Periodic Reporting for period 3 - MyelinPlasticity (Neuronal regulation of CNS myelin plasticity)
Okres sprawozdawczy: 2021-06-01 do 2022-11-30
Myelin is essential for normal brain function, as it provides fast signal transmission, promotes synchronisation of neuronal signals and helps to maintain neuronal function. Alterations in myelination are increasingly being implicated as a mechanism for sensory-motor learning. The importance of myelin becomes evident in diseases, such as multiple sclerosis (MS), where myelin damage causes cognitive and motor disability. Moreover, recent studies have highlighted the contribution of myelin to many diseases that were previously considered to be ‘neuronal’, such as dementia, schizophrenia, autism and bipolar disorder. Despite the profound importance of myelin, there are serious deficits in our understanding of how myelination is regulated and to what extent myelin is plastic; which are impediments for understanding both the functional connectivity of the central nervous system (CNS) and white matter disease.
We, and others, have shown that oligodendrocyte precursor cells (OPCs), which differentiate into myelinating oligodendrocytes, receive synaptic input from axons, express glutamate receptors and that neuronal activity can regulate myelination by activating glutamate receptors. Thus, I hypothesise that neuronal activity is a driver for myelin plasticity, just as it drives synaptic plasticity. The aim of this work is to determine how, and to what extent, changes in neuronal activity regulate myelin formation on unmyelinated axons, and myelin changes on already myelinated axonal tract.
To test our hypothesis we have now set up an innovative approach combining electrophysiology, optogenetics, pharmacogenetics, imaging, transgenic animals, behavioural tests, and in vitro and in vivo models of myelination.
The overall objectives of this project are divided into three main questions:
(1) How does action potential frequency regulate myelination?
(2) Do myelin changes occur with non-motor learning?
(3) Is myelination bidirectionally regulated by neuronal activity?
The outcome of this proposal will break new ground in our understanding of myelin plasticity, and has the potential to provide novel therapeutic strategies for myelin regeneration in white matter diseases such as MS.
We, and others, have shown that oligodendrocyte precursor cells (OPCs), which differentiate into myelinating oligodendrocytes, receive synaptic input from axons, express glutamate receptors and that neuronal activity can regulate myelination by activating glutamate receptors. Thus, I hypothesise that neuronal activity is a driver for myelin plasticity, just as it drives synaptic plasticity. The aim of this work is to determine how, and to what extent, changes in neuronal activity regulate myelin formation on unmyelinated axons, and myelin changes on already myelinated axonal tract.
To test our hypothesis we have now set up an innovative approach combining electrophysiology, optogenetics, pharmacogenetics, imaging, transgenic animals, behavioural tests, and in vitro and in vivo models of myelination.
The overall objectives of this project are divided into three main questions:
(1) How does action potential frequency regulate myelination?
(2) Do myelin changes occur with non-motor learning?
(3) Is myelination bidirectionally regulated by neuronal activity?
The outcome of this proposal will break new ground in our understanding of myelin plasticity, and has the potential to provide novel therapeutic strategies for myelin regeneration in white matter diseases such as MS.
The overall aim of this project is to determine how neuronal activity influences myelination and to what extent myelin plasticity occurs.
The relocation of our Institute and subsequent COVID-19 related restrictions have had a severe negative impact on the progress of this work. Nevertheless, we have made reasonable progress towards our overall aims. Here below, I list our main achievements to date:
List of main results in the first 30 months of this project
(1) We identified that oligodendrocyte precursor cells become heterogenous with age and differ in properties between brain regions. This heterogeneity will alter the way the cells respond to neuronal activity (Spitzer et al, Neuron 2019).
(2) We have identified that the acquisition of cognitive strategy necessary to solve a complex working memory task - Trial-Unique Non-matching to Location (TUNL) is associated with an increase in myelination in the brain structures that are necessary to solve the task. Moreover, we have found that developing cognitive strategies to solve the task depends on new myelination. We included in our experiments a new mouse model where we can prevent the formation of new myelin, and we find that these mice do not learn the task, whereas they can perform normal motor sensory tasks. We have now extended this work to trace neuronal axons to determine the underlying neuronal circuit involved, and to include magnetic resonance imaging, to determine how specific myelination is to the areas involved, alongside further controls for the behavioural tasks. We aim to submit this work for publication in 2021.
