Scientists transplant human brain cells into rats to study mental disorders, brain development

This “living laboratory” of a rat’s brain will allow researchers to perform experiments that would be too invasive or difficult and sometimes outright impossible to perform on humans, the researchers noted.

“We can now study healthy brain development as well as brain disorders understood to take root in development in unprecedented detail, without needing to excise tissue from a human brain. We can also use this new platform to test new drugs and gene therapies for neuropsychiatric disorders,” said Sergiu Pasca, corresponding author of the study published in the journal Nature, in a press statement. Pasca is a professor of psychiatry and behavioural sciences at the Stanford School of Medicine.

The method

For this study, human skin cells were first transformed into stem cells.  Under laboratory conditions, the stem cells were guided to differentiate into many different brain-cell types to form an “organoid” that resembles the outermost layer of the brain, the cerebral cortex, which is also the most recently evolved part.

“We’ve been making ever more complicated circuits in a dish using organoids and sophisticated combinations of them, called assembloids. But neurons within these lab dishes are still lagging behind in their development compared with what you’d see in a naturally developing human brain,” added Pasca.

After these assembloids spent two months in culture, they were transplanted into the brains of young rats who were between two and three days old. This age is  equivalent to infancy in humans. It was important that baby rats were used instead of adults because brain connections are formed early in development and the brain becomes much less receptive to forming new connections.

Over the course of the study, this transplant was done on over 100 rats, with the organoids being placed in the same location on each rat’s brain so that they can be monitored easily. Soon, the rat’s cells began migrating into human tissue. Rats’ endothelial cells penetrated into the brain implants and assembled blood vessels, thus supplying nutrients and signalling substances to the human cells. Or as Pasca described it, “they moved right in.”

Did it work?

Now that transplants were successful, the next step was to understand whether these organoids would actually be helpful in finding the causes of human neuropsychiatric disorders. For this, the researchers chose Timothy syndrome, which is a genetic disorder that is strongly associated with autism and epilepsy. They created an organoid from a Timothy syndrome patient’s skin cells and transplanted it into one side of the rat’s brain.

On a corresponding spot on the other side, they transplanted an organoid created using a healthy individual’s cells, to serve as a control. After five to six months, the researchers were able to observe clear differences between electrical activity on both sides. The Timothy syndrome neurons were much smaller and sprouted much fewer dendrites or brush-like extensions that act as an antenna for input from nearby regions.

“This is the most advanced human brain circuitry ever built from human skin cells and a demonstration that implanted human neurons can influence an animal’s behaviour. Our platform provides, for the first time, behavioural readouts for human cells and could, we hope, accelerate our understanding of complex psychiatric conditions,” Pasca added.

Pasca believes that similar comparisons can be made using cells from people with schizophrenia, autism and other disorders to better understand how such diseases affect the brain.