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How Experience Shapes Adult Neurogenesis

Interneurons and mature granule cells in the adult mouse brain are critical for newborn neurons’ responses to novel environments.

By Ruth Williams | October 27, 2016

Granule neurons in the mouse dentate gyrusWIKIMEDIA, AVILA, J.Newly made cells in the brains of mice adopt a more complex morphology and connectivity when the animals encounter an unusual environment than if their experiences are run-of-the-mill. Researchers have now figured out just how that happens. According to a study published today (October 27) in Science, a particular type of cell—called an interneuron—in the hippocampus processes the animals’ experiences and subsequently shapes the newly formed neurons.

“We knew that experience shapes the maturation of these new neurons, but what this paper does is it lays out the entire circuit through which that happens,” said Heather Cameron, a neuroscientist at the National Institute of Mental Health in Bethesda who was not involved with the work. “It’s a really nicely done piece of work because they go step-by-step and show all of the cells that are involved and how they’re connected.”

Most of the cells in the adult mammalian brain are mature and don’t divide, but in a few regions, including an area of the hippocampus called the dentate gyrus, neurogenesis occurs. The dentate gyrus is thought to be involved in the formation of new memories. In mice, for instance, exploring novel surroundings electrically activates the dentate gyrus and can affect the production, maturation, and survival of the newly born cells. Now, Alejandro Schinder and his team at the Leloir Institute in Buenos Aires, Argentina, have investigated the process in detail.

Newborn dentate gyrus neurons, which are called granule cells, take six weeks to fully develop and integrate into the mouse brain’s existing neural networks, said Schinder. To examine these cells’ development, the team labeled newborn granule cells with red fluorescent protein in the brains of mice and then either left the animals in their regular cages (controls) or exposed them to enriched environments—cages with tunnels and other unusual objects—for different 48 hour periods. Three weeks after the new cells were labeled, the team examined their morphology and activity.

The researchers found that in animals who had been exposed to the enriched environment during a particular period (9 to 11 days after labeling), the young granule cells had longer dendrites with evidence of increased connections with other neurons. Specifically, these cells had a greater number of dendritic spines, the sites of incoming synapses, and more detectable electrical inputs.

Granule cells receive different inputs from surrounding neurons at different stages of their development, Schinder said, which may explain why they are apparently receptive to experiential input only within a short period (day 9 to 11), rather than throughout their development.

The team went on to analyze these neuronal inputs more closely. Through a series of optogenetic and chemogenetic experiments, the researchers showed that mature granule cells activated their younger counterparts via intermediary cells called interneurons. Artificially stimulating either the mature granule cells or the interneurons could recapitulate the effects of environmental enrichment on the young granule cells. Moreover, the team showed that blocking the activity of the interneurons during the animals’ exposure to enriched environments prevented the expected experience-induced morphology in the young granule cells.

“The take home message is that experience can change how these young cells are incorporating into the brain and how they are contributing to brain circuitry,” said Hongjun Song, who studies neurogenesis at the Johns Hopkins University School of Medicine in Baltimore and who did not participate in the research. But, he asked, “what’s the functional impact? Does this process make the mice better learners? Or if you block the process, do they get worse [at learning]?”

As yet, those questions remain unanswered.

D. D. Alvarez et al., “A disynaptic feedback network activated by experience promotes the integration of new granule cells,” Science, 354:459-65, 2016.

Tags

neuroscience, neurogenesis, learning, hippocampus and behavior

Physical Exercise Beefs Up the Brain

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also see update comment on this article  and this Science article

Creation Date: 28 Aug 2013 | Review Date: 28 Aug 2013

Physical Exercise Beefs Up the Brain

Source: Society for Neuroscience

Boost your brainpower. Train your brain. These days it's hard not to become distracted by ads for the latest program that promises to help you learn faster and hold onto memories longer.

Run for your life! Regular aerobic exercise has been associated with increased cognitive abilities, including benefits to learning and memory.  But, even as scientists continue to explore the effects of various brain-training programs, a wealth of evidence makes one thing quite clear: physical exercise benefits the brain. Over a decade of research in animals and people shows that engaging in regular aerobic activity leads to changes in the brain associated with improved cognition.

Exercise increases birth of new nerve cells

One of the earliest clues about exercise-induced changes in the brain came in the late 1990s, when a group of scientists decided to compare the brains of mice given unlimited access to an exercise wheel (runners) to those of mice without exercise wheels in their cages (non-runners).

