Neurons are the powerhouse cells in the brain, responsible for transmitting electrical signals that govern every thought, emotion, and action. For decades, scientists have believed that once neurons develop from stem cells, they are hardwired into a specific subtype, unable to change in response to their environment. This view has dominated neuroscience for years, suggesting that once a neuron commits to being either an excitatory or inhibitory cell, it remains locked into that identity for life, unaffected by external influences. However, groundbreaking new research challenges this conventional wisdom, providing fresh insights into how neurons might be more adaptable and influenced by their surroundings than previously thought.
A team of researchers known as the Braingeneers, a collaboration between UC Santa Cruz and UC San Francisco, has uncovered compelling evidence that neuronal identity may not be as fixed as once believed. Their findings, published in the journal iScience, are based on pioneering experiments involving cerebral organoids—three-dimensional (3D) brain tissue models that replicate key features of human brain development. The implications of this research are profound, opening up new avenues for understanding brain development, neurodevelopmental disorders, and the flexible nature of neuronal identity.
Neurons and Their Traditional Roles in Brain Function
To understand the significance of the Braingeneers’ findings, it’s important to first appreciate the critical role neurons play in the brain. There are two primary types of neurons in the cerebral cortex, the brain’s outermost layer: excitatory neurons, which make up approximately 80% of the neuronal population, and inhibitory neurons, which account for the remaining 20%. Excitatory neurons release neurotransmitters that increase the likelihood of neighboring neurons firing, while inhibitory neurons, conversely, release neurotransmitters that decrease this likelihood, acting as a brake on neural activity.
Inhibitory neurons, especially a subtype known as parvalbumin-positive neurons, are particularly crucial in regulating brain plasticity. These neurons are involved in fine-tuning the brain’s response to stimuli, facilitating processes like language learning without an accent or enhancing sensory perception after the loss of one sense. Furthermore, dysfunction in these inhibitory cells has been linked to several neurodevelopmental disorders, including autism, schizophrenia, and epilepsy.
Traditionally, neuroscientists have assumed that once neurons like these parvalbumin-positive cells develop, they are fixed in their identity, essentially “programmed” to remain as they are throughout their lifespan. The Braingeneers’ work challenges this assumption and suggests that the identity of neurons may be more fluid than once thought.
The Breakthrough: Creating Parvalbumin-Positive Neurons in the Lab
The Braingeneers’ work has introduced a revolutionary method of studying neuronal development by utilizing cerebral organoids—3D models of human brain tissue that mimic the structure and function of the brain more closely than traditional 2D cell cultures. These organoids are grown from human stem cells and develop into complex, multi-layered structures resembling miniaturized versions of the human brain. The advantage of using 3D models is that they replicate the natural brain environment more accurately, allowing for a more realistic understanding of how neurons develop and behave.
One of the team’s most significant achievements was their ability to produce a large number of parvalbumin-positive inhibitory neurons in the lab—something that had never been done before. Prior to this, researchers had only been able to generate small quantities of these cells. Using the 3D organoid model, the team was able to successfully grow and maintain these neurons, providing a new and abundant source of this critical neuronal subtype. This breakthrough has the potential to revolutionize research on neurodevelopmental diseases, as it allows scientists to better study the role of these neurons in conditions like autism and schizophrenia.
“It’s a critical step forward because when you’re assembling brain models, missing this specific cell type—parvalbumin-positive neurons—could lead to an incomplete and inaccurate representation of how the brain functions,” said Mohammed Mostajo-Radji, a research scientist at the UC Santa Cruz Genomics Institute and the lead author of the study. “With this breakthrough, we can create a more realistic model of the brain.”
Rethinking Neuronal Identity: Environmental Influence
The most striking aspect of the Braingeneers’ study is the discovery that neuronal identity may not be entirely fixed. In their experiments, the researchers investigated how the external environment—specifically the 3D structure of the cerebral organoids—could influence the fate of neurons. Their experiments with another type of inhibitory neuron, known as somatostatin neurons, demonstrated a surprising result.
