Neurology  

Scientists have now shown that it's possible to pick out key changes in the genetic code between chimpanzees and humans and visualize their respective contributions to early brain development in mouse embryos. The findings may lend insight what makes the human brain special and why people get some neurological disorders.

Scientists at Duke University have shown that it's possible to pick out key changes in the genetic code between chimpanzees and humans and then visualize their respective contributions to early brain development by using mouse embryos.

The team found that humans are equipped with tiny differences in a particular regulator of gene activity, dubbed HARE5, that when introduced into a mouse embryo, led to a 12% bigger brain than in the embryos treated with the HARE5 sequence from chimpanzees.

The findings, published in Current Biology, may lend insight into not only what makes the human brain special but also why people get some diseases, such as autism and Alzheimer's disease, whereas chimpanzees don't.

"I think we've just scratched the surface, in terms of what we can gain from this sort of study," said Debra Silver, an assistant professor of molecular genetics and microbiology in the Duke University Medical School. "There are some other really compelling candidates

Every genome contains many thousands of short bits of DNA called 'enhancers,' whose role is to control the activity of genes. Some of these are unique to humans. Some are active in specific tissues. But none of the human-specific enhancers previously had been shown to influence brain anatomy directly.

Silver discusses her work in a recent interview on NPR:

In the new study, researchers mined databases of genomic data from humans and chimpanzees, to find enhancers expressed primarily in the brain tissue and early in development. They prioritized enhancers that differed markedly between the two species.

The group's initial screen turned up 106 candidates, six of them near genes that are believed to be involved in brain development. The group named these 'human-accelerated regulatory enhancers,' HARE1 through HARE6.

The strongest candidate was HARE5 for its chromosomal location near a gene called Frizzled 8, which is part of a well-known molecular pathway implicated in brain development and disease. The group decided to focus on HARE5 and then showed that it was likely to be an enhancer for Frizzled8 because the two DNA sequences made physical contact in brain tissue.

"What we found is a piece of the genetic basis for why we have a bigger brain. It really shows in sharp relief just how complicated those changes must have been. This is probably only one piece—a little piece."

The human HARE5 and the chimpanzee HARE5 sequences differ by only 16 letters in their genetic code. Yet, in mouse embryos the researchers found that the human enhancer was active earlier in development and more active in general than the chimpanzee enhancer.

"What's really exciting about this was that the activity differences were detected at a critical time in brain development: when neural progenitor cells are proliferating and expanding in number, just prior to producing neurons," Silver said.

The researchers found that in the mouse embryos equipped with Frizzled8 under control of human HARE5, progenitor cells destined to become neurons proliferated faster compared with the chimp HARE5 mice, ultimately leading to more neurons.

As the mouse embryos neared the end of gestation, their brain size differences became noticeable to the naked eye. Graduate student Lomax Boyd started dissecting the brains and looking at them under a microscope.

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"After he started taking pictures, we took a ruler to the monitor. Although we were blind to what the genotype was, we started noticing a trend," Silver said.

All told, human HARE5 mice had brains 12% larger in area compared with chimpanzee HARE5 mice. The neocortex, involved in higher-level function such as language and reasoning, was the region of the brain affected.

Producing a short list of strong candidates was in itself a feat, accomplished by applying the right filters to analysis of human and chimpanzee genomes, said co-author Gregory Wray, professor of biology and director of the Duke Center for Genomic and Computational Biology.

"Many others have tried this and failed," Wray said. "We've known other people who have looked at genes involved in brain size evolution, tested them out and done the same kinds of experiments we've done and come up dry."

The Duke team plans to study the human HARE5 and chimp HARE5 mice into adulthood, for possible differences in brain structure and behavior. The group also hopes to explore the role of the other HARE sequences in brain development.

"What we found is a piece of the genetic basis for why we have a bigger brain," Wray said. "It really shows in sharp relief just how complicated those changes must have been. This is probably only one piece—a little piece."

Could the research be used to uplift animals to human-level intelligence?

