Numerical simulations using non-linear hyper-elastic material models to describe interactions between brain white matter (axons and extra cellular matrix (ECM)) have enabled high-fidelity characterization of stress-strain response. In this paper, a novel finite element model (FEM) has been developed to study mechanical response of axons embedded in ECM when subjected to tensile loads under purely non-affine kinematic boundary conditions. FEM leveraging Ogden hyper-elastic material model is deployed to understand impact of parametrically varying oligodendrocyte-axon tethering and analyze influence of aging material characteristics on stress propagation. In proposed FEM, oligodendrocyte connections to axons are represented via spring-dashpot model, such tethering technique facilitates contact definition at various locations, parameterize connection points and vary stiffness of connection hubs. Two FE submodels are discussed: 1) multiple oligodendrocytes arbitrarily tethered to the nearest axons, and 2) single oligodendrocyte tethered to all axons at various locations. Root mean square deviation (RMSD) were computed between stress-strain plots to depict trends in mechanical response. Axonal stiffness was found to rise with increasing tethering, indicating role of oligodendrocytes in stress redistribution. Finally, stress state results for aging axon material, with varying stiffnesses and number of connections in FEM ensemble have also been discussed to demonstrate gradual softening of tissues.
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.
more » « less- Award ID(s):
- 1763005
- NSF-PAR ID:
- 10311771
- Date Published:
- Journal Name:
- International Mechanical Engineering Congress and Exposition, IMECE 2020
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract A novel finite element method (FEM) is developed to study mechanical response of axons embedded in extra cellular matrix (ECM) when subjected to harmonic uniaxial stretch under purely non-affine kinematic boundary conditions. The proposed modeling approach combines hyper-elastic (such as Ogden model) and time/frequency domain viscoelastic constitutive models to evaluate the effect of parametrically varying oligodendrocyte-axon tethering under harmonic stretch at 50Hz. A hybrid hyper-viscoelastic material (HVE) model enabled the analysis of repeated uniaxial load on stress propagation and damage accumulation in white matter.
In the proposed FEM, oligodendrocyte connections to axons are depicted via a spring-dashpot model. This tethering technique facilitates contact definition at various locations, parameterizes connection points and varies stiffness of connection hubs. Results from a home-grown FE submodel configuration of a single oligodendrocyte tethered to axons at various locations are presented. Root mean square deviation (RMSD) are computed between stress-strain plots to depict trends in mechanical response. Steady-state dynamic (SSD) simulations show stress relaxation in axons. Gradual axonal softening under repetitive loads is illustrated employing Prony series - HVE models. Representative von-Mises stress plots indicate that undulated axons experience bending stresses along their tortuous path, suggesting greater susceptibility to damage accumulation and fatigue failure due to repeated strains.
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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 embryonic 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.more » « less
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null (Ed.)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, we 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.more » « less
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Oligodendrocytes are multifunctional central nervous system (CNS) glia that are essential for neural function in gnathostomes. The evolutionary origins and specializations of the oligodendrocyte cell type are among the many remaining mysteries in glial biology and neuroscience. The role of oligodendrocytes as CNS myelinating glia is well established, but recent studies demonstrate that oligodendrocytes also participate in several myelin-independent aspects of CNS development, function, and maintenance. Furthermore, many recent studies have collectively advanced our understanding of myelin plasticity, and it is now clear that experience-dependent adaptations to myelination are an additional form of neural plasticity. These observations beg the questions of when and for which functions the ancestral oligodendrocyte cell type emerged, when primitive oligodendrocytes evolved new functionalities, and the genetic changes responsible for these evolutionary innovations. Here, I review recent findings and propose working models addressing the origins and evolution of the oligodendrocyte cell type and adaptive myelination. The core gene regulatory network (GRN) specifying the oligodendrocyte cell type is also reviewed as a means to probe the existence of oligodendrocytes in basal vertebrates and chordate invertebrates.more » « less
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Accepted Manuscript1.0
- Conference Paper:
- https://doi.org/10.1115/IMECE2020-24667
