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"... The team ... created localised damage to myelin – the main component of white matter – in a well-defined brain circuit and followed what happened over time. They found that small, localised myelin damage triggered a striking response in a connected, remote grey matter region. Neuronal activity fell, microglia – the brain’s immune cells – became activated, and connections between neurons were lost.
Crucially, these changes were not permanent. After myelin was regenerated, neuronal activity recovered, connections between neurons returned, and the inflammatory response subsided.
The study also challenges a common assumption about brain inflammation. Grey matter inflammation is traditionally viewed as harmful. But here, the team found that this transient response was part of the repair process itself. When they prevented grey matter inflammation, myelin regeneration was impaired.
Conversely, when the team blocked myelin regeneration, the grey matter response did not resolve and instead became chronic. This suggests that failed myelin regeneration may help drive the persistent low-grade inflammation seen in neurodegenerative disease. ..."
"Focal white matter lesions occur in most neurodegenerative disorders. Despite occurring early in disease, white matter lesions are considered to be independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity. Notably, their functional effect on neuronal circuits remains understudied.
To address this, we generated a focal white matter lesion in the rat brain within a clinically relevant, anatomically well-defined circuit, in which these lesions occur in many neurodegenerative disorders.
Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglial engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered to be detrimental; however, we show that it is an integral part of regeneration and is conserved across three distinct mouse circuits and lesioning methods.
Preventing these transient changes in the grey matter blocks myelin regeneration in the white matter.
Conversely, inducing myelin regeneration failure leads to chronic grey matter neuroinflammation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration.
Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function, which may underlie multiple neurodegenerative conditions, and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation."
Fig. 3: Focal white matter lesions evoke changes in microglial states and neuronal mitochondria.
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