save new brain cells

New nerve cells are created in the adult brain every day. These new studies help, in the end, in learning complex tasks, and the more they are challenged, the more they rise and flourish

By Tracy J. Shores
If you watch TV, read newspapers or surf the Internet, you must have come across ads imploring you to engage in mental gymnastics. Some brain training programs encourage people to maintain mental flexibility through daily brain training, from memorizing lists and solving crossword puzzles to estimating the number of trees in Central Park.

These programs sound like a publicity stunt, but they may have a real neurobiological basis. Recent studies, although conducted in rats, indicate that learning increases the survival of new nerve cells in the adult brain. And the more fascinating and challenging the learning, the more new neurons survive. It is likely that these cells will be available to help in other conditions that make it difficult for the brain. It therefore seems that mental exercise can strengthen the brain, just as physical exercise builds the body.

These findings may be of particular interest to intellectual couch potatoes, whose brain-blanket positions may benefit their gray cells. But mostly, these results support the belief that people who are in the early stages of Alzheimer's disease or suffer from other forms of dementia may delay cognitive decline by making sure they are mentally active.

New nerve cell!

In the 90s of the last century, the field of neurobiology underwent a severe shakeup when it became clear that the brains of adult mammals are capable of generating new nerve cells. Before that, biologists believed that neurogenesis, that is, the ability to produce new nerve cells, was reserved for young and developing brains, and it disappeared over the years. But at the beginning of the decade, Elizabeth Gould, then at Rockefeller University, showed that new cells are nevertheless formed in the adult brain, mainly in an area known as the hippocampus, which is associated with learning and memory processes. Shortly after, similar reports were published regarding different species, starting with mice and ending with marmosets (a type of monkey), and in 1998, neurobiologists in the USA and Sweden showed that there is neurogenesis in humans as well.

Studies of neurogenesis in rodents usually involve injecting a substance called BrdU (bromo-deoxyuridine), which marks new cells so they can be easily seen under a microscope. These studies indicate that 5,000-10,000 new nerve cells are created in the hippocampus of rats every day. (Although new nerve cells are also formed in the human hippocampus, we do not know their number.)

The rate of cell production is not constant, but is influenced by several environmental factors. For example, it turned out that alcohol consumption inhibits the creation of new nerve cells in the brain. On the other hand, it is possible to increase the rate of their production with the help of exercise. Rats and mice that spend time on a treadmill boast twice as many new cells as sedentary mice. Even eating blueberries may stimulate the creation of new nerve cells in the hippocampus of rats.

use or throw away

Exercise and other activities may therefore help produce more brain cells, but these newly recruited cells don't necessarily stay. Many of them, and even most of them, disappear a few weeks after their formation. Of course, most cells in the body don't survive forever, so it's no surprise that the new brain cells die too. But their short life time nevertheless raises questions. Why does the brain bother to make new cells only to let them die quickly?

From our work in rats, the answer seems to be that the brain produces these cells "just in case." If the rats encounter a cognitive challenge, the cells stay, but if not, the cells will disappear. Gould, now at Princeton University, and I made this discovery in 1999 when we performed a series of experiments that tested the effect of learning on the survival of new neurons in the hippocampus of rats.

The learning task we used, known as eyeblink conditioning, is similar in some ways to the experiments in which Pavlov's dogs began to bark when they heard a sound they associated with food. In blink conditioning, the animal hears a sound and after a fixed time (usually 500 milliseconds, i.e. half a second), it is made to blink with a puff of air or a slight stimulation of the eyelid.

After enough repetitions, usually a few hundred, the animal makes a connection in its mind between the sound and the visual stimulus. She learns to anticipate when the stimulus will come and blink right before it occurs. This "conditioned" response indicates that the animal has learned to associate the two events with the same time. The rat's achievement may seem marginal, but this setup provides a good way to measure "forward learning" in animals, meaning the ability to predict the future based on the past.

To examine the relationship between biolearning and neurogenesis, we injected all animals with BrdU at the beginning of the experiments. After a week, half of the rats were included in the blink training program. The others remained in the cage. After 4-5 days of training, we found that in the hippocampus of rats that learned to time their blinks correctly, more BrdU-labeled neurons remained than in the rats that remained in the cages. We concluded that learning this task saved cells from death. In untrained animals, very few new cells labeled with BrdU at the beginning of the experiment survived to the end. And the better the animal learned, the more new nerve cells survived. The same phenomenon was observed in animals that learned to navigate a maze.

When we started doing the blink studies in the late 90s, we tested the effect of training only in animals that had learned well, that is, rats that had learned to blink up to 50 milliseconds before eyelid stimulation, and that did so in more than 60% of the repetitions. We recently asked whether new neurons survived even in animals that failed to learn, or that learned unsuccessfully. The answer is - no. In studies published in 2007, rats that underwent about 800 repetitions of the experiment but never learned to anticipate the eyelid stimulus had as few new neurons as animals that never left the cage.

