Scientists transplant human brain tissue into rats to study brain disorders

In work that could further our understanding of brain disorders and to enable the discovery of new drugs to treat them, researchers at the Stanford University School of Medicine transplanted human brain tissue into rats, where it became a functional part of their brains.

Their to study, published Wednesday in the journal Nature, took seven years to complete and involved extensive ethical discussions on animal welfare and other issues. The most immediate applications of the study will involve research into conditions such as autism, epilepsy, schizophrenia and intellectual disabilities.

The implanted human brain tissue was created in the laboratory using a technique that allows scientists to convert skin cells into the equivalent of embryonic stem cells, the cells from which all other cells develop as the brain grows. embryo. In the lab, scientists can push these cells down the developmental path, growing them into any one of 200 or more. Types of cells in the human body.

The researchers created clusters of these cells that resemble parts of the brain. The clusters, known as organoids, resembled the cerebral cortex, the outermost layer of the brain associated with some of its most advanced processes, including language, memory, thinking, learning, decision-making, emotion, intelligence and personality.

Using syringes, the scientists injected human brain tissue into the brains of two- or three-day-old rat pups. The rat brain cells then migrated into human tissue and formed connections, incorporating the human cells into the machinery of their brain.

“We didn’t remove that part of the rat’s brain. Essentially, what happens is the rat’s tissue pulls away,” said Sergiu Pasca, a professor of psychiatry and behavioral sciences at Stanford who led the study.

The human brain tissue was about one-fifth of an inch when transplanted, but it expanded and by six months it represented about one-third of the hemisphere of the rat brain. The brain is organized into two hemispheres, right and left, each responsible for different functions.

Deep in the rat brain, human and rat cells were connected in the thalamus, the critical area for sleep, consciousness, learning, memory, and information processing from all the senses except smell.

“Overall, I think this approach is a step forward for the field and offers a new way to understand disorders” involving brain cell malfunction, said Madeline A. Lancaster, group leader in the Molecular Biology Laboratory. of the Medical Research Council. in Cambridge, England, who was not involved in the study.

“Ethically, there can be animal welfare concerns and, like all animal experiments, the benefits must always be weighed against the risks to the animal.” Lancaster said. “But I’m not concerned if human transplants would make the animal more ‘human-like’, since the size of these transplants is small and their overall organization is still lacking.”

Pasca said the researchers had extensive discussions with ethicists about animal welfare in preparation for the experiments. She said the rats in the study showed no signs of anxiety, nor was there any evidence that they were experiencing pain or seizures.

Japanese stem cell pioneer Yoshiki Sasai is credited with developing the first neuronal organoids in 2008, but these have had limited impact because they lacked the system of vessels that carry blood throughout the body, Lancaster said. This deficit caused the organoid cells to become stressed and die.

“This study overcomes this limitation by transplanting organoids into the rat brain where the organoids can become vascularized,” Lancaster said. “The result is much more mature structures, connections and activity of the transplanted tissue inside the rat.

In one experiment, the Stanford team took skin cells from a person with a rare genetic condition called timothy syndrome, which has some of the features of autism and epilepsy and has been diagnosed in fewer than 100 people worldwide. Using the ability to change skin cells into other cell types, the researchers created brain organoids from the patient and implanted them into one side of the rat’s brain.

For comparison, they transplanted organoids from a healthy person to the other side of the brain of the same rat. They found that after five to six months, Timothy syndrome cells were smaller and engaged in very different electrical activity than healthy brain cells.

“I’m not entirely surprised by the findings, but it’s great,” said Bennett Novitch, a fellow at the Broad Center for Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles, who was not involved in the study. . In 2021, Novitch and her colleagues developed organoids that produce brain waves, the electrical pulses that brain cells use to communicate with each other.

He said the Stanford scientists showed that human brain organoids can not only be integrated into the rat brain, but can also be used to change the animal’s behavior.

In a complex experiment, they created clusters of human brain cells that had been customized so that individual neurons could fire with a specific frequency of blue laser light. Those clusters were then injected into the brains of rats, and after three months, the scientists placed ultrathin fiber-optic cables into the rats’ brains so that the researchers could emit blue light.

The rats were placed in glass boxes with a water spout. The researchers then conditioned the rats to wait for water only after their brains had received a pulse of blue light. The rats came to associate blue light with receiving water, showing that the implanted human cells were now involved in the complex reward-seeking machinery within. their brains.

“This is very difficult experimentation to do,” Novitch said.

He noted, however, that using rats implanted with human brain tissue to test drugs would work for small studies, but not for pharmaceutical companies because of the speed and scale required.

Pasca said he hopes to teach other researchers how to use his group’s techniques to study different brain disorders.

“There are enough problems in neuroscience to solve for many years,” he said. “The challenge of understanding psychiatric disorders is immense.”

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