Half of the human brain is white matter. Its function relies on oligodendrocytes producing myelin sheaths that are essential for neuronal communication, cognitive function, and motor performance. Throughout life, oligodendrocyte precursor cells (OPCs) differentiate into myelin-forming oligodendrocytes and represent the primary proliferative cells in the adult brain. OPCs can sense neuronal activity through synaptic inputs, voltage-gated ion channels, and neurotransmitter receptors, and they differentiate into myelinating oligodendrocytes in response to changes in neuronal activity—a mechanism increasingly recognised for learning and adaptation.

Whilst myelin’s importance is well-established in demyelinating diseases like multiple sclerosis, emerging evidence suggests its critical role in conditions traditionally viewed as neuronal disorders, including dementia. However, with normal ageing, myelin maintenance and regeneration decline, with the primary cause of regenerative failure being the inability of OPCs to differentiate into new myelinating oligodendrocytes.  With age focal white matter lesions, characterised by oligodendrocyte loss and myelin damage, accumulate and the number correlate with cognitive decline. Focal white matter lesions are prevalent across neurodegenerative conditions, yet their mechanistic relationship to grey matter pathology remains poorly understood.

Using an anatomically well-defined circuit model, we demonstrate that focal white matter lesions trigger a cascade of events beginning with transient neuronal activity changes and microgliosis. This is followed by synapse loss and increased microglial engulfment in grey matter regions, which can be reversed upon successful myelin regeneration.

Critically, we show that grey matter microgliosis, often considered pathological, is in fact integral to the myelin regenerative process. Experimental prevention of these transient grey matter changes blocks white matter myelin regeneration, whilst myelin regeneration failure results in chronic grey matter neuroinflammation. These findings reveal a bidirectional relationship between white and grey matter pathology, suggesting that myelin regeneration failure may drive the sustained microglial activation characteristic of chronic neuroinflammation in neurodegenerative diseases. This novel mechanism provides a potential unifying framework for understanding multiple neurodegenerative conditions and highlights myelin regeneration as a promising therapeutic target for preventing chronic neuroinflammation.