People have been told for more than 100 years that once they reach adulthood, it’s all downhill for their brains. We don’t make new brain cells after birth, it was said, we only lose them, perhaps at the rate of about a million a day.
So when Henriette van Praag saw the results of her experiment at the Salk Institute, she rushed out to buy a pair of running shoes in hopes of proving that old adage wrong.
The reason for her optimism was that she had just discovered to her amazement that adult rats exercising on a running wheel were building new brain cells at an incredibly faster rate than sedentary animals.
Working in the same La Jolla, Calif., laboratory where Fred Gage just a year earlier had shown for the first time that adult humans can make new brain cells, van Praag thought she could speed up her production of new neurons, and possibly increase her intellect, by running.
Many scientists now think she may be right, especially in light of new research, reported by Elizabeth Gould of Princeton University and Tracey Shors of Rutgers, showing for the first time that newborn brain cells in adult rats are crucial for forming new memories.
“The people in my lab have certainly taken up more exercise,” Gage said. “We take long walks at lunch and stuff like that. The fact that humans make new brain cells changed everything. It was a big surprise. The field changed from being an animal curiosity to something pretty extraordinary.”
But science is hard-nosed, and clear proof is needed that exercise, or anything else, such as new experiences, can multiply brain cells in humans and that they improve memory. It’s an enticing challenge that is attracting an increasing number of scientists into the hot field of neurogenesis (the production of new nerve cells).
The field is racing ahead–Gage’s discovery came in 1998, van Praag’s in 1999 and Gould’s this year–because the tantalizing findings suggest amazing new powers of the brain–that physical and mental workouts may rejuvenate the thinking process. The findings also may help solve some fundamental mysteries.
Feeling a bit smarter after a good workout may be the result of additional brain cells. But if you then get dumber when under constant pressure or down in the dumps, it may be because stress and depression not only stop the production of new cells, but also cause existing ones to shrink.
“You have a situation then where stress literally does make you stupid,” said Bruce McEwen of Rockefeller University, who pioneered studies showing that long-term exposure to stress hormones can damage and even kill neurons.
“Fortunately, it’s probably largely reversible,” he said. “If you terminate stress the brain will pop back to its normal state. But it takes maybe weeks for that to happen.”
Breaking depression
Psychiatrists have long known that exercise can lift people out of depression, and now neuroscientists are finding physical changes in the brain that may make that happen. There is also early evidence that antidepressant drugs such as Prozac may work in part by increasing the production of neurons.
These findings suggest a whole new concept of depression: that much of depression may be due to things that dampen neurogenesis, while recovery is assisted by things that enhance the birth of neurons.
The ability of environmental experiences to dramatically change the population of brain cells, and the way they function, may also explain why postmenopausal women on estrogen-replacement therapy seem to retain their smarts, and why people who do crossword puzzles, read a lot or engage in some other regular mental gymnastics remain sharp.
On the other hand, it may also tell us why boring environments seem to make people duller, and why people with the least amount of education have a higher risk for Alzheimer’s disease.
The new research may also tell us why a good night’s sleep is so important for learning–because it takes time for new memory cells to form connections to the brain’s established memory bank.
Holding on to brain cells
These are some of the remarkable possibilities that arise as a result of the recent discovery that people constantly make new brain cells throughout life–perhaps thousands a day–and whether they keep them depends on what they do.
“The old idea of `use it or lose it’ is very appropriate here,” McEwen said. “What we’re talking about is that the brain is giving you this capacity to replace nerve cells and add new ones and make connections, but unless you make use of them they’re not necessarily going to last.”
Researchers hope the new findings will lead to relatively simple ways to enhance the brain’s neuron-building process to improve learning and memory, repair the damage from stroke or trauma and prevent or reverse Alzheimer’s and Parkinson’s disease, as well as other neurodegenerative disorders.
Preventing the memory loss of aging also may become possible as a result of experiments showing that stress hormones increase with age and that these are the same hormones produced in psychosocial stress that quash new brain cells. Blunting this age-related increase of stress hormones in animals allows new neurons to proliferate and performance to improve.
Amazing brain
The new findings come on the heels of discoveries made during the past 15 to 20 years that have revealed the brain to be highly malleable and constantly rewiring itself. New learning was found to occur with the construction of synaptic connections between brain cells. In essence, the brain builds itself from its experiences.
While the brain’s ability to rewire itself remains a cornerstone of learning and memory, the new findings of the past three to five years indicate that the brain has a second mechanism for enhancing learning and memory–it can create more neurons, thereby greatly increasing its computing power.
So far there are two areas of the brain that scientists agree make new neurons: the olfactory bulb, which is important for new smells, and the hippocampus. The hippocampus, in the lower middle region of the brain between the ears, plays an extremely important role in regulating not only learning and memory but also emotions.
Adding neurons to the hippocampus may give the brain the ability to leap across time and space, giving it the unique faculty to make associations between unrelated experiences–the key to inventiveness, creativity and imagination.
“It’s not just that your brain controls behavior, but your behavior can control your brain function and structure, and that subsequently affects who you are and what you do,” Gage said.
