Scientists have successfully implanted and integrated human brain cells into newborn rats, creating a new way to study complex psychiatric disorders such as schizophrenia and autism, and perhaps eventually test treatments. Studying how these conditions develop is incredibly difficult – animals don’t experience them the way humans do, and humans simply cannot be opened up for research.
Scientists can assemble small pieces of human brain tissue made from stem cells in petri dishes and have already done so with more than a dozen brain regions. But in the dishes, “neurons don’t grow to the size that a human neuron would grow in a real human brain,” said Sergiu Pasca, the study’s lead author and a professor of psychiatry and behavioral sciences at Stanford University.
And isolated from the body, they cannot tell us what symptoms the defect will cause. To overcome these limitations, the researchers implanted clusters of human brain cells, called organoids, into the brains of young rats. The age of the rats was important: human neurons have been implanted into adult rats before, but the animal’s brain stops developing at a certain age, limiting how well the implanted cells can integrate.
“By transplanting them at these early stages, we found that these organoids can grow relatively large, the rat will vascularize them (receive nutrients), and they can cover about a third of the rat’s (brain) hemisphere,” Pasca said.
Blue light reward
To test how well the human neurons integrated with the rats’ brains and bodies, air was blown through the animals’ whiskers, which triggered electrical activity in the human neurons. This showed the input connection – external stimulation of the rat’s body was being processed by human tissue in the brain. The researchers then tested the opposite: could human neurons send signals back to the rat’s body?
They implanted human brain cells altered to respond to blue light and then trained rats to expect a “reward” of water from a nozzle when blue light was shone on the neurons through a cable in the animals’ skulls. After two weeks, pulsing blue light sent the rats to the sink, according to research published Wednesday in the journal Nature.
The team has now used this technique to show that organoids developed from Timothy syndrome patients grow more slowly and show less electrical activity than organoids from healthy people. Tara Spires-Jones, a professor at the University of Edinburgh’s UK Dementia Research Institute, said the work “has the potential to advance what we know about human brain development and neurodevelopmental disorders”. But she noted that human neurons “did not replicate all the important features of the human developing brain” and more research is needed to ensure the technique is a “robust model”.
Ethical debates
Spiers-Jones, who was not involved in the research, also pointed out potential ethical issues, “including whether these rats will have more human thinking and consciousness.” Pasca said that careful observation of the rats indicated that the brain implants did not change them or cause pain. “There are no changes in the rats’ behavior or their well-being … there is no increase in function,” he said. He argued that limiting how deeply human neurons integrate into a rat’s brain provides “natural barriers” that prevent the animal from becoming too human.
Rat brains develop much faster than human brains, “so there’s only so much the rat cortex can integrate,” he said. But in species closer to humans, those barriers may no longer exist, and Pasca said he won’t support using the technique in primates for now. But he believes there is a “moral imperative” to find ways to better study and treat psychiatric disorders. “Of course, the more human these models become, the more uncomfortable we feel,” he said. But “human psychiatric disorders are very much uniquely human. So we’re going to have to think very carefully … how far we want to go with some of these models.”