Compared with the non-runners, the researchers discovered that physically fit mice had double the number of new nerve cells in a region of the hippocampus — an area of the brain involved in learning and memory. When the scientists later taught the runners and non-runners to navigate a water maze, they found the runners learned the task faster than the non-runners and took a more direct route to the maze end. 

Fred Gage, a neuroscientist at the Salk Institute for Biological Studies who led both studies, explained that the researchers were "very surprised" to find that the physical activity of a mouse "affects the number of new brain cells and impacts its ability to remember things." At the time, scientists largely agreed the brain affects behavior. Gage's studies suggested the opposite was also true.

Exercising monkeys learn faster

Rodents are avid runners. In fact, with access to the exercise wheel, they will run for hours, racking up several miles each day. Since most people don't put in the hours or mileage running that rodents do, some scientists began to ask: Are long hours of aerobic activity required to see the positive effects of exercise on the brain, or might a more moderate exercise routine do the trick?

To test whether moderate exercise changes the brain, Judy Cameron, a neuroscientist at the University of Pittsburgh, trained a group of middle-aged and older monkeys to run on a treadmill for one hour each day, five days per week for five months — a running regimen similar to that recommended for average, middle-aged adults. As the one group of monkeys ran, a second group of monkeys sat on the treadmills. Over the course of the study the researchers evaluated the monkeys' ability to learn new things.

Regardless of the age of the monkeys, Cameron's group discovered that the monkeys on the running regimen learned new things twice as fast as the sedentary animals.

"We were excited to see that the same moderate level of exercise that is recommended for middle-aged people is able to improve how the brain works in monkeys — increasing alertness, attentiveness, and leading to faster learning," Cameron says.

According to Cameron, it's possible that the cognitive improvements associated with exercise are the result of increased blood flow to the brain. The greater the blood flow, the faster oxygen and other important nutrients can reach nerve cells.

When Cameron's group compared the brains of the monkeys that ran to the brains of sedentary animals they found that the older runners developed more brain blood vessels. However, when the scientists examined the brains of older runners that stopped exercising for three months, they found that the older runners had no more brain blood vessels than their sedentary counterparts.

"These findings suggest that it's important to keep exercising to retain the benefits of exercise," Cameron says.

Brain benefits across lifespan

Studies of animals and people show an association between physical activity and improved cognitive performance across the lifespan, says Art Kramer, who studies how fitness can change the aging brain at the University of Illinois at Urbana-Champaign. According to recent human studies, even people who hold off on regular aerobic activity until later in life may still be able to gain from exercise in their senior years.

As people get older, it is natural for some regions of the brain to begin to shrink. For instance, studies show the hippocampus shrinks one to two percent annually in people without dementia — a loss that is associated with an increased risk for developing cognitive difficulties. Curious about whether exercise could help slow or reverse these changes, Kramer and his colleagues recruited a group of healthy, sedentary adults from ages 55 to 80 to participate in a yearlong exercise program.

These adults were divided into two teams — one spent their time walking for 40 minutes three days per week while the other performed a variety of strength and balance exercises during this time. At the start, middle, and completion of the study, the researchers used magnetic resonance imaging (MRI) to measure the volume of the hippocampus.

The size of the hippocampus increased by 2 percent on average in the adults that completed the walking regimen and memory improved. In contrast, the participants who completed a yearlong balance and strength training program experienced a 1 percent decrease in the volume of the hippocampus.

"These findings suggest that brain and cognitive health can benefit from very modest increases in exercise and physical activity," Kramer says. "It's never too late to reap the benefits of exercise."

References

Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, et al. Cardiovascular fitness, cortical plasticity, and aging. Proceedings of the National Academy of Sciences USA. Mar 2; 101(9):3316-21 (2004).

Cotman C, Berchtold N, Christie L.  Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends in Neuroscience. 9: 464-72 (2007).

Eriksson P, Perfilieva E, Björk-Eriksson T, Alborn A, Nordborg C, et al. Neurogenesis in the adult human hippocampus. Nature Medicine. 4: 1313 – 1317 (1998).     

Gómez-Pinilla F, Hillman C. The influence of exercise on cognitive abilities. Comprehensive Physiology. 3:403-428 (2013).

Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Medicine and Science in Sports and Exercise. Aug;39(8):1423-34 (2007).