That’s a far different view of the brain than the one that has persisted for more than a century. In the mid-1960s, when Joseph Altman, then at the Massachusetts Institute of Technology, suggested from his preliminary experiments that rats made new brain cells all their life, his work was not believed.
It was ignored because scientists stuck to the old belief that the adult brain had a fixed number of cells and that the number gradually got smaller as cells died off from aging or disease.
Failing to have his seminal work recognized, Altman left the field. He was denied tenure at MIT but had a successful career at Purdue University.
Even when Fernando Nottebohm, chief of the laboratory of animal behavior at Rockefeller University, showed in the 1980s that songbirds continuously make new brain cells to accommodate the learning of new songs during mating season, most scientists thought it didn’t apply to mammals.
Monkey brains
The scientific community didn’t take neurogenesis seriously until the mid-’90s, when Gould showed that monkey brains produced new neurons.
Then in 1996, using more sophisticated techniques for identifying the birth of neurons and following them to maturation, Gage confirmed adult neurogenesis and went on to demonstrate that it occurs in elderly people.
Gould’s and Shors’ report in March nailed down the role between neurogenesis and memory formation. Rats trying to find a submerged platform in a pool of water use the walls and other cues in their environment to remember where the hidden platform is. This type of learning involves associating things separated by space and time.
Given chemicals to block the formation of new cells in the hippocampus, the animals do not remember where the platform is. When neurogenesis is restored, they quickly learn the whereabouts of the platform, demonstrating the vital role that new cells in the hippocampus play in associative learning.
The brain’s potential to make neurons may be far broader than researchers suspect. Gould and Charles Gross at Princeton, and William Greenough of the University of Illinois at Urbana-Champaign, for instance, have found early evidence that neurons are being minted in the neocortex, the front part of the brain involved in thinking and reasoning.
Fixing stroke damage
There is also some evidence that any part of the brain is capable of making new cells under special circumstances, a finding that Harvard University’s Jeffrey Macklis hopes to convert into a repair kit for the damage caused by stroke, trauma, Alzheimer’s, Parkinson’s or other neurological diseases.
By carefully destroying all the cells of one type in the cortex of mice, Macklis found that the surrounding cells send out chemical messengers that cause stem cells that reside in the fluid-filled ventricles in the center of the brain to produce fledgling neurons that then migrate to the damaged site. Stem cells can make other types of brain cells.
After they arrive at their destination, the new cells take on the form and function of the destroyed cells and make connections to far-away neurons that were the normal targets of the missing cells.
When a similar experiment was performed on zebra finches, the new cells that replaced destroyed song-producing neurons enabled the birds to regain their ability to make musical love notes.
Macklis’ goal is to identify the sequence of specific molecular signals that orchestrate the birth, migration and maturation of new neurons and turn them into drugs that can produce cells to replace the damaged circuitry of the diseased human brain.
Destroying neurons
But just as the brain can make new neurons, it can also destroy existing ones. Researchers have found a link between neuron death and depression.
Stress, considered to be a major factor in causing depression, increases levels of the stress hormone cortisol, which can damage or even kill neurons. It also decreases levels of growth factors that enable brain cells to thrive, and reduces levels of serotonin, which promotes neurogenesis.
Gage and van Praag at the Salk Institute and Princeton’s Barry Jacobs believe that depression is caused by a decline of neurogenesis and that recovery is accompanied by a fresh burst of neuronal growth in the hippocampus.
Rat neurogenesis comes to a halt, for example, within minutes after an animal is exposed to the smell of a fox, a natural predator. When monkeys living happily by themselves are put into the cage of an aggressive monkey for just an hour, frightening them out of their wits, their ability to make new neurons stops.
In both of these examples, the hippocampi of the rats and monkeys shrink and their mental performance declines.
Dr. Yvette Sheline of Washington University finds a similar response in depressed women. Women who are otherwise healthy but who have recovered from long-term depression, have hippocampi that are 10 percent smaller than healthy women of the same age (23 to 86 years) who had not been depressed. Women with a history of depression also did less well on memory tests.
Effect of Prozac
Prozac has become a wildly successful antidepressant drug because it is a member of a new family of compounds that increase serotonin in the brain. Ronald Duman of Yale University found that rats given Prozac increased neuronal production in the hippocampus by 70 percent.
Among other things that increase neurogenesis are estrogen, testosterone, electroconvulsive shock therapy and various hormonelike growth factors. But it is still unclear how they work.
Stress hormones also play a big role in age-related memory loss. As people get older, their adrenal glands pump out increasing amounts of stress hormones, which can depress neurogenesis and cause gradual shrinkage of the hippocampus.
Removing the adrenal glands of older animals cuts off the supply of stress hormones, and neurogenesis rebounds to levels found in younger animals.
Sheline believes the typical hippocampal shrinkage seen in older people can be prevented. Her super-healthy normal volunteers, those who had no history of depression, did not have smaller hippocampi in old age.
She attributes their thriving hippocampi to the fact that the women were doing all the right things to keep neurogenesis operating at a high level–eating well, exercising and keeping mentally active.
