Scientists have long known that myelin doesn’t appear everywhere in the brain at once. Some regions myelinate early, others much later, and the timing shapes everything from motor development to cognitive maturation. What has remained elusive is why these regional differences emerge in the first place. A new study in Nature Neuroscience, titled “Glucose-dependent spatial and temporal modulation of oligodendrocyte progenitor cell proliferation via ACLY-regulated histone acetylation,” points to an unexpected driver: shifting glucose levels that act as a metabolic switch, telling progenitor cells when to divide and when to mature into myelin‑forming oligodendrocytes.

The work, led by researchers at the Advanced Science Research Center at the CUNY Graduate Center (CUNY ASRC), maps glucose distribution across the developing mouse brain and reveals that these spatial and temporal fluctuations are not just metabolic background noise. They are instructive signals. “Regions with high glucose levels exhibited greater OPC proliferation and histone acetylation than regions with low glucose,” the authors wrote in the paper’s abstract, suggesting glucose as a key regulator of oligodendrocyte progenitor cell (OPC) population dynamics.

Using MALDI imaging at the CUNY ASRC MALDI Imaging Core Facility, the team visualized glucose concentrations across brain regions during early development in mice. Areas rich in glucose contained actively dividing OPCs, while regions with lower glucose levels harbored cells beginning to differentiate into oligodendrocytes. This pattern suggested that glucose availability helps determine whether OPCs expand their numbers or transition toward myelin production.

“Our findings show that glucose is not just fuel for the brain, it’s also a signal for the cells to divide,” said lead author Sami Sauma, PhD, a postdoctoral researcher with the CUNY ASRC Neuroscience Initiative. “When glucose levels are high in a particular brain region, progenitors use it to drive proliferation. As glucose levels shift, the same cells switch gears and begin maturing.”

An enzyme, ATP‑citrate lyase (ACLY), which converts glucose‑derived citrate into acetyl‑CoA in the nucleus, is central to this process. This acetyl‑CoA fuels histone acetylation, activating genes required for cell proliferation. When the researchers deleted Acly in OPCs, the cells could no longer proliferate efficiently, leading to a temporary reduction in myelin due to decreased OPC numbers. Yet differentiation still occurred, thanks to a compensatory pathway: mature oligodendrocytes can generate acetyl‑CoA outside the nucleus from alternative fuels such as ketone bodies.

This metabolic flexibility proved more than a biochemical curiosity. When mice lacking ACLY in OPCs were placed on a ketogenic diet, their myelin deficits improved. “The same cell lineage interprets different metabolic signals at distinct stages of development,” said senior author Patrizia Casaccia, MD, PhD, founding director of the CUNY ASRC Neuroscience Initiative. “By understanding how glucose and alternative energy sources regulate proliferation and myelin formation, we are uncovering new metabolic strategies that could be harnessed to protect myelin in the developing brain.”

The developmental window examined in mice corresponds to roughly 32 to 40 weeks of human gestation—a period when premature infants are particularly vulnerable to white‑matter injury. The findings raise the possibility that metabolic support during this stage could help preserve the progenitor cells responsible for building myelin. They may also inform future approaches to repairing myelin in disorders such as multiple sclerosis.

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