Pereira A, Huddleston D, Brickman A, Sosunov A, Hen R, et al.  An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proceedings of the National Academy of Sciences. 13: 5638-5643 (2007).

Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, et al. Regional brain changes in aging healthy adults: General trends, individual differences and modifiers. Cerebral Cortex 15:1676–1689 (2005).

Rhyu IJ, Bytheway JA, Kohler SJ, Lange H, Lee KJ, et al. Effects of aerobic exercise training on cognitive function and corticol vascularity in monkeys.  Neuroscience. 4: 1239-1248 (2010).         

van Praag H, Kempermann G, Gage F. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neuroscience. 2: 266-270 (1999).

Voss M, Nagamatsu, L, Liu-Ambrose T, Kramer A. Exercise, brain, and cognition across the life span. Journal of Applied Physiology. 5: 1505-1513 (2011).

Further Reading

Ratey J. Spark: The Revolutionary New Science of Exercise and the Brain. Boston, 2008.

Reynolds G. Lobes of steel. New York Times, 2007.

Rosen M. Art Kramer, neuroscientist. UC Santa Cruz, 2012.

About the Authors

Jen Uscher

Jen Uscher is a freelance science writer based in Brooklyn, New York. She has written for ScientificAmerican.com, Popular Science, APA Monitor on Psychology, the Dana Foundation, the American Committee for the Weizmann Institute of Science, and the web site of the PBS science series NOVA.

Jennifer Carr

Jennifer Carr is the former manager of science writing at the Society for Neuroscience. While working as a technician at a neuroscience lab at the University of Pennsylvania, Jennifer discovered she is happiest when communicating the excitement of scientific discovery to the general public. She has written for Kaiser Health News, The Scientist, and The Times-Picayune.

reposted from

The smart mouse with the half-human brain

• 12:45 01 December 2014 by Andy Coghlan
• For similar stories, visit the The Human Brain Topic Guide

What would Stuart Little make of it? Mice have been created whose brains are half human. As a result, the animals are smarter than their siblings.

The idea is not to mimic fiction, but to advance our understanding of human brain diseases by studying them in whole mouse brains rather than in dishes.

The altered mice still have mouse neurons – the "thinking" cells that make up around half of all their brain cells. But practically all the glial cells in their brains, the ones that support the neurons, are human.

"It's still a mouse brain, not a human brain," says Steve Goldman of the University of Rochester Medical Center in New York. "But all the non-neuronal cells are human."

Rapid takeover

Goldman's team extracted immature glial cells from donated human fetuses. They injected them into mouse pups where they developed into astrocytes, a star-shaped type of glial cell.

Within a year, the mouse glial cells had been completely usurped by the human interlopers. The 300,000 human cells each mouse received multiplied until they numbered 12 million, displacing the native cells.

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

Astrocytes are vital for conscious thought, because they help to strengthen the connections between neurons, called synapses. Their tendrils (see image) are involved in coordinating the transmission of electrical signals across synapses.

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.

Intelligence leap

A battery of standard tests for mouse memory and cognition showed that the mice with human astrocytes are much smarter than their mousy peers.

In one test that measures ability to remember a sound associated with a mild electric shock, for example, the humanised 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."

Goldman first reported last year that mice with human glial cells are smarter. But the human cells his team injected then were mature so they simply integrated into the mouse brain tissue and stayed put.

This time, he injected the precursors of these cells, glial progenitor cells, which were able to divide and multiply. That, he says, explains how they were able to take over the mouse brains so completely, stopping only when they reached the physical limits of the space.

Species cross

"It would be interesting to find out whether the human astrocytes function the same way in the mice as they do in humans," says Fred Gage, a stem cell researcher at the Salk Institute in La Jolla, California. "It would show whether the host modifies the fate of cells, or whether the cells retain the same features in mice as they do in humans," he says.

"That the cells work at all in a different species is amazing, and poses the question of which properties are being driven by the cell itself and which by the new environment," says Wolfgang Enard of Ludwig-Maximilians University Munich in Germany, who has shown that mice are better at learning if they have the human Foxp2 gene, which has been linked with human language development.

In a parallel experiment, Goldman injected immature human glial cells into mouse pups that were poor at making myelin, the protein that insulates nerves. Once inside the mouse brain, many of the human glial cells matured into oligodendrocytes, brain cells that specialise in making the insulating material, suggesting that the cells somehow detected and compensated for the defect.