(3) We have set up electroretinogram (ERG) to record neuronal activity in retinal ganglion cells, and recorded a dose response curve for CNO, clozapine and identified the dose that provides maximum control of neuronal activity without affecting other aspects of the ERG. We have further tested at this dose the effect of altering neuronal activity in the retinal ganglion cells. Using our new mouse models where we can label either newly formed or existing myelinating cells, we now have exciting data that indicate that myelination is bidirectionally regulated by activity after developmental myelination is completed, and that neuronal firing rate seems to regulate internodal lengths. We are currently completing the analysis of this work and preparing it for publication.
(4) We have established new methods of analysis and data acquisition, focused on artificial intelligence and automated image capture, for higher throughput and an unbiased approach.
The relocation of our Institute and subsequent COVID-19 related restrictions have had a severe negative impact on the progress of this work. Nevertheless, we have made reasonable progress towards our overall aims. Here below, I list our main achievements to date:
List of main results in the first 30 months of this project
(1) We identified that oligodendrocyte precursor cells become heterogenous with age and differ in properties between brain regions. This heterogeneity will alter the way the cells respond to neuronal activity (Spitzer et al, Neuron 2019).
(2) We have identified that the acquisition of cognitive strategy necessary to solve a complex working memory task - Trial-Unique Non-matching to Location (TUNL) is associated with an increase in myelination in the brain structures that are necessary to solve the task. Moreover, we have found that developing cognitive strategies to solve the task depends on new myelination. We included in our experiments a new mouse model where we can prevent the formation of new myelin, and we find that these mice do not learn the task, whereas they can perform normal motor sensory tasks. We have now extended this work to trace neuronal axons to determine the underlying neuronal circuit involved, and to include magnetic resonance imaging, to determine how specific myelination is to the areas involved, alongside further controls for the behavioural tasks. We aim to submit this work for publication in 2021.
(3) We have set up electroretinogram (ERG) to record neuronal activity in retinal ganglion cells, and recorded a dose response curve for CNO, clozapine and identified the dose that provides maximum control of neuronal activity without affecting other aspects of the ERG. We have further tested at this dose the effect of altering neuronal activity in the retinal ganglion cells. Using our new mouse models where we can label either newly formed or existing myelinating cells, we now have exciting data that indicate that myelination is bidirectionally regulated by activity after developmental myelination is completed, and that neuronal firing rate seems to regulate internodal lengths. We are currently completing the analysis of this work and preparing it for publication.
(4) We have established new methods of analysis and data acquisition, focused on artificial intelligence and automated image capture, for higher throughput and an unbiased approach.
This project is already extended beyond the state-of-the-art in its investigation of myelin plasticity and the mechanisms of how neuronal activity regulates oligodendrocyte precursor cell differentiation and myelination.
For the remainder of the project, we will continue with our experimental work as set out in the original proposal to determine the mechanisms and extent of myelin plasticity. This project will clarify to what extent myelin plasticity occurs and highlight the underlying mechanisms, and thus will deliver novel concepts to fundamental neuroscience. Given the importance of myelin regeneration in white matter diseases, understanding how new myelin is formed in the adult will have direct relevance to therapeutically improving myelin regeneration in the adult, and thus may influence therapeutic strategies for diseases like multiple sclerosis.
For the remainder of the project, we will continue with our experimental work as set out in the original proposal to determine the mechanisms and extent of myelin plasticity. This project will clarify to what extent myelin plasticity occurs and highlight the underlying mechanisms, and thus will deliver novel concepts to fundamental neuroscience. Given the importance of myelin regeneration in white matter diseases, understanding how new myelin is formed in the adult will have direct relevance to therapeutically improving myelin regeneration in the adult, and thus may influence therapeutic strategies for diseases like multiple sclerosis.