In the 3D environment of the cerebral organoid, some somatostatin neurons began to change their identity and transition into parvalbumin-positive neurons. This transformation was not induced by any genetic modification or engineered process but occurred naturally within the organoid. While the exact mechanisms driving this change are still unclear, the observation that neurons can “reprogram” their identity in response to their surroundings challenges the long-held belief that once a neuron’s identity is established, it cannot change.
“It’s possible that this process of changing identity might actually happen naturally in the brain, but it has been overlooked until now,” Mostajo-Radji explained. “We don’t know for sure, but this observation opens up a new window of possibility. It could mean that in the brain, neuronal identities are more flexible than we thought.”
The team’s findings suggest that the process of neuronal identity may not be as rigid as previously assumed. The ability of somatostatin neurons to transform into parvalbumin-positive neurons could reflect a level of plasticity in the brain that allows neurons to adapt to environmental conditions. This discovery has significant implications for our understanding of brain function and development, as well as for the treatment of neurodevelopmental disorders.
Investigating the Genetic Pathways Behind Neuronal Plasticity
While the exact factors driving this transformation remain unknown, the research team has several hypotheses about the genetic pathways at play. The Braingeneers are now focused on identifying the specific genetic and molecular signals that facilitate the transition of one neuronal subtype into another. In particular, they are looking for markers that could indicate when and how this process occurs in the brain, as well as the environmental cues—such as the 3D structure of the brain—that may trigger these changes.
Mostajo-Radji emphasized that this discovery does not mean that neurons can randomly change identities, but rather that the brain might be capable of more flexible and adaptive processes than we realize. “This finding suggests that environmental factors—things like the 3D structure of brain tissue—play a crucial role in how neurons develop and maintain their identities,” he said.
One of the exciting aspects of this research is the potential to apply these insights to neurodevelopmental disorders. Many conditions, including autism and schizophrenia, are associated with an imbalance in excitatory and inhibitory neurons. The ability to manipulate the environment to induce changes in neuronal identity could open new therapeutic possibilities for these disorders.
Implications for Brain Models and Neurodevelopmental Diseases
This research has the potential to dramatically alter the way scientists study brain development. By generating and maintaining specific types of neurons—such as the parvalbumin-positive cells—scientists can now create more accurate brain models that better reflect the complexities of the human brain. These models could be invaluable for studying how neurodevelopmental diseases arise and progress, as well as for developing new treatments.
“The ability to create accurate brain models that include all the relevant cell types, including parvalbumin-positive neurons, is a major step forward,” said Mostajo-Radji. “We can now explore how the interplay between different types of neurons affects brain function, and how disruptions in this balance contribute to diseases like autism and schizophrenia.”
In addition to its implications for neurodevelopmental diseases, this research also raises important questions about the plasticity of the brain in general. Can the brain adapt to new challenges by reprogramming its neurons in this way? What other types of cells in the brain might be capable of changing their identities in response to environmental signals? These questions are just the beginning of what promises to be a new era in neuroscience.
Conclusion: A New Era of Brain Research
The Braingeneers’ work offers a groundbreaking perspective on the nature of neuronal identity. Their discovery that neurons can change their identities based on environmental cues challenges a long-standing assumption in neuroscience and opens up new possibilities for research and treatment. With the ability to generate specific types of neurons in the lab and study their plasticity, scientists are poised to unlock new insights into brain function, development, and disease.
As research continues, the implications of these findings may extend far beyond the laboratory. Understanding the flexible nature of neuronal identity could lead to new treatments for neurodevelopmental disorders and even offer insights into the brain’s remarkable ability to adapt and heal itself. The future of brain research has never looked more promising, and the Braingeneers’ work is at the forefront of this exciting new frontier.
Reference: Mohammed A. Mostajo-Radji et al, Fate plasticity of interneuron specification, iScience (2025). DOI: 10.1016/j.isci.2025.112295