Scientists have discovered that the brain's earliest stem cells, called radial glia, use both nutrients and physical signals to decide what types of brain cells to produce. A study led by researchers at the University of California, Los Angeles (UCLA), shows that these stem cells are responsible for generating most of the cerebral cortex, the brain region involved in thinking, memory, and language. Radial glia change their behavior depending on how they process glucose and the physical contact they have with signals from the thalamus, a deep brain structure that helps relay information across the nervous system. Published in two studies in the journals Cell and Science, the research reveals that radial glia respond to two distinct types of information: the way they process nutrients and physical signals from other parts of the developing brain. These findings suggest that metabolism doesn't just support brain development in the background but actively influences which types of cells are created. In the Cell study, researchers created a detailed map of metabolism in the developing human cortex. This work was a collaboration between UCLA scientists Aparna Bhaduri and Heather Christofk. Using donated human brain tissue and brain organoids—miniature models of the brain grown in the lab—they found that radial glia rely heavily on the pentose phosphate pathway, a metabolic process that uses glucose to make materials needed by rapidly dividing cells. When the scientists reduced the amount of glucose available or disrupted this pathway, the stem cells began producing more inhibitory neurons and other cell types that typically appear later in development. The second study, published in Science, focused on signals from the thalamus. Researchers discovered that while the brain is still developing, thalamic projections physically touch radial glia. This contact influenced the stem cells, prompting them to produce more excitatory neurons, which are the main signal-carrying neurons in the cortex. This effect was especially pronounced in upper-layer neurons, which are much more developed in the human brain than in other species. The researchers also found a link between this physical interaction and NRXN1, a gene associated with autism spectrum disorder. Mutations in NRXN1 have previously been linked to autism. In models made from cells taken from patients with an NRXN1 mutation, the altered thalamic signals behaved differently compared to signals from unaffected cells. These differences changed the balance between the number of stem cells and the neurons they produced. The studies highlight that radial glia do not act in isolation but are constantly influenced by signals from their environment. The research also shows how organoid technology has transformed the study of human brain development. These models allow scientists to recreate key features of human brain development in the lab, enabling them to explore questions that are difficult or impossible to study using animal models alone.