How does neuronal activity regulate central nervous system myelination?

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Discovery Brain Sciences

Abstract

Approximately half of the volume of our brain and spinal cord, our central nervous system, is comprised of white matter. White matter is essential for normal brain formation, function and health, and damage to white matter causes the symptoms of many human diseases, such as multiple sclerosis, MS. The "white" in white matter refers to the presence of a fatty substance called myelin, which is made by specialized cells called oligodendrocytes, and which is wrapped around the nerve cables of our brain (called axons). The presence of myelin on axons insulates them and allows our neurons to rapidly transmit electrical impulses over long distances. Myelin also provides nutritional support to axons, essential for their health. Until recently it was though that myelin was a static structure, but in recent years it has become clear that myelin is made throughout our lives, and that it is dynamically regulated by brain activity, perhaps to optimize brain function and repair.
Humans make new myelin well into adult life, by the formation of new oligodendrocytes, and, likely, by remodeling of existing myelin. Very interestingly, studies in humans have shown that learning new tasks, e.g. juggling, can stimulate changes in our white matter and investigations in animal models have shown that the learning of new tasks in adulthood requires the formation of new myelin-producing oligodendrocytes. Importantly, the ability of our brain to make new myelin is also key to the regeneration that is observed following the loss of myelin in diseases such as MS. In line with a role for brain function in regulating myelination, own work has shown that the electrical activity of our brain cells stimulates myelin production by oligodendrocytes, and studies by our colleagues have shown that neuronal activity is required for normal myelin regeneration. However, many important questions remain: how do our brain cells tell our oligodendrocytes to promote myelination? Can stimulating brain activity promote regeneration of myelin?
We use zebrafish as an animal model to study myelination. Zebrafish produce embryos that are small, transparent, and develop very quickly, and we have made zebrafish where myelin and myelinated axons are fluorescently labelled. These properties of fish together with our tools means that we can directly visualize myelin as it is made, remodelled, and even regenerated over time. To study myelin regeneration (called remyelination), we have recently made a transgenic fish in which we can delete two-thirds of oligodendrocytes in a non-invasive manner, which leads to the loss of myelin (demyelination) from axons. Although the nervous system of both fish and man has the capacity to replace lost myelin through remyelination, this process is imperfect, and ultimately fails in diseases like MS. Therefore it is an important goal of medical research to find ways to promote our endogenous capacity for remyelination. The possibility to directly observe myelination and remyelination in a living animal is a great strength of the system and will be exploited through the work of this proposal.
The aim of this proposal is to use zebrafish to directly observe how myelin is made along axons over time in the normal animal, and to assess how this can be regulated by the electrical activity of neurons. We will carry out the first ever (to our knowledge) direct observations of remyelination of single axons over time in a living animal and investigate whether promoting brain function can enhance the regeneration of myelin. This work will provide much needed insight into how our brain builds and regenerates myelin and how brain activity could be manipulated to stimulate myelination in humans in the future.

Technical Summary

The myelination of central nervous system axons by oligodendrocytes is essential for nervous system formation and function. In addition to facilitating rapid nerve impulse conduction, it is now clear that myelin provides metabolic support to axons, and that myelin is an important regulator of learning and memory. Myelin is made well into adult life by newly differentiating oligodendrocytes and remodeling of existing myelin, and the ability to make new myelin is central to our nervous system's capacity to replace myelin lost in diseases such as multiple sclerosis. However, the regeneration of myelin by oligodendrocytes (remyelination) is imperfect and ultimately fails, and thus the promotion of endogenous remyelination is an important goal.
It is now clear that neuronal activity regulates myelination and remyelination in the CNS. Using zebrafish as a model, we have shown that activity-driven vesicular release from axons regulates the number and length of myelin sheaths made along single axons. In recent years we have generated a suite of transgenic reporters to directly observe many aspects of myelination in vivo over time, and methods to visualize and manipulate neuronal activity and vesicular release in the living animal. We have recently developed a transgenic system to non-invasively induce oligodendrocyte cell death and demyelination in zebrafish, a model in which we can use our transgenic reporters to visualize remyelination as it happens in vivo.
In this proposal we will use live imaging, transgenic manipulation of neuronal activity and genetic analyses to answer three key outstanding questions: 1, How dynamic is myelination along single axons over time and how are distinct stages of myelination regulated by vesicular release? 2, What are the molecular mechanisms by which vesicular release regulates myelination? 3, How does activity-driven vesicular release regulate remyelination? This work will provide insights into brain formation, function, and repair.

