Researchers at Stanford University have transplanted human neurons into rat brains, seen them mature into hybridized brain circuits and then used them to influence the rodents’ behavior. The work marks an impressive step forward for neuroscience, and could see rat brains serve as living laboratories for the study of cognitive disorders.
When it comes to organs in the human body, the brain is as complex as they come, and by the same token, an incredibly difficult object to study. In recent years we’ve seen scientists make impressive advances with lab-grown brain organoids. These begin with stem cells that are exposed to growth factors to stimulate their maturation into different types of brain cells, which then go on to assemble themselves into 3D structures that resemble those found in the brain.
This doesn’t result in consciousness, but does provide scientists with a model to study disorders such as epilepsy, autism, schizophrenia, and to investigate the effects of different drugs. We’ve also seen versions of brain organoids that can grow their own blood vessels, give off electrical signals and even grow basic eyes capable of sensing light.
Last year, Sergiu Pasca, a professor of psychiatry and behavioral sciences at the Stanford School of Medicine, co-authored a study on 20-month-old lab grown brain organoids. Prior to this work, it was thought that lab-grown brains weren’t capable of maturing past the stage equal to fetal development. The study proved that these organoids can mature much like a human brain, following an internal clock to reach postnatal maturity in a timeline parallel to in vivo development.
While Pasca and others in the field continue to develop advanced organoids representing different brain regions, such as the cerebral cortex, studying these structures in a dish has its limitations.
“We’ve been making ever more complicated circuits in a dish using organoids and sophisticated combinations of them, called assembloids,” Pasca said. “But neurons within these lab dishes are still lagging behind in their development compared with what you’d see in a naturally developing human brain. Numerous challenges – such as a lack of nutrients and growth factors, blood-vessel-forming endothelial cells or sensory input – hinder development in a lab dish.”
In their latest work, Pasca and his team transplanted brain organoids resembling the human cerebral cortex into nearly 100 young rats. The rats were two or three days old, equivalent to human infancy, and were implanted at this stage so the organoids could form connections and co-evolve in step with their own brains.
Before long, rat endothelial cells migrated into the human tissue to form blood vessels, supplying it with nutrients and signaling abilities to dispose of waste products. Immune cells in the rat brain followed suit, making themselves at home in the transplanted tissue. From there, the implanted organoids not only survived, but grew to the point where they occupied around a third of the rat brain hemisphere that they’d been implanted in.
Individual neurons from the organoids also grew rapidly, taking hold in the rat brains to form connections with the rodent’s natural brain circuitry, including with the thalamus region, which is responsible for relaying sensory information from the body.
“This connection may have provided the signaling necessary for optimal maturation and integration of the human neurons,” Pasca said.
The scientists then turned their eye to disease, creating an organoid using skin cells derived from a patient with Timothy syndrome, a brain condition associated with autism and epilepsy. This organoid was transplanted into one side of a rat brain, while an organoid created from a healthy subject’s cells was transplanted into the other side to serve as a control. Five to six months later, this revealed significant differences in electrical activity, while the Timothy syndrome neurons were also much smaller and featured fewer signaling structures called dendrites.
“We’ve learned a lot about Timothy syndrome by studying organoids kept in a dish,” Pasca said. “But only with transplantation were we able to see these neuronal-activity-related differences.”
But the most striking finding came from experiments designed to gauge the hybrid brains’ ability to process sensory information. Puffs of air were directed at the rats’ whiskers, which the scientists found made the human neurons electrically active in response.
Another experiment involved organoids modified to respond to blue light, which was administered through ultrathin fiber-optic cables. Pulses of blue light were used to activated these neurons, with water made available to the rats only after these blue-light events. This took place over a 15-day “training period,” teaching the rats that activation of these neurons meant a reward was coming, prompting them to scurry toward the water spout in anticipation. That the rats learned to associate blue-light stimulation with the availability of water shows the implanted human tissue could function as part of the rat brain’s reward-seeking circuitry.
“The researchers show that the human neurons, when activated, interfere with the rats’ behavior,” said Dr Jürgen Knoblich, Scientific Director Austria’s Institute for Molecular Biotechnology, who was not involved in the research. “The human cells functionally connect to the rat brain. This is the reason why the work is so outstanding.”
Pasca describes this as the most advanced human brain circuitry ever concocted from human skin cells, and says the platform is the first to offer behavioral readouts for human cells in this context. With the ability to control and observe the effects on the rats’ behavior, the technology opens up exciting new opportunities for the study of neuropsychiatric disorders.
“We can now study healthy brain development as well as brain disorders understood to take root in development in unprecedented detail, without needing to excise tissue from a human brain,” said Pasca. “We can also use this new platform to test new drugs and gene therapies for neuropsychiatric disorders.”
The research was published in the journal Nature.
Source: Stanford University