Scientists sew human brain tissue into the brains of rats

(ORDO NEWS) — Self-organizing clumps of human brain tissue grown in the lab have been successfully transplanted into the nervous systems of newborn rats, in a move to find new ways to treat neuropsychiatric disorders.

3D stem cell-derived organoids resembling a simplified model of the human cerebral cortex connected and integrated with surrounding tissues in each rat’s cerebral cortex to form a functional part of the rodent’s own brain, displaying activity associated with sensory perception.

This, according to a team of researchers led by Stanford University neuroscientist Sergiu Pasca, overcomes the limitations of organelles grown on a platter and gives us a new platform to model the development and disease of the human brain in a living system.

“Most of the work my lab does is motivated by this mission to try to understand mental disorders at a biological level so that we can find effective treatments,” Pașca explained at a press briefing.

“Many of these mental disorders, such as autism and schizophrenia, are probably uniquely human, or at least they are associated with unique features of the human brain.

And the human brain, of course, was not very accessible, which hindered the progress that we progress in understanding the biology of these diseases.”

In 2008, scientists made a breakthrough: brain cells were grown from induced pluripotent stem cells.

Mature cells taken from adult humans have been reverse engineered (or induced) to return them to the “empty” state of stem cells, the shape cells take before growing into specialized cells such as skin cells or heart cells. .

These stem cells were then directed to develop into brain cells, which the scientists cultured to form clumps of brain-like tissue called organelles. These models of key areas of brain anatomy, such as the wrinkled outer cortex, can be used to study brain function and development up close.

For all their usefulness, in vitro cortical organoids have their limitations. Since they are not connected to living systems, their maturation is not complete, making it impossible for researchers to observe how they integrate with other major parts of the brain.

In addition, a brain organoid in a cup cannot reveal the behavioral consequences of any defects that scientists can detect. Since mental disorders are behaviorally determined, it is difficult to identify the physiological characteristics of these disorders.

Previous studies have tried to overcome these hurdles by implanting human brain organelles into the brains of adult rats. Due to a developmental mismatch, the grafts did not take root: the developing neurons in the organoid could not form a strong connection with the fully developed adult rat brain network.

So Pașca and his colleagues tried something else: transplanting human brain tissue into the brains of newborn rats, whose own brains had not yet developed and matured.

Human cortical organelles were grown on a platter and then transplanted directly into the somatosensory cortex (a region of the brain responsible for receiving and processing sensory information) in rat pups that were only a few days old.

These pups were then left to grow into adults for another 140 days (rats become fully sexually mature between 6 and 12 weeks of age).

The scientists then studied the rats. They genetically engineered organoids to respond to simulated blue light by firing neurons when blue light was shone on them. This stimulation of human neurons was done while rats were being trained to lick their noses to get water.

Later, when the organoids were shone with blue light, the rats automatically licked them, demonstrating a response not seen in the control groups.

This indicated that the organoid not only functioned as part of the rat’s brain, but could also control reward-seeking behavior.

Another group of neurons in the organoid showed activity when the scientist pressed the whiskers of the rats, evidence that neurons can respond to sensory stimulation.

Brain cells grown from three human patients with a genetic disorder called Timothy’s syndrome were also used for some organoids. Timothy syndrome affects the heart, digits, and nervous system and usually results in early death.

After conducting behavioral tests, the rats were euthanized and their brains removed and dissected, allowing the researchers to observe organelle integration at the cellular level.

They found that the organoid neurons grew much larger than any neurons grown in vitro, spread into the brains of rats, and formed networks with those of native rats.

The neurons of rats with transplanted Timothy’s syndrome had a less complex shape and formed different synaptic connections with surrounding brain tissues compared to control groups. This is a new discovery that could not be found in the brain organoid in the dish.

While the platform still has some limitations, the team believes it has the potential to become a powerful new tool for understanding brain development and disease.

“Overall, this in vivo platform represents a powerful resource to complement in vitro research on human brain development and disease,” the authors write in their paper.

“We anticipate that this platform will allow us to identify novel chain-level phenotypes in patient-derived cells that have so far remained elusive and test new therapeutic strategies.”

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