We also performed experiments in which we limited the animals' learning opportunities. This time we only gave the rats one day, i.e. 200 repetitions, to learn. In these experiments, some of the rats learned to anticipate the stimulus and some did not. Again, the rats that learned had more nerve cells left than the rats that didn't learn, even though they all went through the same training program. These data imply that the learning process, and not just the training or the exposure to a different cage or a different daily routine, is what saves the new nerve cells from death.

hard in training easy in battle

Although learning must occur for new neurons to survive in the hippocampus, not all types of learning are effective. For example, if an animal is trained to swim towards a visible buoy in a pool of water, there is no increase in cell survival. The same is true when training an animal to recognize that two stimuli, for example a sound and an eyelid stimulus, occur almost simultaneously.

The reason these tasks fail to save new cells from death is that they don't require much thought. Swimming towards a visible buoy is a task that the rats eagerly perform. After all, they don't want to drown. And if the eyelid stimulation coincides with the sound, the animals do not need to remember a past event, namely the sound, to predict when the eyelid stimulation will occur. They just react when they hear the sound.

We believe that the tasks that saved most of the new nerve cells are the most difficult to learn, those that require a great mental effort to succeed in them. To test this assumption, we took a fairly simple task and made it slightly more challenging. We began with the easy blink task, in which the sound precedes, but still coincides in time with, the eyelid stimulus. Learning this connection, as mentioned, does not save new neurons. Next, we increased the difficulty level of this task by greatly increasing the duration of the sound, so that the stimulus appeared near the end of a very long sound.

In the second task it is more difficult to learn to blink than in the first and easier task, because in this case, blinking immediately after the sound starts playing, similar to runners running after a gun shot, is not the correct response. The task is also more difficult than the 500 millisecond task, because the animal cannot use the end of the sound as a "get ready" signal. In fact, the rat has to pay attention to exactly when the sound is played and estimate when the eyelid stimulus will occur. This is a real challenge for all animals, and humans in general. We discovered that this task saves the same number of neurons as the 500 millisecond task, and sometimes even more.

It is interesting to note that among the animals that were able to learn the conditioning tasks, in those that learned somewhat slowly, that is, they needed more repetitions to perform the task correctly, more new neurons survived than in animals that learned quickly. That is, it seems that new neurons in the hippocampus respond in the best way to learning, which involves the joint effort of many cells.

The timing is decisive

It is not clear to us why intensive learning is necessary for cell survival. One theory is that tasks that require more thinking, or that take longer to learn, activate more vigorously the neural networks in the hippocampus, networks that also include the new nerve cells, and that this activity is a key factor. I tend to support this opinion for several reasons.

First, some researchers have shown that tasks involving learning, such as classical eyeblink conditioning, often lower the electrical stimulation threshold of neurons in the hippocampus, so that they become more active. Moreover, the activity in the hippocampus goes hand in hand with learning. That is, animals in which the most neural activity was observed are the ones that learned the task in the best way.

Second, there seems to be a very short time window during which learning can save new neurons. In rodents, it is one to two weeks after the cells are formed. One recent study in rats showed, for example, that learning can save cells when the cells are 7-10 days old. Training that occurs after this time is too late. The nerve cells are already starting to die. And training that occurs before this time period is too early to help. This learning window corresponds to the period when these new cells, which begin their lives as undifferentiated cells, begin to differentiate into nerve cells. They grow dendrites (whose job is to receive the signals from other areas of the brain), and axons (which carry the information to a nearby area in the hippocampus, known as CA3). At about the same time the cells also begin to respond properly to the neurotransmitters, the chemicals that transmit the signals from one nerve cell to another.

These observations suggest that the new cells need to mature and integrate into existing neural networks before they can respond to learning. When learning is complicated, neurons throughout the hippocampus, including the new recruits, work at full steam. And these recruits survive. But if the animal is not challenged, the new nerve cells do not receive the stimuli they need to survive and they simply die out.

what are they doing there

Thus, thousands of new cells are created in the hippocampus every day, and if the animal is challenged with learning tasks, the cells survive. But what is their role? They cannot, of course, help with real-time learning as soon as they are created. A significant part of the learning takes place almost immediately (within a few seconds, if not less than that). When the brain is faced with a new task, it cannot wait about a week for the new nerve cells to form, mature and connect to existing networks so that the animal can start learning. My colleague and I suspected that the cell pool affects later aspects of the learning process.