"One can never say never, but I think it's a pretty long-shot, far-fetched type concern," says Ruth Faden, who directs the Johns Hopkins Berman Institute of Bioethics tells NPR.

An experiment like this recent one is not going to create mice that talk and think like people, Faden says. But it could be more ethically worrisome to try to genetically enhance the brains of nonhuman primates or other reasonably intelligent animals — like pigs.

That's something our own species might prefer to avoid, says Faden. "The prospect of, sort of, tearing down the barriers between humans and other nonhuman species in ways that really threaten our sense of ourselves as special is disturbing," she points out.


SOURCE  Duke University via EurekAlert

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 Neuroscience  

Mice have been created whose brains are made up of half human cells. These animals are much smarter than their siblings. The idea is not to create a science fiction scenario, but to advance our understanding of human brain diseases by studying them in whole mouse brains rather than in dishes.

By injecting human cells into baby mice, scientists have created mice whose brains are essentially part human. These hybrid, or chimeric mice grew to be much more intelligent than other mice, especially in tests for memory and cognition.

With this work, researchers hope to glean a lot of data. For example, by studying brain diseases in whole organisms rather than in cells in a dish, researchers should gain a better understanding of how the conditions develop and progress.

Uplift, a concept from science fiction author David Brinis the process of actively upgrading the capacities of a species, perhaps most recently played out in the Planet of the Apes movies, but according to the researchers, this is not their intention.

"This does not provide the animals with additional capabilities that could in any way be ascribed or perceived as specifically human," lead researcher Steven A. Goldman told New Scientist. "Rather, the human cells are simply improving the efficiency of the mouse's own neural networks. It's still a mouse."

"It's still a mouse brain, not a human brain, but all the non-neuronal cells are human." he says.

However, the team decided not to try putting human cells into monkeys. "We briefly considered it but decided not to because of all the potential ethical issues," Goldman says.

In the study, which has been published in The Journal of Neuroscience, researchers from the University of Rochester Medical Center started off by isolating immature glial cells from donated human fetuses. Glial cells are one of the two main cell types that build the nervous system, the other being neurons. Glia perform a variety of roles in the nervous system, such as providing support and protection for neurons, but unlike nerve cells they do not participate directly in electrical signaling, which is a form of communication used to transmit information between cells.

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The researchers then injected these cells into the brains of newborn mice, where they were found to change into star-shaped glial cells called astrocytes. These larger cells, which are the most common type of glial cell, wrap their tendrils around synapses, the active junctions between neurons through which chemical or electrical signals flow. In doing so, astrocytes provide support to neighboring neurons and also strengthen their synaptic connections.  It widely regarded that this support is essential for conscious thought.

"These were whopping effects. We can say they were statistically and significantly smarter than control mice."

Human astrocytes are 10 to 20 times the size of mouse astrocytes and carry 100 times as many tendrils. This means they can coordinate all the neural signals in an area far more adeptly than mouse astrocytes can. "It's like ramping up the power of your computer," says Goldman.

Within just one year, the astrocytes had proliferated so much that they displaced the native cells, resulting in populations of cells in some brain areas that were largely, and sometimes entirely, of human origin. The cells eventually reached 12 million, but they only stopped replicating because they reached the physical limits of the space.

“We could see the human cells taking over the whole space,” Goldman says. “It seemed like the mouse counterparts were fleeing to the margins.”

With the human astrocytes being dramatically larger than mouse astrocytes and possessing so many more many projections, the transplanted cells could coordinate the signaling in neural networks much more efficiently than native cells. This essentially gave their brains an upgrade, but it didn’t make the animals more human, say the researchers.

The researchers then performed various memory and cognitive tests on the mice and compared them with control mice, which revealed that they were significantly smarter than their peers. One test even suggested that their memory was four times better than the controls. “These were whopping effects,” Goldman remarked.

In one test that measures ability to remember a sound associated with a mild electric shock, for example, the chimeric mice froze for four times as long as other mice when they heard the sound, suggesting their memory was about four times better. "These were whopping effects," says Goldman. "We can say they were statistically and significantly smarter than control mice."

