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Neurons are the cells in the brain responsible for sending messages to the rest of the body, and scientists have long thought that they are settled into one subtype once they develop from stem cells, no matter what is happening in the environment around them.

New research from the Braingeneers, a collaborative group of researchers from UC Santa Cruz and UC San Francisco, reveals that this traditional way of thinking about the fate of neurons may not be true.

A paper published in the journal iScience reports on the project, which reflects the Braingeneers’ expertise in using cerebral organoids—3D models of brain tissue—to learn about the mysteries of brain development. Their insights can help scientists learn more about how subtypes of neurons impact neurodevelopmental conditions and the overall function of the brain.

“This goes against this idea that neuronal identity is completely stable,” said Mohammed Mostajo-Radji, a research scientist at the UC Santa Cruz Genomics Institute and the paper’s lead author. “It’s making all of us rethink how neurons are actually made and maintained, and the influence of the environment in this process.”

First-of-their-kind models

There are two main types of neurons in the cerebral cortex, the outermost layer of the brain: excitatory, which make up 80% of neurons, or inhibitory, the remaining 20%. Of inhibitory neurons in the cerebral cortex, the majority (60%) are parvalbumin-positive neurons.

These inhibitory cells have control over plasticity in the brain, affecting the time period in which a person has the ability to learn a new language without an accent, or enhance other senses after the loss of one. They are also recognized to be involved in many neurodevelopmental disorders, including autism and schizophrenia.

This paper shows that the scientists were able to create a large number of parvalbumin-positive neurons in the living models in the lab, the first instance when scientists were able to produce more than just a small number of these cells. These brain cells were transplanted into and cultured within cerebral organoids, and the researchers believe the 3D structure, which more closely mimics the brain, may have been key to the breakthrough.

“I think part of the answer is that it does not work if you try 2D models,” Mostajo-Radji said. “We provide what I believe is the first evidence that you need a 3D environment. It might challenge us to think about what other cell types we still can’t make in-vitro, and if that’s because we always thought everything could be done in 2D, but actually they need a 3D environment.”

The ability to produce and maintain these parvalbumin-positive neurons in the lab opens the door for a wide range of research into these important cell types. Scientists could learn more about their role in neurodevelopmental disease and the brain as a whole.

“When thinking about assembling brain models, missing this cell type is actually quite critical,” Mostajo-Radji said. “Now, we can make a more realistic model of the brain.”

Changing identity

Next, to further challenge the idea that these cells have a fixed identity, the researchers investigated how the external environment around subtypes of neurons can affect the cell’s identity.

To do so, they took another kind of inhibitory neuron, called somatostatin neurons, and added them to the 3D organoid model. They observed that in these conditions, some somatostatin neurons transitioned into parvalbumin-positive neurons.

While they are not sure about the exact genetic and environmental conditions that enabled the transition, just knowing that this change can occur in living cells in the lab opens up the possibility that the processes could be happening in the brain as well.

“It’s possible that this process of changing identity might actually happen naturally in the brain,” Mostajo-Radji said. “We don’t know that yet, but maybe there is a process in which this has actually been observed in the brain, but overlooked. It’s an exciting window we should explore, and some other labs around the country are starting to think the same way.”

While they have some initial ideas about which genetic pathways might be at play, the researchers want to further explore what factors are responsible for enabling this fluidity of neuronal identity. The researchers also want to further investigate the excitatory cells to find out how they influence the fate of the inhibitory cells.