This could be useful for treating diseases in which the myelin sheath is damaged, such as multiple sclerosis, says Goldman, and he has already applied for permission to treat MS patients with the glial progenitor cells, and hopes to start a trial in 12 to 15 months.

Still a mouse

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.

Although this may sound like the work of science fiction – think Deep Blue Sea, where researchers searching for an Alzheimer's cure accidently create super-smart sharks, or Algernon, the lab mouse who has surgery to enhance his intelligence, or even the pigoons, Margaret Atwood's pigs with human stem cells – and human thoughts – Goldman is quick to dismiss any idea that the added cells somehow make the mice more human.

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

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.

Enard agrees that it could be difficult to decide which animals to put human brain cells into. "If you make animals more human-like, where do you stop?" he says.

Journal reference: Journal of Neuroscience, DOI: 10.1523/JNEUROSCI.1510-14.2014

reposted from

The smart mouse with the half-human brain

• 12:45 01 December 2014 by Andy Coghlan
• For similar stories, visit the The Human Brain Topic Guide

What would Stewart Little make of it? Mice have been created whose brains are half human. As a result, the animals are smarter than their siblings.

The idea is not to mimic fiction, but to advance our understanding of human brain diseases by studying them in whole mouse brains rather than in dishes.

The altered mice still have mouse neurons – the "thinking" cells that make up around half of all their brain cells. But practically all the glial cells in their brains, the ones that support the neurons, are human.

"It's still a mouse brain, not a human brain," says Steve Goldman of the University of Rochester Medical Center in New York. "But all the non-neuronal cells are human."

Rapid takeover

Goldman's team extracted immature glial cells from donated human fetuses. They injected them into mouse pups where they developed into astrocytes, a star-shaped type of glial cell.

Within a year, the mouse glial cells had been completely usurped by the human interlopers. The 300,000 human cells each mouse received multiplied until they numbered 12 million, displacing the native cells.

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

Astrocytes are vital for conscious thought, because they help to strengthen the connections between neurons, called synapses. Their tendrils (see image) are involved in coordinating the transmission of electrical signals across synapses.

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.

Intelligence leap

A battery of standard tests for mouse memory and cognition showed that the mice with human astrocytes are much smarter than their mousy peers.

In one test that measures ability to remember a sound associated with a mild electric shock, for example, the humanised 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."

Goldman first reported last year that mice with human glial cells are smarter. But the human cells his team injected then were mature so they simply integrated into the mouse brain tissue and stayed put.

This time, he injected the precursors of these cells, glial progenitor cells, which were able to divide and multiply. That, he says, explains how they were able to take over the mouse brains so completely, stopping only when they reached the physical limits of the space.

Species cross

"It would be interesting to find out whether the human astrocytes function the same way in the mice as they do in humans," says Fred Gage, a stem cell researcher at the Salk Institute in La Jolla, California. "It would show whether the host modifies the fate of cells, or whether the cells retain the same features in mice as they do in humans," he says.

"That the cells work at all in a different species is amazing, and poses the question of which properties are being driven by the cell itself and which by the new environment," says Wolfgang Enard of Ludwig-Maximilians University Munich in Germany, who has shown that mice are better at learning if they have the human Foxp2 gene, which has been linked with human language development.

In a parallel experiment, Goldman injected immature human glial cells into mouse pups that were poor at making myelin, the protein that insulates nerves. Once inside the mouse brain, many of the human glial cells matured into oligodendrocytes, brain cells that specialise in making the insulating material, suggesting that the cells somehow detected and compensated for the defect.

This could be useful for treating diseases in which the myelin sheath is damaged, such as multiple sclerosis, says Goldman, and he has already applied for permission to treat MS patients with the glial progenitor cells, and hopes to start a trial in 12 to 15 months.

Still a mouse

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.

Although this may sound like the work of science fiction – think Deep Blue Sea, where researchers searching for an Alzheimer's cure accidently create super-smart sharks, or Algernon, the lab mouse who has surgery to enhance his intelligence, or even the pigoons, Margaret Atwood's pigs with human stem cells – and human thoughts – Goldman is quick to dismiss any idea that the added cells somehow make the mice more human.

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

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.

Enard agrees that it could be difficult to decide which animals to put human brain cells into. "If you make animals more human-like, where do you stop?" he says.

Journal reference: Journal of Neuroscience, DOI: 10.1523/JNEUROSCI.1510-14.2014