In what seems like it came straight out of a science-fiction movie, researchers from The University of Tokyo have developed a new method for connecting mini-brains, or cerebral organoids, in the lab. These connected organoids exhibit complex and coordinated electrical activity that closely resembles what is seen in the actual human brain. This exciting advancement — published in the journal Nature Communications — opens up new possibilities for studying brain development and disorders, and could eventually lead to better treatments.
What exactly are cerebral organoids? They are tiny, three-dimensional clumps of human brain tissue grown from stem cells in a dish. While they don’t have the full complexity and structure of a real brain, organoids allow scientists to study aspects of human brain development and function in a way that was not possible before. Each organoid typically mimics a specific brain region.
In this new study, Japanese researchers found an ingenious way to connect two cerebral organoids together using a special microfluidic device. This device has tiny channels that guide the organoids to grow towards each other. Over time, the neurons from each organoid reach out and form connections called axon bundles, creating a two-way bridge between the mini-brains.
Researchers were amazed after, once connected, the organoids started exhibiting synchronized bursts of electrical activity, as if they were communicating and working together. This coordinated activity became more complex as the connections between the organoids strengthened over time. Scientists used a technique called multi-electrode array recording to measure these electrical signals.
What sparked researchers’ interest is that the activity in the connected organoids was more intense and intricate compared to single, unconnected organoids or two organoids that were simply fused together. This suggests that it’s the axon connections between regions that enable the organoids to generate brain-like waves and rhythms.
“In single-neural organoids grown under laboratory conditions, the cells start to display relatively simple electrical activity,” says co-lead study author Tomoya Duenki, of The University of Tokyo’s Institute of Industrial Science, in a media release. “When we connected two neural organoids with axonal bundles, we were able to see how these bidirectional connections contributed to generating and synchronizing activity patterns between the organoids, showing some similarity to connections between two regions within the brain.”
By mapping the genetic profiles of individual neurons, researchers discovered that the neurons extending axons into the connecting bundles showed signs of being more mature and active. It’s possible that the act of reaching out and forming connections with neurons in the other organoid helps drive the development and stabilization of the cells.
But researchers didn’t stop there — they went on to show that these axon bundles could be stimulated with light to alter the organoids’ electrical patterns. Using a method called optogenetics, they expressed light-sensitive proteins in the organoid neurons. Shining light on the axon bundles triggered corresponding bursts of activity in the organoids.
Researchers were more intrigued when repeated light stimulation caused the organoids to change their firing in enduring ways — a simple form of learning and memory. With each round of stimulation, the organoids started responding faster and with more vigor. Blocking key cellular receptors and processes disrupted this short-term plasticity, confirming it arose from specific molecular mechanisms.
While science is still a long way from growing complete human brains in the lab, this organoid model provides a powerful platform to explore the role of connections between brain regions. Because the axon tracts are so accessible in this system, scientists can manipulate them in ways not possible in a real brain.
“These findings suggest that axonal bundle connections are important for developing complex networks,” explains senior study author Yoshiho Ikeuchi, of The University of Tokyo’s Institute of Industrial Science. “Notably, complex brain networks are responsible for many profound functions, such as language, attention, and emotion.”
These organoids may also yield insights into disorders thought to arise from faulty brain wiring, such as schizophrenia and autism. Researchers could use organoids to test the effects of drugs or genetic tweaks on neuronal connections.
Although cerebral organoids are remarkable, they still lack many supportive brain cells and structures, like blood vessels. Overcoming these limitations will be essential as scientists work to build more complete and realistic mini-brain models.
Nevertheless, these findings underscore the importance of inter-region connectivity in constructing brain function. Science still has much to learn about how the brain’s wiring gives rise to our thoughts, feelings and sense of self. But bit by bit, inventive studies like this are helping to solve the puzzle. Connected organoids provide an unprecedented window into the networked nature of this most complex of organs.