To test this idea, we decided to get rid of the new brain cells. If these cells become important for learning, animals lacking these cells will be worse students. Of course, it is technically impossible to get all the new cells out of the animals' brains. Instead, we prevented the cells from forming in the rats' brains in the first place, for several weeks, by giving them a drug called MAM, which prevents the cells from dividing. After that, the animals joined the curriculum.

We found that rats treated with MAM were poor students in the 500 millisecond task. They had difficulty learning to anticipate the stimulus. But these animals did well with many other learning tasks that depend on the hippocampus, such as the Morris water maze. In this task, rats are placed in a pool of cloudy liquid, and the rats must swim until they discover a standing platform submerged in the water. The sides of the pool are marked with spatial signals that help the animals to navigate. Rats lacking new neurons mastered the task as quickly as their untreated sisters.

In our laboratories, MAM-treated animals also learned to remember the place where an emotional event occurred. For example, rats that received an unpleasant paw stimulus when placed in a particular cage froze as soon as they were placed there again. This type of emotional learning, known as contextual fear conditioning, also depends on the hippocampus, but it did not pose a problem for our treated animals.

Overall, the learning abilities of rats with few new neurons were largely unaffected. The animals did have difficulty learning certain complicated contexts, such as understanding that the sound always precedes the eyelid stimulation by half a second. We therefore conclude that if the new neurons are important at all for learning, they play a role only in certain situations, most likely those that require cognitive effort.

Biologically, this kind of specialization makes sense. An animal would not want to rely on the production and development of an entire set of new nerve cells to respond to situations that affect its immediate survival. It is therefore assumed that the extra cells, once they mature, are used to fine-tune or strengthen already existing problem-solving skills. In psychological language, strengthening such skills is known as "learning how to learn".

What about my brain?

All the studies described so far have been conducted on rats or mice. What will happen to people who do not produce new neurons in the hippocampus? Modern medicine, unfortunately, provides us with a population of ready-made subjects, that is, people undergoing chemotherapy treatments for cancer. Like the MAM treatment, chemotherapy impairs the cell division needed to make new cells. Therefore, it is probably no coincidence that people treated with chemotherapy often complain of learning and memory difficulties.

This situation is consistent, in several ways, with our animal data. Like the rodents, who had very mild cognitive impairment after MAM treatment, people undergoing chemotherapy also function well under most circumstances. They get dressed, go to work, prepare meals, spend time with friends and family, and continue living their lives. It makes sense. Given the findings regarding laboratory animals, we would not expect to find profound deficits in basic cognitive function. However, we would also expect to find selective deficits in more complex learning processes, the type of tasks that challenge each of us, such as performing several tasks at the same time so that it is necessary to switch from task to task while processing new information.

To determine what role neurogenesis plays in human learning, researchers must accomplish two goals: develop noninvasive methods to identify new nerve cells in the living brain, and find reversible ways to prevent cell maturation during learning processes. Methods to achieve the first goal are currently under development, but it is assumed that achieving the second goal will take longer.

However, let's assume for a moment that an available pool of new nerve cells does help maintain the intellectual flexibility of the human brain. Is it possible to use neurogenesis in some way to prevent or treat diseases that impair cognitive ability?

In the case of Alzheimer's disease, for example, the degeneration of nerve cells in the hippocampus causes a worsening and progressive loss of memory and the ability to learn. Alzheimer's patients continue to produce new nerve cells, but it seems that many of them do not survive and mature. It is possible that the processes of neurogenesis and neural maturation are damaged in these people. Or the new cells do not survive because the disease impairs the ability to learn.

Nevertheless, some of the findings are hopeful, at least for those in the early stages of dementia. As mentioned, studies in animals and healthy people suggest that simple actions such as aerobic exercises can increase the creation of new nerve cells. It also turns out that antidepressants are powerful modulators of the neurogenesis process. A 2007 study showed that long-term treatment with antidepressants improves the day-to-day and general functioning of Alzheimer's patients, suggesting that such treatment may promote the production and survival of new nerve cells in patients.

Anecdotal reports indicate that learning that involves effort may also help some patients. Recently, I presented our animal research data at a conference on Alzheimer's and other dementias. The doctors in the audience were intrigued by the findings indicating that the effort to learn something new may preserve young nerve cells. They report seeing the benefits of such efforts in their patients. And they say that patients who are able to fully engage themselves in strenuous cognitive activity may delay the progression of the disease that robs their brains.

Of course, it would be foolish to think that cognitive activity combined with antidepressants or physical activity can repair the damage caused by diseases such as Alzheimer's disease, which kills many brain cells, not just the new ones. But it is possible that such activities may slow the rate of cognitive decline, both in people dealing with neurodegenerative diseases and, perhaps, in all of us as we age.

