Finally, the effect of multiple axon-myelin connections in the central nervous system and the effect of the distribution of these connections in the brain tissue is further investigated at present.« less
5. Sensitivity analysis of effective transverse shear viscoelastic and diffusional properties of myelinated white matter

   https://doi.org/10.1088/1361-6560/aba0cc  

   Sullivan, Daniel ; Wu, Xuehai ; Gallo, Nicolas R ; Naughton, Noel Martin ; Georgiadis, John G ; Pelegri, Assimina A ( June 2020 , Physics in Medicine & Biology)

   Motivated by the need to interpret the results from a combined use of in vivo brain Magnetic Resonance Elastography (MRE) and Diffusion Tensor Imaging (DTI), we developed a computational framework to study the sensitivity of single-frequency MRE and DTI metrics to white matter microstructure and cell-level mechanical and diffusional properties. White matter was modeled as a triphasic unidirectional composite, consisting of parallel cylindrical inclusions (axons) surrounded by sheaths (myelin), and embedded in a matrix (glial cells plus extracellular matrix). Only 2D mechanics and diffusion in the transverse plane (perpendicular to the axon direction) was considered, and homogenized (effective) properties weremore »derived for a periodic domain containing a single axon. The numerical solutions of the MRE problem were performed with ABAQUS and by employing a sophisticated boundary-conforming grid generation scheme. Based on the linear viscoelastic response to harmonic shear excitation and steady-state diffusion in the transverse plane, a systematic sensitivity analysis of MRE metrics (effective transverse shear storage and loss moduli) and DTI metric (effective radial diffusivity) was performed for a wide range of microstructural and intrinsic (phase-based) physical properties. The microstructural properties considered were fiber volume fraction, and the myelin sheath/axon diameter ratio. The MRE and DTI metrics are very sensitive to the fiber volume fraction, and the intrinsic viscoelastic moduli of the glia phase. The MRE metrics are nonlinear functions of the fiber volume fraction, but the effective diffusion coefficient varies linearly with it. Finally, the transverse metrics of both MRE and DTI are insensitive to the axon diameter in steady state. Our results are consistent with the limited anisotropic MRE and co-registered DTI measurements, mainly in the corpus callosum, available in the literature. We conclude that isotropic MRE and DTI constitutive models are good approximations for myelinated white matter in the transverse plane. The unidirectional composite model presented here is used for the first time to model harmonic shear stress under MRE-relevant frequency on the cell-level. This model can be extended to 3D in order to inform the solution of the inverse problem in MRE, establish the biological basis of MRE metrics, and integrate MRE/DTI with other modalities towards increasing the specificity of neuroimaging.« less