Human brain cells transplanted into rat brains show promise for neuropsychiatric research (2023)

Advanced research on mental disorders and brain development,Stanford medicineThe researchers successfully connected live human nerve cells, or neurons, and supporting brain cells to mouse brain tissue to form hybrid working circuits.

The research described in ato studypublished online on October 12 inNature, demonstrates a method for conducting experiments that would otherwise be invasive, difficult, or impossible. By growing and manipulating human brain tissue in a living laboratory of a mouse brain, researchers can observe the effects on the animal's behavior, he said.Sergio Easter, MD, Professor of Psychiatry and Behavioral Sciences at Stanford School of Medicine.

"We can now study healthy brain development, as well as brain disorders known to be ingrained in development, in unprecedented detail without having to remove tissue from a human brain," said Pasca, director of Bonnie Uytengsu and Family ofStanford Organogenesis of the Brain."We can also use this new platform to test new drugs and gene therapies for neuropsychiatric disorders."

Pasca is the lead author of the study. Senior authorship is shared by former postdoctoral fellow Omer Revah, PhD, DMV; Livelihood Researcherlucky gore, Physician; and Resident Psychiatrist and Postdoctoral Fellow Kevin Kelley, MD, PhD.

(Video) Using Human Brain Cells in Rats to Understand Psychiatric Disorders with Dr. Sergiu Pasca

ingredients for success

The researchers first started with the Pasca methodreportedInsideNature's methodsin 2015. In this study, human skin cells were transformed into stem cells for the first time, which can differentiate into most of the body's 200 cell types. Under carefully controlled conditions in laboratory dishes, these cells differentiated into different types of brain cells and proliferated into organoids resembling the cerebral cortex, the outermost layer of the human brain, as well as its youngest part.

Variations on this protocol allowed Pasca and his colleagues to create organoids representing a dozen different brain regions.

"We've been making more and more complicated circuits on a board using organoids and intricate combinations of them, calledAssemblies🇧🇷 But the neurons in these lab plates are still lagging behind in development compared to what you would see in a naturally developing human brain," Pasca said. Numerous challenges such as a lack of nutrients and growth factors, endothelial cells that form blood vessels, or sensory information make growth difficult in the lab, he said.

The transplant recipients in the study were baby mice that were only two to three days old, which is the equivalent of human infancy. It would be highly unlikely that an identical procedure would be worth performing in adult mice, Pasca said, since brain connections are largely formed early in development. The brain becomes significantly less tolerant to making more connections after those initial critical periods have passed, he said.

After about two months in culture, organoids closely resembling the human cerebral cortex were transplanted into the brains of young mice, nearly 100 of them over the course of the study. The organoids were placed in the same place in each mouse's brain to make it easier to monitor their development.

Mouse cells soon migrated into human tissue: mouse endothelial cells invaded human brain implants and collected in blood vessels that supply human cells with nutrients and signaling substances and transport waste products. Immune cells resident in the mouse brain also populated the human transplant.

"They moved immediately," Pasca said.

The implanted human organoids survived, thrived, and grew. After the transplant, they measured maybe a fifth of an inch and expanded to the point where, six months later, they occupied a third of the brain hemisphere of the mouse they were implanted in.

Individual neurons from human organoids in the brains of mice were now at least six times larger than those in organoids created the same way while remaining in a dish rather than being transplanted. They also showed much more sophisticated branching patterns.

Organoid neurons settled in the rat brain and formed working connections with native circuits. One of the mouse brain structures that human neurons made direct connections to was the thalamus, a region deep in the brain that relays multiple sensory inputs to the cortex.

(Video) Transplanting human-derived “organoids” allows scientists to study brain disorders | 90 Seconds

"This connection may have provided the necessary signals for optimal maturation and integration of human neurons," Pasca said.

The last controlled experiment

To assess the ability of transplanted organoids to identify the molecular basis of human neuropsychiatric disorders, Pasca and his colleagues turned to Timothy syndrome, a rare genetic disorder strongly associated with autism and epilepsy. The scientists transplanted an organoid generated from the skin cells of a patient with Timothy syndrome into one hemisphere of the mouse brain. In the appropriate place, on the other side, they transplanted an organoid generated from a healthy individual, which served as a control.

Five to six months later, the researchers observed clear differences in the electrical activity of both sides. The neurons of Timothy syndrome were also much smaller and lacked branching, brush-like projections called dendrites, which act as antennae for information from nearby neurons.

"We learned a lot about Timothy syndrome by studying organoids stored in a dish," Pasca said. "But only with the transplant were we able to see these differences in terms of neural activity."

Similar comparisons -- transplanting organoids from people with, say, schizophrenia or autism versus people without those disorders into opposite sides of the same mouse brain -- can reveal differences in size, complexity, functionality and connectivity, Pasca said.

Pawlows Ratten

The Stanford Medicine researchers were careful to place the organoids in the region of the mouse brain that processes sensory information from the animals' whiskers. The long hairs that protrude from their snout detect nearby objects and surfaces, helping them avoid collisions when moving quickly or in unfamiliar locations.

(Video) المخضرم | فئران بعقول بشرية

"We can now study healthy brain development, as well as brain disorders known to be ingrained in development, in unprecedented detail without having to remove tissue from a human brain."

Scientists have clearly shown that human neurons can be activated by information from mouse senses. When they disrupted the now-adult rats' whiskers with puffs of air, human neurons in the rats' brains electrically fired, responding synchronously to each puff of air.

Cognitive testing approximately 200 days after transplantation showed that the mice were no more anxious than control mice, retained similar memory abilities, and had no seizures.

"Overall, we haven't seen any improvement or deficit," Pasca said.

In another experiment, the scientists implanted human organoids modified so that their neurons could be activated by specific frequencies of blue laser light. About three months later, the researchers inserted ultra-thin fiber optic cables capable of carrying laser light from a distant source into human organoids in the brains of mice. These mice were then placed in a glass box with a small water spout. The researchers used a form of Pavlovian conditioning, emitting random bursts of blue light to activate human organoid tissue in the mice's brains, but only providing the mice with water after the blue light bursts. At the end of a 15-day training period, simply press a blue light on the organoid to make the mice run towards the bomb.

Rats learned to associate the blue light stimulation of their transplanted human neurons with the water reward, showing that the implanted human tissue has integrated and can participate in the rat's reward-seeking circuitry, a complex of neural pathways that normally regulate the behavior of Align mammals to activities associated with prior pleasurable outcomes.

"This is the most advanced human brain circuitry ever built from human skin cells and demonstrates that implanted human neurons can influence animal behavior," Pasca said. "Our platform is delivering behavioral data from human cells for the first time, and we hope it can accelerate our understanding of complex psychiatric disorders."

(Video) Back to the future: The promise of brain cell reprogramming | Professor Bronwen Connor

The study was supported by the National Institutes of Health (Grant R01MH115012, K99DA050662 and S10RR026917-01), Stanford Wu Tsai Institute of Neuroscience, Stanford Brain Organogenesis Program, Bio-X, Kwan Funds, Senkut Funds and the New York Stem Cell Fund Foundation funded, Chan Zuckerberg Initiative, Coates Foundation, Ludwig Family Foundation, and Alfred E. Mann Foundation.

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What happens when human brain tissue is implanted into rats? ›

After the transplants, he said, the human neurons grew to six times their original size over about eight months, making up roughly one-third of a single hemisphere in the rat brains. The rats didn't show signs of health issues like seizures or epilepsy, which the researchers had worried might arise.

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