To explore further how the human astrocytes affect intelligence, memory and learning, Goldman is already grafting the cells into rats, which are more intelligent than mice. "We've done the first grafts, and are mapping distributions of the cells," he says.

Whether they proceed up the hierarchy of mammals with this work is a very serious ethical matter.


SOURCE  New Scientist

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 Genetics  

Researchers have shown that the human version of a gene called FOXP2 makes it easier to transform new experiences into routine procedures. When they engineered mice to express humanized FOXP2, the mice learned to run a maze much more quickly than normal mice.

Mice that receive a human version of a speech and language gene display accelerated learning, according to a new study.

While the researchers are careful not to call this an uplift gene, the work reveals something new and fascinating about the evolution of human speech and language.

The gene for the protein called FOXP2 has been firmly linked to human speech and language. Humans with just one functional copy of this gene experience difficulties in learning and struggle with spoken and written language.

The investigators discovered the mice with the human form of FOXP2 learned profoundly faster than regular mice when both declarative and procedural forms of learning were involved. The scientists published their findings in the Proceedings of the National Academy of Sciences.

The findings suggest that FOXP2 may help humans with a key component of learning language -- transforming experiences, such as hearing the word "glass" when we are shown a glass of water, into a nearly automatic association of that word with objects that look and function like glasses, says Ann Graybiel, an MIT Institute Professor, member of MIT's McGovern Institute for Brain Research, and a senior author of the study.

"This really is an important brick in the wall saying that the form of the gene that allowed us to speak may have something to do with a special kind of learning, which takes us from having to make conscious associations in order to act to a nearly automatic-pilot way of acting based on the cues around us."

“This really is an important brick in the wall saying that the form of the gene that allowed us to speak may have something to do with a special kind of learning, which takes us from having to make conscious associations in order to act to a nearly automatic-pilot way of acting based on the cues around us,” Graybiel says.

The gene itself is not unique—chimps have a version of it. But because the human and chimpanzee lineages diverged roughly 6 million years ago, they don't have two key changes in amino acids that humans have evolved.

To learn more about how FOXP2 alters the brain, scientists genetically engineered mice with the human form of FOXP2. In experiments with these rodents, the researchers focused on two modes of learning thought to be crucial for speech and language—declarative learning, which involves knowledge learned consciously, and procedural learning, which involves knowledge learned by experiencing something enough times for it to become habit.

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The scientists had mice run through a maze to get a reward of chocolate milk. The animals could figure out the location of the reward either through sensory cues such as rough or smooth floors, which corresponds to declarative learning. Or, they could discover the reward was always linked to either a left or right turn, which corresponds to procedural learning.

Declarative learning involves circuits in the central part of the striatum region of the brain, while procedural learning involves circuits in more peripheral parts of the striatum. The scientists found that both sets of circuits were altered in the mice with the human form of FOXP2.

Prior studies found that mice with the human version of FOXP2 demonstrate profound changes in the chemistry and anatomy of brain circuits essential for acquiring habits and other physical and mental behaviors, such as songbirds learning song. The kinds of changes seen in these studies may once have helped the human brain evolve speech and language.

"I don't think the goal is to make smarter animals, but rather to dissect out the biology underlying smartness," Smith says. "Having said that, if we can find a procedure like this that would help treat neurological or psychiatric disorders, that would be a wonderful purpose. For example, Parkinson's disease involves the same brain circuits being studied in this article — perhaps genes could be tweaked in similar ways to help."

This study "provides new ways to think about the evolution of Foxp2 function in the brain," says Genevieve Konopka, an assistant professor of neuroscience at the University of Texas Southwestern Medical Center who was not involved in the research. "It suggests that human Foxp2 facilitates learning that has been conducive for the emergence of speech and language in humans. The observed differences in dopamine levels and long-term depression in a region-specific manner are also striking and begin to provide mechanistic details of how the molecular evolution of one gene might lead to alterations in behavior."


SOURCE  MIT

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