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.
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.
"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.
"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."
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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FAQs
Do human brain cells transplanted into rat brains hold promise for neuropsychiatric research? ›
Human brain cells transplanted into rat brains hold promise for neuropsychiatric research. Lab-grown clusters of human brain cells integrate so well into young rats' brains they enable researchers to study neurodevelopmental disorders' molecular and circuit underpinnings.
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.
How did human brain cells implanted in rats prompt excitement and concern? ›The team trained the rats to lick a spout to receive water while the light was switched on. Afterwards, when the researchers shone the light on the hybrid brains, the rats were prompted to lick the spout, meaning that the human cells had become integrated well enough to help drive the animals' behaviour.
Do human brain cells transplanted into baby rats continue to grow? ›Human neurons transplanted into a rat's brain continue to grow, forming connections with the animals' own brain cells and helping guide their behavior, new research has shown. In a study published in the journal Nature today, lab-grown clumps of human brain cells were transplanted into the brains of newborn rats.
Why are rats used for brain research? ›Rats are commonly used for behavioral studies because they are much more social than mice and their behavior better mimics behavior seen in humans.
Are rats with human brain cells still just rats? ›Throughout the study, the team examined the rats to see if those with human cells were any smarter, or experienced more suffering, than rats that didn't receive organoid transplants. They found no sign of human traits or behaviors.
Have rats been given human brain cells? ›Scientists have successfully transplanted clusters of human neurons into the brains of newborn rats, a striking feat of biological engineering that may provide more realistic models for neurological conditions such as autism and serve as a way to restore injured brains.
How are scientists using rats to study human brain diseases? ›Scientists have transplanted human brain cells into the brains of baby rats, where the cells grew and formed connections. It's part of an effort to better study human brain development and diseases affecting this most complex of organs, which makes us who we are but has long been shrouded in mystery.
What is the difference between rat brain and human brain? ›One very notable difference between the human and rodent developing brain is gyrification, which is essentially absent in the rodent brain.
What is one reason the researcher would want to use rats instead of humans in this experiment? ›Another reason rodents are used as models in medical testing is that their genetic, biological and behavior characteristics closely resemble those of humans, and many symptoms of human conditions can be replicated in mice and rats.
How do rats help mental health? ›
Learning tricks, solving puzzles, playing with toys, and completing obstacle courses are just a few of a pet rat's favorite pastimes. This provides endless entertainment for the rat and the owner alike, and it can really help cheer someone up when dealing with depression or anxiety.
What do the rat experiments tell us about memory? ›The rats demonstrated a response bias that suggests that they have the ability to retrospectively recollect their self-behavior, i.e., episodic memory. We next made excitotoxic lesions in the retrosplenial cortex (RSC) and investigated the effects of the lesions on the unexpected recollection.
Are humans born with all the brain cells they will ever have? ›Although the majority of neurons are already present in our brains by the time we are born, there is evidence to support that neurogenesis (the scientific word for the birth of neurons) is a lifelong process.
Will human brains continue to grow? ›Over the past 6 million years, hominin brain size roughly tripled, suggesting selection for big brains driven by tool use, complex societies and language. It might seem inevitable that this trend will continue, but it probably won't. Instead, our brains are getting smaller.
Do human brain cells grow back? ›And one of the most exciting and important recent discoveries is that brain cells DO regenerate throughout your entire life. We now know that neurogenesis — the formation of new brain cells — is not only possible, it happens every day. This is not simply a fascinating piece of information, it's news you can use.
How do rats benefit humans? ›They balance the ecosystem. With reports of infestations popping up every day, rats being vital to the ecosystem might seem like a surprising reality, but rats actually play an important role in prompting tree growth around the world by spreading seeds.
Are rats more intelligent than humans? ›Even though the rat brain is smaller and less complex than the human brain, research has shown that the two are remarkably similar in structure and function. Both consist of a vast amount of highly connected neurons that are constantly talking to each other.
How much DNA do we share with rats? ›Our feline friends share 90% of homologous genes with us, with dogs it is 82%, 80% with cows, 69% with rats and 67% with mice [1]. Human and chimpanzee DNA is so similar because the two species are so closely related. They both descended from a single ancestor species 6 or 7,000,000 years ago.
Can rats think about thinking? ›Rats Can Think About Thinking
Rats are capable of an intricate thought process called metacognition, which is uncommon among non-human and non-primate animal species. Simply put, metacognition is the ability to think about your own thinking.
Neuroscientists have been able to simulate the circuitry of a sand-grain-sized piece of rat brain with the help of a supercomputer.
Which organ is present in humans but missing in rats? ›
The spleen of mice and rats exhibits an additional well-delineated B-cell compartment, the marginal zone, between white and red pulp. This area is, however, absent in human spleen. Human splenic secondary follicles comprise three zones: a germinal centre, a mantle zone and a superficial zone.
Does the human brain need meat? ›There's scientific reasons for this phenomenon, and research shows that meat is essential for optimal brain function. Our bodies are best able to absorb nutrients from sources that are straight from nature with vitamins and minerals available in their most bioavailable forms.
What did stress do to the rat's brain cells? ›Summary: A single, socially stressful situation can kill off new nerve cells in the brain region that processes learning, memory and emotion, and possibly contribute to depression, new animal research shows.
What animal brain is closest to human brain? ›The studies were recently published in eLife. The chimpanzee is often thought of as the animal most similar to humans.