They say you can't teach an old dog new tricks, and indeed, as adults, many of us struggle to learn something completely new. But if we want to keep our brains in shape, it probably wouldn't hurt to learn a new language or step, or play a violent computer game with the Wii console - such fitness training might even help.

key concepts

Thousands of new cells are created in the adult brain every day, mainly in the hippocampus, a structure associated with learning and memory.

Within about two weeks, most of these new neurons will die, unless the animal is faced with the challenge of learning something new. Learning, and especially one that involves a lot of effort, may keep these nerve cells alive.

Although neurons are apparently not necessary for most types of learning, they may play a role in predicting the future based on past experience. Increasing neurogenesis (production of new nerve cells) may therefore slow down cognitive decline and preserve the mental capacity of healthy minds.

on the notebook

Tracy J. Shors, a professor in the Department of Psychology and Center for Collaborative Neuroscience at Rutgers University, has long been interested in the neurobiology of learning and memory. She collaborates with Elizabeth Gold from Princeton University, who discovered the phenomenon of neurogenesis in adults. Together they showed that learning increases the survival of new neurons in the hippocampus, and that these neural circuits are apparently involved in certain aspects of learning. About 10 years later, Shores still continues to wonder about the question: "Neurogenesis: what about it and learning?"

Basic facts

Where new nerve cells are formed

In the adult brain, new nerve cells are formed in the hippocampus, a structure associated with learning and memory. Although the original discovery was made in rodents, since then new nerve cells have also been found in the adult human brain. More specifically, the new neurons emerge in an area of ​​the hippocampus known as the dentate gyrus, highlighted in the brain slices on the right.

Learning tests

What do studies in rats teach us?

The author and her colleagues relied on "blink conditioning" experiments to discover that a great effort to learn something increases the survival level of new nerve cells. They started by performing a classic experiment, in which the animal hears a sound and half a second later they make it blink with a stimulus. After several hundred repetitions, most animals begin to blink immediately before the stimulus. Because the sound and the blink stimulus are separated in time, it is difficult to know when to blink. This task saves a significant part of the new nerve cells.

The rats easily master an easier version of the task, in which the stimulus to blink coincides with the time the sound is played. This task does not increase the survival of new nerve cells. However, if you raise the level of difficulty even more, by making the rat have to wait a longer time before the stimulus arrives to blink, more neurons are saved even compared to the classic version.

hypothesis

How learning helps save new nerve cells

During the first week of life, new cells in the hippocampus migrate from the edge of the dentate gyrus towards a deeper region. There they mature and join a neural network. Learning that occurs when the cells are one to two weeks old increases their survival. It is possible that the reason for this is the activation of existing nerve cells, which release, in turn, signals that encourage the maturation of the young cells. In the absence of learning during the maturation period, most of the new hippocampal cells will die.

What helps, what harms

Learning encourages the survival of new nerve cells, but does not affect the number of cells produced. But it turns out that other activities do affect the production of nerve cells in rodents.

Encouraged: physical activity, antidepressants, blueberries
Depressants: alcohol, nicotine

What next?

Much has been revealed about the way in which learning affects the survival of new neurons in the hippocampus. First, we are interested in understanding the molecular mechanisms used to rescue cells during cognitive challenges. What neurotransmitters are involved? Which receptors? And when exactly do these mechanisms work? Does learning help new neurons integrate into neural networks, or does it increase the survival of those already integrated? How do nerve cells produced in the adult brain contribute to the ability to accumulate knowledge?

Studies of this type are conducted in animals. But we would also like to understand more about neurogenesis in humans, both in healthy people and in people with diseases such as Alzheimer's.

To do so, we will need non-invasive methods to monitor the birth and death of new neurons in the human brain. These methods will allow us to understand some interesting issues, such as the degree of neurogenesis in a healthy human brain compared to a brain with Alzheimer's. Ultimately, we will also be able to test whether any treatment, for example gene therapy, can increase the number of new neurons remaining in the hippocampus, and whether a given brain exercise can help and preserve the new cells.

And more on the subject

Learning Enhances Adult Neurogenesis in the Hippocampal Formation. Elizabeth Gould, Anna Beylin, Patima Tanapat, Alison Reeves and Tracey J. Shores in Nature Neuroscience, Vol. 2, no. 3, pages 260–265; March 1999.

Neurogenesis in the Adult Is Involved in the Formation of Trace Memories. Tracey J. Shors, George Miesegaes, Anna Beylin, Mingrui Zhao, Tracy Rydel and Elizabeth Gould in Nature, Vol. 410, pages 372–376; March 15, 2001.

Neurogenesis, Learning and Associative Strength. Jaylyn Waddell and Tracey J. Shors in European Journal of Neuroscience, Vol. 27, no. 11, pages 3020–3028; June 2008