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1. 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)

   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. 

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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 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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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. Evolutionary Origins of the Oligodendrocyte Cell Type and Adaptive Myelination

   https://doi.org/10.3389/fnins.2021.757360  

   Hines, Jacob H. (December 2021, Frontiers in Neuroscience)

   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. 

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