Brain organoids may provide a window into autism


Whatever you do, don’t call them “mini-brains,” say the scientists. Regardless, the seed-sized organoids—which are grown in the lab from human cells—provide insights into the brain and uncover differences that may contribute to autism in some people.

“We used to think it would be too difficult to model the organization of cells in the brain,” says the senior author. “But these organoids self-organize. Within a few months, we see layers of cells that are reminiscent of the cerebral cortex in the human brain.”

The research describing the organoids and their potential for understanding neural diseases publishes in Nature Communications.

Having the ability to model aspects of the brain in this way gives scientists a glimpse into the inner workings of a living organ that is otherwise nearly impossible to access. And since the organoids grow in a dish, they can be tested experimentally in ways that a brain cannot.

The team used an innovative process to investigate effects of a genetic abnormality associated with autism spectrum disorder and human brain development. They found that organoids engineered to have lower levels of the gene, called SHANK3, had distinct features.

Even though the autism organoid model appeared normal, some cells did not function properly:

  • Neurons were hyperactive, firing more often in response to stimuli,

  • Other signs indicated neurons may not efficiently pass along signals to other neurons,

  • Specific molecular pathways that cause cells to adhere to one another were disrupted.

These findings are helping to uncover the cellular and molecular causes of symptoms associated with autism, the authors say. They also demonstrate that the lab-grown organoids will be valuable for gaining a better understanding of the brain, how it develops, and what goes wrong during disease.

“One goal is to use brain organoids to test drugs or other interventions to reverse or treat disorders,” says a co-author.

Scientists have long searched for suitable models for the human brain. Lab-grown organoids are not new, but previous versions did not develop in a reproduceable way, making experiments difficult to interpret.

To create an improved model, the team took cues from how the brain develops normally. The researchers prompted human stem cells to become neuroepithelial cells, a specific stem cell type that forms self-organized structures, called neural rosettes, in a dish. Over the course of months, these structures coalesced into spheres and increased in size and complexity at a rate similar to the developing brain in a growing fetus.

After five months in the lab, the organoids were reminiscent of “one wrinkle of a human brain” at 15 to 19 weeks post-conception, the author says. The structures contained an array of neural and other cell types found in the cerebral cortex, the outermost layer of the brain involved in language, emotion, reasoning, and other high-level mental processes.

Like a human embryo, organoids self-organized in a predictable fashion, forming neural networks that pulsated with oscillatory electrical rhythms and generated diverse electrical signals characteristic of a variety of different kinds of mature brain cells.'

“These organoids had patterns of electrophysiological activity that resembled actual activity in the brain. I didn’t expect that,” another author says. “This new approach models most major cell types and in functionally meaningful ways.”

The senior author explains that these organoids, which more reliably reflect intricate structures in the cortex, will allow scientists to study how specific types of cells in the brain arise and work together to perform more complex functions.

“We’re beginning to understand how complex neural structures in the human brain arise from simple progenitors,” the author says. “And we’re able to measure disease-related phenotypes using 3D organoids that are derived from stem cells containing genetic mutations.”

The author adds that using the organoids, researchers will be able to better investigate what happens at the earliest stages of neurological conditions, before symptoms develop.

https://www.nature.com/articles/s41467-022-33364-z

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmodeling-human&filter=22&keep_no_swfupload=1

Edited

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