Human neurons transplanted into a rat’s brain influence its behaviour

Researchers propose that rats with human neurons derived from stem cells implanted into their brains could be used to test new psychiatric drugs

By Jason Arunn Murugesu

A transplanted human organoid labelled with a fluorescent protein in a section of rat brain

Stanford University

Human neurons have been transplanted into the developing brains of young rats for the first time. The human neurons can control the rats’ actions and the technique could be used to test new psychiatric drugs.

In the past decade, researchers have developed mini models of the brain called organoids, made by growing stem cells into three-dimensional structures in the lab. They can be used to study the effects of drugs on human cells, but even the most complex brain organoids lack the intricacy of real neurons in the brain.

By transplanting human organoids into a rodent brain, researchers can manipulate the cells and see how this affects the animal’s behaviour, says Sergiu Pasca at Stanford University in California.

Researchers have previously carried out this type of transplant in adult rats, but Pasca and his colleagues have now transplanted human brain organoids into rats that were just a few days old. By targeting the rats when their brains were still developing, the researchers hoped that the human neurons would be better integrated into the organs. The rats all had dysfunctional immune systems to ensure that the human cells wouldn’t be rejected.

The human neurons became far more mature and about six times larger than they would have had they developed in a dish. They grew to fill around a third of one hemisphere of each rat’s brain and formed connections known as synapses with rat neurons.

To see if the human neurons could influence the rats’ behaviour, the researchers used a technique called optogenetics, which involves genetically altering cells so they respond to light.

They gave the rats water each time they shone blue light onto the human neurons in the rat brains. After about two weeks, the rats started licking in expectation of water when the team shone blue light on these neurons.

Pasca says this new model can overcome some of the limitations of using organoids in drug testing. As many psychiatric conditions are behaviourally defined, it is difficult to link the activity of human brain cells in a petri dish with a behaviour associated with the condition. By implanting organoids into rats, researchers can study human cells and see how interventions affect animals’ actions.

“There are a couple of previous studies with transplantation of human brain organoids into rodent brains,” says Guo-li Ming at the University of Pennsylvania. “This current study by Pasca’s group has taken it to the next level by using several state-of-the-art technologies. Not only did they show long-term growth – up to eight months – and maturation after transplantation, but also synaptic integration and contribution to the behaviour of those human cells.”

“This research will expand various neurological research [in areas] such as neurodevelopmental disorders, neuropsychiatric disorders, substance use disorders, neurogenerative disorders and many other diseases that are known to disrupt brain circuits,” says Julia TCW at Boston University.

However, many will question whether it is ethical to manipulate rats in this way. “I do not think that it is ever — ever — ethically justified to treat animals as resources humans can exploit for human advantage,” says Taimie Bryant, a professor of animal law at the University of California, Los Angeles. “It seems to me that rats’ consciousness as it is, without human manipulation, is rather remarkable and that damaging a rat’s brain is emblematic of an attitude towards nature that imperils human and non-human animals’ prospects for continued life on Earth.”

Journal reference: Nature, DOI: 10.1038/s41586-022-05277-w