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1. 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 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. 

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2. Synaptic vesicle release regulates pre-myelinating oligodendrocyte-axon interactions in a neuron subtype-specific manner

   https://doi.org/10.3389/fncel.2024.1386352  

   Gronseth, James R; Nelson, Heather N; Johnson, Taylor L; Mallon, Taryn A; Martell, Madeline R; Pfaffenbach, Katrina A; Duxbury, Bailey B; Henke, John T; Treichel, Anthony J; Hines, Jacob H (May 2024, Frontiers in Cellular Neuroscience)

   Miyata, Shingo (Ed.)

   Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron–glia interactions involves synaptic vesicle release. In this study, we used fluorescent reporters in the larval zebrafish model to track pre-myelinating oligodendrocyte process extensions interacting with spinal axons utilizingin vivoimaging. Monitoring motile oligodendrocyte processes and their interactions with individually labeled axons revealed that synaptic vesicle release regulates the behavior of subsets of process extensions. Specifically, blocking synaptic vesicle release decreased the longevity of oligodendrocyte process extensions interacting with reticulospinal axons. Furthermore, blocking synaptic vesicle release increased the frequency that new interactions formed and retracted. In contrast, tracking the movements of all process extensions of singly-labeled oligodendrocytes revealed that synaptic vesicle release does not regulate overall process motility or exploratory behavior. Blocking synaptic vesicle release influenced the density of oligodendrocyte process extensions interacting with reticulospinal and serotonergic axons, but not commissural interneuron or dopaminergic axons. Taken together, these data indicate that alterations to synaptic vesicle release cause changes to oligodendrocyte-axon interactions that are neuron subtype-specific. 

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3. 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 blocker 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. 

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4. Developmental exposure to domoic acid targets reticulospinal neurons and leads to aberrant myelination in the spinal cord

   https://doi.org/10.1038/s41598-023-28166-2  

   Panlilio, Jennifer M.; Hammar, Katherine M.; Aluru, Neelakanteswar; Hahn, Mark E. (December 2023, Scientific Reports)

   Abstract Harmful algal blooms (HABs) produce neurotoxins that affect human health. Developmental exposure of zebrafish embryos to the HAB toxin domoic acid (DomA) causes myelin defects, loss of reticulospinal neurons, and behavioral deficits. However, it is unclear whether DomA primarily targets myelin sheaths, leading to the loss of reticulospinal neurons, or reticulospinal neurons, causing myelin defects. Here, we show that while exposure to DomA at 2 dpf did not reduce the number of oligodendrocyte precursors prior to myelination, it led to fewer myelinating oligodendrocytes that produced shorter myelin sheaths and aberrantly wrapped neuron cell bodies. DomA-exposed larvae lacked Mauthner neurons prior to the onset of myelination, suggesting that axonal loss is not secondary to myelin defects. The loss of the axonal targets may have led oligodendrocytes to inappropriately myelinate neuronal cell bodies. Consistent with this, GANT61, a GLI1/2 inhibitor that reduces oligodendrocyte number, caused a reduction in aberrantly myelinated neuron cell bodies in DomA-exposed fish. Together, these results suggest that DomA initially alters reticulospinal neurons and the loss of axons causes aberrant myelination of nearby cell bodies. The identification of initial targets and perturbed cellular processes provides a mechanistic understanding of how DomA alters neurodevelopment, leading to structural and behavioral phenotypes. 

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5. 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 a 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. 

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