What is it about?
This study investigates how metabolism—the way cells produce energy and build essential components—changes as human brain cells develop into neurons in the neocortex. Using human neural stem cells tracked over four months, the researchers followed their progression into fully functional neurons. They found that early-stage cells rely mainly on glycolysis, a fast but less efficient way to generate energy. As development progresses, cells gradually shift to oxidative phosphorylation (OXPHOS), a more efficient process required for proper neuronal function. This transition occurs early and is critical for successful maturation. Rather than being simply reduced, glycolysis is reorganized during this process: some of its components continue to support biosynthesis, while others decrease. At the same time, developing neurons activate antioxidant defenses, preparing for the increased energy demands and stress associated with maturation. These findings were confirmed not only in lab-grown cells but also in human brain tissue, revealing a coordinated metabolic program that unfolds over time and across different regions of the developing cortex. Overall, the study shows that metabolic changes are not just a consequence of neuronal development but actively contribute to shaping it, providing new insights into brain development and metabolic-related neurological disorders.
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Why is it important?
This research is important because it shows that metabolism is not just a background process, but a key driver of how human brain cells develop into functional neurons. Understanding this is crucial because the correct “energy switch” from glycolysis to oxidative phosphorylation is necessary for neurons to mature and work properly. By mapping these metabolic changes in detail, the study helps explain what can go wrong in neurodevelopmental and neurodegenerative disorders. If this metabolic transition is disrupted, neurons may fail to develop correctly or become vulnerable to damage, which is linked to conditions such as developmental brain disorders and diseases later in life. The findings also provide a framework for studying human brain development in more realistic models, including patient-derived cells. This opens the possibility of identifying metabolic defects in specific diseases and testing targeted treatments in a controlled way. Ultimately, this work is important because it connects energy use to brain development, offering new avenues for understanding, diagnosing, and potentially treating neurological disorders.
Perspectives
The study opens several important future directions for both basic research and clinical applications. First, it provides a roadmap to better understand neurodevelopmental and neurodegenerative diseases. Since proper metabolic switching is essential for neuron maturation, future studies can investigate how this process is altered in specific disorders and whether correcting metabolic defects could restore normal development or function. Second, the work highlights the potential of using patient-derived cells (such as iPSCs) to study disease in a personalized way. Researchers could compare metabolic profiles between healthy and patient cells, making it possible to identify disease-specific alterations and test targeted therapies in vitro. Another key perspective is the use of non-invasive metabolic imaging techniques, like NAD(P)H FLIM, to monitor cell metabolism in real time. This could become a powerful tool for tracking disease progression or evaluating how cells respond to treatments without disrupting their structure. In addition, the study suggests new therapeutic strategies. By targeting metabolic pathways—such as boosting oxidative phosphorylation or enhancing antioxidant defenses—it may be possible to support neuron survival and function in conditions where energy metabolism is impaired. Finally, this research lays the groundwork for exploring metabolism in more complex and realistic brain models, including organoids and human tissue. This will help clarify how different cell types, such as neurons and glial cells, interact metabolically during brain development. Overall, the study opens the way toward integrating metabolism into the understanding, diagnosis, and treatment of brain disorders, moving closer to more precise and personalized approaches in neuroscience.
Maria Teresa Dell'Anno
Fondazione Pisana per la Scienza
Read the Original
This page is a summary of: Metabolic trajectories in developing human neocortical neurons, Proceedings of the National Academy of Sciences, March 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2509980123.
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