Human-to-rat brain tissue implant boosts psychiatric disease research

Scientists researching ways to treat psychiatric diseases have successfully implanted human brain tissue into newborn rats, where it grew neural connections that stimulated the rodents’ awareness of the outside world.

The experiments at Stanford University in California are the most successful attempts yet to get human neurons to thrive and function inside the brains of animals, after more than two decades of research around the world.

In one test, the human cells in the rat brains became electrically active in synchrony with puffs of air blown at their whiskers. In another, pulses of blue light were directed towards the human neurons in the hybrid brain to train the rats to associate this with the availability of drinking water.

After two weeks, light directed into the human neurons sent the rodents straight to the water spout, showing that the implanted cells were engaging with the reward-seeking circuits of the rat brains and influencing their behaviour in a specific way.

“Our mission is trying to understand psychiatric diseases at the biological level so we can find effective therapies,” said Sergiu Pașca, project leader and Stanford’s professor of psychiatry and behavioural sciences.

Madeline Lancaster, group leader at the MRC Laboratory of Molecular Biology in Cambridge, England who was not involved in the research, called it an “exciting” system for modelling brain disorders and neural development.

The research was published on Wednesday in Nature magazine.

The work builds on more than a decade of research into human brain organoids, sometimes called “mini-brains” though neuroscientists dislike the term.

These three-dimensional cerebral structures a few millimetres across are produced from stem cells derived from skin, which are treated with a biochemical cocktail. The organoid assembles into a structure with many of the features of a real brain.

But the absence of a blood supply or sensory input in a lab dish stops them from developing beyond a certain point. This led the Stanford team to implant their organoids into newborn rats from a strain with no immune system, which would allow them to grow without rejection.

Cells from the rat brain then migrated into the human tissue, forming blood vessels and supplying nutrients. At the same time, the organoids formed connections with structures in the host brain including the thalamus which relays sensory information to the cortex.

The scientists watched for changes in the rats’ social behaviour. Perhaps surprisingly, there was no observable difference between implanted animals and controls.

Although human neurons filled about 30 per cent of one brain hemisphere, they produced neither improvement nor deterioration in the rodents’ memory and cognitive functioning.

As a test of the technology’s ability to show the molecular effects of brain disease, the team made organoids from people with Timothy syndrome, a rare genetic condition associated with autism and epilepsy.

When a Timothy organoid was implanted into one side of the rat brain and an organoid from a healthy person put into the other hemisphere, the researchers found that the former developed much smaller neurons with fewer connections to neighbouring cells.

Pașca said his team had been “very preoccupied from the beginning by the ethical implications of this work”, with bioethicists at Stanford and elsewhere consulted about the research.

Lancaster, who in 2011 created the world’s first brain organoid, stressed that she had no fears about “whether the human transplants would cause the animal to become more human”.

“The size of these transplants is small and their overall organisation is still lacking,” she said. “There are minimal concerns around their potential for higher cognitive functions.”