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Myelination in the auditory brainstem
Myelination in the auditory brainstem
The evolution of myelin was a major key event in vertebrates which aimed to enhance conduction velocity of electrical impulses in axons. Distinct myelination patterns along axons can shape the speed and timing of action potentials. Exact arrival time of inputs at target neurons are crucial for proper neural circuit function. Two key determinants for tuning conduction velocity of myelinated axons are the length of individual myelin sheaths together with the axon diameter. However, it remains unanswered who determines specific myelination patterns along axons – the oligodendrocyte or the axon? And further, when and how do structural parameters of myelinated axons develop in neural circuits in general, in terms of their functionally relevant myelination patterns, axonal morphology and nodes of Ranvier? A system with highest temporal demands is the mammalian sound localization system. Globular bushy cell (GBC) axons involved in circuits processing sound location information are some of the fastest and most precise conducting axons in the mammalian central nervous system. In the Mongolian gerbil (Meriones unguiculatus) GBCs that are tuned to low sound frequencies transmit sound signals to the binaural comparator neurons in the medial superior olive (MSO) where the arrival time of sound at the two ears (interaural time differences; ITDs) is computed. These differences can be as low as only a few microseconds and thus, computation of ITDs relies on explicitly fast and highly precise axons. To cope with the need for exact input timing, low-frequency GBC axons exhibit specific structural adaptations to adjust conduction velocity. Their exceptional thick axons combined with comparably short internodes result in unusual low ratios of internode length to axon diameter (L/d ratios) which in turn increase the conduction velocity along their axons. To gain insight into when and how the specific myelin sheath lengths, axon diameter and thus L/d ratios are established, we characterized the developmental time course of these structural parameters at timepoints before and after the onset of hearing. Our findings show the internode length is set prior to a significant axon diameter increase. While the internode length is established already two days before hearing onset, which is at P12, the axon diameter only increases five days after hearing onset, and thereby decreasing its L/d ratio. This strongly suggests that, at least in GBCs, the axon itself is the key determinant in ensuring that the required conduction velocity is met by adjusting its diameter retrospectively. Together with the length of myelin sheaths and the axon diameter, nodes of Ranvier are critical determinants of action potential speed and timing of and therefore the development of all these structures must be tightly regulated. By assessing the development of nodes of Ranvier we found that axon and node morphology by and large mature synchronously. Early nodal clusters appear already when myelination of GBC axons is initiated at P6/P7 and these premature clusters subsequently progress until reaching maturity during the 4th postnatal week. Interestingly, we were able to show that node maturation depends on the location along the axon with nodes closer to the cell body develop earlier compared to nodes close to the synaptic terminal.
Myelinaton, Auditory Brainstem, Node of Ranvier, Globular Bushy Cells, Development, MSO, SOC
Nabel, Alisha
2021
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Nabel, Alisha (2021): Myelination in the auditory brainstem. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)
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Abstract

The evolution of myelin was a major key event in vertebrates which aimed to enhance conduction velocity of electrical impulses in axons. Distinct myelination patterns along axons can shape the speed and timing of action potentials. Exact arrival time of inputs at target neurons are crucial for proper neural circuit function. Two key determinants for tuning conduction velocity of myelinated axons are the length of individual myelin sheaths together with the axon diameter. However, it remains unanswered who determines specific myelination patterns along axons – the oligodendrocyte or the axon? And further, when and how do structural parameters of myelinated axons develop in neural circuits in general, in terms of their functionally relevant myelination patterns, axonal morphology and nodes of Ranvier? A system with highest temporal demands is the mammalian sound localization system. Globular bushy cell (GBC) axons involved in circuits processing sound location information are some of the fastest and most precise conducting axons in the mammalian central nervous system. In the Mongolian gerbil (Meriones unguiculatus) GBCs that are tuned to low sound frequencies transmit sound signals to the binaural comparator neurons in the medial superior olive (MSO) where the arrival time of sound at the two ears (interaural time differences; ITDs) is computed. These differences can be as low as only a few microseconds and thus, computation of ITDs relies on explicitly fast and highly precise axons. To cope with the need for exact input timing, low-frequency GBC axons exhibit specific structural adaptations to adjust conduction velocity. Their exceptional thick axons combined with comparably short internodes result in unusual low ratios of internode length to axon diameter (L/d ratios) which in turn increase the conduction velocity along their axons. To gain insight into when and how the specific myelin sheath lengths, axon diameter and thus L/d ratios are established, we characterized the developmental time course of these structural parameters at timepoints before and after the onset of hearing. Our findings show the internode length is set prior to a significant axon diameter increase. While the internode length is established already two days before hearing onset, which is at P12, the axon diameter only increases five days after hearing onset, and thereby decreasing its L/d ratio. This strongly suggests that, at least in GBCs, the axon itself is the key determinant in ensuring that the required conduction velocity is met by adjusting its diameter retrospectively. Together with the length of myelin sheaths and the axon diameter, nodes of Ranvier are critical determinants of action potential speed and timing of and therefore the development of all these structures must be tightly regulated. By assessing the development of nodes of Ranvier we found that axon and node morphology by and large mature synchronously. Early nodal clusters appear already when myelination of GBC axons is initiated at P6/P7 and these premature clusters subsequently progress until reaching maturity during the 4th postnatal week. Interestingly, we were able to show that node maturation depends on the location along the axon with nodes closer to the cell body develop earlier compared to nodes close to the synaptic terminal.