Planned Impact

Inspiring the next generation
We use zebrafish as a model to study nervous system formation, function and repair. Through this specific project we will train 1 PhD student, 1 MSc student, and 1-2 Honours level BSc students in the use of zebrafish as a model organism. We also hope to attract new trainees, who will be exposed to our work at scientific meetings and through publications.
We host practical demonstrations for BSc, MSc, and PhD students. The suitability of embryonic zebrafish for live imaging serves as a visually compelling teaching aid, and helps convey biologically complex events simply. This can serve as motivation for students to pursue challenging research projects.
I have also given talks on our work to groups of school children through association with Dr. David Colthurst and the Authentic Biology programme and I will give a public lecture as part of the "Let's talk about health" series that aims to inspire school leavers to enter the field of biomedical and biological research, and also educate the general public about health related research.

Public engagement
I am committed in promoting the understanding of research to the general public. Two of our recent publications have led to significant press coverage, being widely covered in the national media, and been featured in editorials in general interest journals. We work closely with the Edinburgh Research and Innovation Press Office in managing the balance between engaging the public and remaining faithful to the potential impact of our work. I have worked closely with journalists featuring our work and given interviews on national radio and with the UK Multiple Sclerosis society about our work.
I also work closely with the Multiple Sclerosis community through my association with the online group shift.ms. We have had numerous visitors to our laboratory from the shift.ms community, and my group has taken an active lead in a new scheme called "MS reporters," whereby someone with MS is assigned to a specific "expert" such as myself and works with a "buddy" to generate a series of filmed interviews where questions from the MS community are fielded to the expert. Five members of my group take part in this scheme, and I have given a series of interviews that are available on YouTube.
My laboratory trainees and I also regularly host visits to our centre by the general public, and take part in the Edinburgh Science festival. I have also recently developed a laboratory web page (www.lyons-lab.com) that I will expand and use to host data of interest to the wider community.

Potential commercial exploitation
The aim of this proposal is study how neuronal activity regulates myelination and remyelination in the living animal. This is a fundamental research proposal, and the likelihood of generating data for direct exploitation during the funding period is low. However, because of the conservation of molecular and cellular function between zebrafish and mammals we do hope to translate our findings in zebrafish to mammalian models and studies in human cells. We collaborate with Profs. Charles ffrench-Constant (Edinburgh), and Robin Franklin (Cambridge), both experts in the use of rodent models to study myelination and remyelination. We also collaborate with Prof. Siddharthan Chandran (Edinburgh), an expert in the use of human stem cells to study myelinating oligodendrocytes.
Of relevance to prospective translation opportunities, we have an ongoing collaboration with Biogen, a market leader in the development of therapies for the treatment of MS, on drug discovery projects that aim to identify compounds to promote remyelination. I was also a Co-I on a recent BBSRC ALERT 2014 award to establish a UK wide platform for chemical biology screens using zebrafish, for which we recently held a launch symposium of >100 delegates, including industry representatives interested in using our screening and imaging capacities for discovery projects in zebrafish.

Publications

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Allen NJ (2018) Glia as architects of central nervous system formation and function. in Science (New York, N.Y.)

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Almeida RG (2018) The Rules of Attraction in Central Nervous System Myelination. in Frontiers in cellular neuroscience

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Almeida RG (2017) On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function. in The Journal of neuroscience : the official journal of the Society for Neuroscience

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Williamson JM (2018) Myelin Dynamics Throughout Life: An Ever-Changing Landscape? in Frontiers in cellular neuroscience

 
Description Chan lab 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution Expertise in myelination, and use of zebrafish as model organism.
Collaborator Contribution Expertise in myelination and use of rodent models.
Impact Publication in Neuron. Publication in Current Biology.
Start Year 2015
 
Description Wyart lab 
Organisation Pitié-Salpêtrière Hospital
Country France 
Sector Hospitals 
PI Contribution Expertise in molecular genetic analyses of zebrafish.
Collaborator Contribution Expertise in functional analyses of neural circuits in zebrafish.
Impact Award of large European ITN grant (>€4M) for training cohort of PhD students.
Start Year 2011