The human brain begins taking shape long before birth through a complex series of decisions made by developing cells.

New research led by scientists at UCLA has revealed that two very different forces — nutrient processing and direct physical contact between cells — can influence how early brain stem cells decide what types of neurons to produce.

The findings come from two studies published in Cell and Science. Both focus on radial glia, specialised stem cells that generate many of the neurons and support cells forming the cerebral cortex, the region involved in functions such as memory, language and thought.

Glucose Helps Shape Cell Fate

In the Cell study, researchers created a detailed map of metabolism in the developing human cortex using donated human tissue and brain organoids grown from stem cells.

They found that radial glia rely strongly on the pentose phosphate pathway, a process that uses glucose to generate materials needed by rapidly dividing cells. When researchers reduced glucose availability or disrupted this metabolic pathway, radial glia changed their behaviour. They began producing greater numbers of inhibitory neurons and other cell types that normally appear later in development.

Bhaduri said the results indicate that metabolism is not simply providing energy in the background. Instead, the way stem cells process nutrients can actively influence developmental decisions and determine which cell types emerge.

The finding may eventually help scientists explore how maternal nutrition, metabolic conditions and other environmental factors could affect prenatal brain development.

Signals From the Thalamus

The second study, published in Science, investigated signals arriving from the thalamus, a deep brain structure involved in relaying information throughout the nervous system.

Scientists already knew that thalamic neurons send long projections toward the cortex. In humans, however, these projections arrive surprisingly early, before they establish their mature connections with cortical neurons. Using stem cell-derived brain models called assembloids, researchers discovered that these projections physically contact radial glia during early development.

That contact changed what the stem cells produced, increasing the formation of excitatory neurons. The effect was particularly noticeable among upper-layer neurons, which are especially abundant in the human cortex.

According to Bhaduri, the study identifies a previously unrecognised point of physical communication between thalamic projections and radial glia that may be particularly important in human brain development.

An Autism-Linked Gene

Researchers also investigated NRXN1, a gene involved in helping neurons form connections and previously associated with autism spectrum disorder.

They created assembloids using patient-derived cells carrying an NRXN1 mutation. In these models, thalamic signals behaved differently from those produced by unaffected cells.

The mutation altered the balance between remaining stem cells and newly generated neurons, offering researchers a laboratory model for examining how early developmental disruptions might influence cortical formation.

A More Dynamic View of Development

Together, the two studies suggest that brain development depends on constant communication between stem cells and their environment.

One set of signals comes from metabolism, while another comes from direct contact with neighbouring neural structures. Both can influence which neurons radial glia ultimately produce.

Organoid technology has made these discoveries possible by allowing scientists to recreate important aspects of human brain development in the laboratory. These models can also address questions that are difficult to investigate using animals alone.

Bhaduri said that understanding how radial glia respond to nutritional and cellular signals could provide an important foundation for studying normal development, vulnerability to neurological disease and the reactivation of similar stem-cell programmes in brain cancer.