What was the rat experiment in psychology? ›The Drowning Rats Psychology Experiments. Curt's experiments focused on how long it takes rats to die from drowning. He conducted his experiments by placing rats into buckets filled with water and seeing how long they survived. He introduced a range of variables into the experiment, that yielded some interested results ...
Why are scientists growing human brain cells in the lab? ›These allow scientists to investigate how certain cell types function, and can even be used to model whole organs. In fact, the first cerebral organoid was made from induced pluripotent stem cells from a patient with microcephaly, where the size of the brain is reduced.
How do rats give humans diseases? ›Rats and mice are known to carry many diseases. These diseases can spread to people directly, through handling of rodents; contact with rodent feces (poop), urine, or saliva (such as through breathing in air or eating food that is contaminated with rodent waste); or rodent bites.
What part of the brain makes humans different from animals? ›Humans have a much larger and more wrinkly cortex compared with other animals of the same size. You might be surprised, but the wrinkles and folds are a very important part of what makes our brain so special.
What's the IQ of a rat? ›Rat Fact - The average IQ of a rat is 105.
Is studying animal brains a good way to study human brains? ›Since complex human thoughts are built on a foundation of simpler mental processes that are evident in animals, animal studies can shed light on uniquely human behaviors. Animal research involving the brain has already produced dramatic improvements in human health and well being, and it promises many more.
Is it ethical to use rats in research? ›
University's research on rats inhumane: usage of rat testing in psychology labs is unethical, cruel. Many readers may be surprised to learn that there is a class in the Psychology Department at the University that conducts animal research.
Why are rats a threat to humans? ›Rodents can infect humans directly with diseases such as hantavirus, ratbite fever, lymphocytic choriomeningitis and leptospirosis. They may also serve as reservoirs for diseases transmitted by ectoparasites, such as plague, murine typhus and Lyme disease.
What is a reason researchers sometimes prefer to use animals as opposed to humans in psychological research? ›Animals are good research subjects for a variety of reasons. They are biologically similar to humans and susceptible to many of the same health problems. Also, they have short life-cycles so they can easily be studied throughout their whole life-span or across several generations.
Can rats sense human emotions? ›Over the past few years we've learned much about the moral lives of animals. Detailed studies have shown that mice and chickens display empathy—and now we know rats do, too. A study published recently has provided the first evidence of empathy-driven behavior in rodents.
How do you mentally stimulate a rat? ›- Keep Several Pet Rats Together. ...
- Get a Large Cage and Provide Supervised Time Outside of It. ...
- Provide Lots of Toys and Rotate Them Regularly. ...
- Remember That Food Is a Form of Enrichment, Too. ...
- Don't Forget the Overall Environment.
Several species of mammal, including mice, rats and dogs, are able to sniff out disease in humans and other animals.
What were the results of the rat Man experiment? ›Participants were shown either a series of animal pictures or neutral pictures prior to exposure to the ambiguous picture. They found participants were significantly more likely to perceive the ambiguous picture as a rat if they had had prior exposure to animal pictures.
What did Tolman's experiment on rats show? ›Tolman's experiments with rats demonstrated that organisms can learn even if they do not receive immediate reinforcement (Tolman & Honzik, 1930; Tolman, Ritchie, & Kalish, 1946).
How good is the memory of a rat? ›Rats have excellent memories
Rats are very clever and have super good memories. They can recognise other rats and humans they've seen before and once they learn how to get somewhere, they're unlikely to forget the route.
One very notable difference between the human and rodent developing brain is gyrification, which is essentially absent in the rodent brain.
What part of the brain is impacted by stress in the research presented on rats? ›
We found that the prefrontal cortex (PFC) was the area with the highest degree of changes induced by chronic stress. Although the hippocampus presented relevant lipidomic changes, the amygdala and to a more extent, the cerebellum, presented few lipid changes upon chronic stress exposure.
What animal has the same brain as a human? ›The brains of early humans were similar to those of chimpanzees. Walrus – It has a brain size of 1.1 kg. This brain size comes very close to a human brain size.
What is the main difference between the brains of animals and humans? ›The primary distinction between humans' and animals' brains is that humans' brains have remarkable cognitive capacity, which is a crowning achievement of evolution, whereas animals' brains have comparatively less cognitive capacity.
Why rat brains are similar to humans? ›Even though the rat brain is smaller and less complex than the human brain, research has shown that the two are remarkably similar in structure and function. Both consist of a vast amount of highly connected neurons that are constantly talking to each other.
What can humans get from rats? ›- Hantavirus.
- Hantavirus Pulmonary Syndrome.
- Hemorrhagic Fever with Renal Syndrome.
- Lassa Fever.
- Leptospirosis.
- Lujo Hemorrhagic Fever.
- Lymphocytic Choriomeningitis (LCM)
- Monkeypox.
The amygdala, hippocampus and prefrontal cortex are areas in the brain that are implicated in the stress response. Phan says high activity in the amygdala shows increased activity in brain scans. Increased and sustained reactivity in the amygdala is characteristic of depression and other mental health diagnosis.
What part of the brain is responsible for mental activity? ›Your brain's frontal lobe is home to areas that manage thinking, emotions, personality, judgment, self-control, muscle control and movements, memory storage and more.
Why are rats often used in research studies on behavior quizlet? ›Because rats have a unique ability to adapt to new environments they are a good animal model for: behavioral research.