Scientists Reveal How Metabolism and Early Neural Signals Shape the Developing Human Brain

Before birth, the human brain is assembled through a vast cascade of cellular decisions. At the heart of this process are radial glia, a specialized population of stem cells that builds much of the cerebral cortex, the region responsible for thought, memory and language. These cells also help explain why the human cortex is larger and more complex than that of many other species.

Radial glia generate a wide range of neurons and support cells before largely disappearing around birth, yet similar stem-like cells can reappear in brain cancers. Because they sit at the crossroads of normal development and disease, scientists have long sought to understand how these cells determine what they become. Two new studies now provide some of the clearest answers to date.

Metabolism guides stem cell choices

In a study published in Cell, researchers at UCLA created a detailed atlas of metabolism in the developing human cortex. Using donated fetal tissue and brain organoids grown from human stem cells, they mapped how different cell types use nutrients as the brain develops. The work revealed that metabolism is not simply background support but can actively influence cell-fate decisions.

The team found that radial glia rely heavily on the pentose phosphate pathway, which uses glucose to produce building blocks needed by rapidly dividing cells. When researchers reduced glucose availability or disrupted this pathway, the stem cells changed what they produced. Instead of generating the usual balance of cells, they produced more inhibitory neurons and other cell types that typically emerge later in development.

This shift suggests that the metabolic state of radial glia can steer brain development along different trajectories. The findings also raise questions about how maternal nutrition, gestational diabetes and other metabolic conditions might influence fetal brain development. The atlas provides a detailed reference for studying human brain metabolism during early development.

Early signals from the thalamus

A companion study published in Science examined a very different influence on radial glia. Researchers focused on the thalamus, a deep brain structure that relays sensory and other information to the cortex. Long before mature neural circuits form, neurons in the thalamus send projections toward the developing cortex, arriving earlier than would be necessary for their final connectivity.

To investigate why this happens, the UCLA researchers used human stem cell-derived brain assembloids, which combine organoids modeling different brain regions. They observed that thalamic fibers physically contacted radial glia in the developing cortex. This direct contact altered the behavior of the stem cells, prompting them to produce more excitatory neurons, the primary signal-transmitting cells of the cortex.

The effect was particularly pronounced for upper-layer excitatory neurons, which are especially expanded in humans and are associated with higher-order cognitive functions. The findings suggest that this early communication between developing brain regions contributes to human cortical architecture. Evidence so far indicates that this type of direct contact is much less prominent, or may be absent, in rodents.

A gene tied to autism and imbalance

The researchers also connected these physical interactions to NRXN1, a gene involved in forming synaptic connections between neurons. Variants and deletions involving NRXN1 have previously been associated with autism spectrum disorder and other neurodevelopmental conditions. The new findings suggest that the gene may also have an important role much earlier in brain development, before classical synapses have fully formed.

Using assembloids derived from patient cells carrying NRXN1 mutations, researchers found that thalamic projections did not influence radial glia in the same way. The altered signaling changed the balance between the number of stem cells and the neurons they generated. Such early developmental differences could potentially contribute to later differences in cortical circuitry associated with neurodevelopmental conditions.

The results provide researchers with a model for investigating how particular genetic changes interact with developmental processes. Scientists can now explore whether modifying NRXN1-related pathways can restore more typical patterns of cell production in experimental models. Such research could eventually contribute to strategies for earlier intervention, although any clinical applications remain distant.

Organoids reshape brain research

Together, the two studies show how radial glia integrate multiple signals from their environment rather than developing in isolation. Nutrient processing, physical contact with projections from other brain regions and gene-specific signaling can all contribute to determining how the cortex is constructed.

The research also demonstrates the growing potential of organoid and assembloid technologies. A decade ago, scientists had limited ways to directly investigate aspects of human brain development that are difficult to reproduce in animals. Today, lab-grown human brain tissue allows researchers to explore questions that cannot easily be addressed using rodents or traditional cell cultures alone.

Beyond fundamental neuroscience, the findings may help researchers investigate why metabolic conditions, nutritional deficiencies or genetic variants are associated with vulnerability to some neurodevelopmental and psychiatric conditions. The work may also have implications for cancer research, as stem-like cells in brain tumors can reuse some developmental programs associated with radial glia.

The studies were supported by a broad group of funders, including U.S. federal agencies, private foundations and university research centers. As researchers continue building on these cellular atlases and experimental models, they hope to develop an increasingly detailed picture of how different cell types in the human cortex emerge.

Understanding these developmental programs could ultimately provide new insight into both the extraordinary complexity of the human brain and the biological processes that make it vulnerable to neurological and psychiatric disorders.