Investigating the formation and remodelling of myelinated axons in vivo
View/ Open
Date
22/01/2020Author
Williamson, Jill M.
Metadata
Abstract
Myelin is a crucial component of the vertebrate nervous system, both in facilitating
rapid conduction of action potentials and in metabolically supporting axons. Recent
research has theorised that myelin sheaths play a more intricate role in nervous
system function by regulating circuits in response to experience. The number, length,
thickness, and distribution of myelin sheaths along an axon all influence its underlying
conduction properties. Thus, establishing or changing particular myelin patterns along
axons could refine the precise timing of signals to change circuit outputs. Yet, how
the myelin patterns along single axons are established, how myelin is remodelled over
time, and how neuronal activity affects these processes, is not yet fully understood. I
sought to investigate how myelin is formed, remodelled and maintained over time
along individual axons in the larval zebrafish central nervous system.
I first characterised the formation of myelin patterns along two different subtypes of
axon in the larval zebrafish spinal cord. Using transgenic tools and confocal
microscopy, I performed live imaging of single axons over a period of time during
developmental myelination. Reticulospinal (RS) axons are involved in locomotor
circuits, and are myelinated in a synaptic vesicle release-dependent manner;
whereas, Commissural Primary Ascending (CoPA) axons are involved in sensory
processing circuits, and are myelinated in a synaptic vesicle release-independent
manner. I hypothesised that myelin patterns along axons are formed in a circuit-dependent
fashion, and, therefore, that axons from different circuits would exhibit
different myelin patterns. However, I found that both RS and CoPA axons have very
similar myelin patterns, in terms of their myelin sheath number, length, myelin
coverage, and nodal gap length, and that these patterns are established within a
defined time window after the onset of myelination.
I, then, assessed how myelin sheaths are remodelled along RS and CoPA axons over
time, and found that myelin sheaths could either grow or shrink in length, or could be
fully retracted from the axon itself. I hypothesised that myelin remodelling would occur
along axons which use activity-related signals to regulate their myelination, and
therefore, that RS axons would exhibit more myelin remodelling than CoPA axons.
However, I found that RS and CoPA axons exhibited very similar degrees of myelin
remodelling.
Finally, I used a chemogenetic tool and live imaging by confocal microscopy to
investigate how increasing activity in individual RS axons affects the dynamics of
myelin sheath growth and the formation of myelin patterns. I found that increasing
neuronal activity promotes the early growth of myelin sheaths within a critical period;
after this period, neuronal activity no longer affects myelin sheath dynamics along RS
axons. By promoting this early sheath growth, activity can change the myelin pattern
established along individual RS axons.
Collectively, this research begins to elucidate how individual myelinated axons are
formed and maintained during nervous system development, and the cellular
mechanisms by which neuronal activity may regulate this process.
Related items
Showing items related by title, author, creator and subject.
-
Microglia regulate myelin growth and integrity in the central nervous system white matter
McNamara, Niamh (The University of Edinburgh, 2023-01-30)Disruption of myelin structure occurs with ageing and neurodegenerative disease, and involves myelin which is outfolding, unravelling, less compact, and thicker. This is associated with nerve dysfunction and cognitive ... -
Development of a human pluripotent stem cell-derived in vitro model of myelination
James, Owen Gwydion (The University of Edinburgh, 2020-11-30)Myelination is essential for central nervous system (CNS) formation, health, and function. Its development is an adaptive and regulated process that, when perturbed, leads to disease. However, our understanding of ... -
Exploring the role of central nervous system myelination in circuit function and behaviour
Madden, Megan Elizabeth (The University of Edinburgh, 2020-08-07)Activity-mediated myelination, the adjustment of myelin morphology in response to neuronal activity, has been proposed as a novel mechanism of central nervous system (CNS) plasticity. As a key regulator of conduction ...