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Neurogenesis Plays Key Role in Learning and Memory--Salk Scientists Find
| Type: | Science in the Spotlight |
| Date: | Spring 2008 |
| Related Topics: | Brain Health, Mental Health |
Not long ago, the suggestion that old brains could grow new nerve cells – or neurons – was unthinkable among neurologists. Today, however, we know that neural stem cells are indeed capable of growing new neurons throughout life. This process is called neurogenesis, which literally means “the birth of new neurons.” Precisely how nerve stem cells function and how they are regulated, however, have remained something of a mystery until recently.
At the Salk Institute for Biological Studies in La Jolla, Calif., Fred H. Gage, Ph.D., a professor in the Laboratory of Genetics, and Ronald M. Evans, Ph.D., a professor in the Gene Expression Laboratory, are now unraveling at least some of the molecular mechanisms involved in neurogenesis. In an article published in the Jan. 30 Advance Online Edition of Nature, the biologists describe their research with a particular protein called TLX.
By using TLX as a genetic switch to turn neurogenesis “off,” Gage, Evans, and their colleagues made two major discoveries. First, they determined that neurogenesis plays a key role in the acquisition and storage of memory in the hippocampus. Second, they confirmed that TLX is essential for maintaining the pool of proliferating stem cells in the brain that give rise to neurogenesis.
“There have been earlier studies using less specific methods to deplete neurogenesis that have implicated neurogenesis in learning and memory,” Gage says. “The findings have been somewhat inconclusive, however. In part, we think that is because the methods used have been indirect.” In contrast to the indirect methods used in these early investigations, Gage and his colleagues purposely switched off production of TLX, the protein required for stem cell behavior in the adult brain.
Specifically, animals inherit two copies of the gene that codes for TLX – one gene from each parent. Because global deletion of TLX leads to a variety of developmental problems, however, the Salk team had to find another approach to directly switch off production when desired. With this end in mind, Chun-Li Zhang, M.D. a post doctoral fellow in the Gene Expression Lab, engineered mice that lacked one copy of this gene. They then knocked out the second copy of this gene by orally giving adult mice tamoxifen – a drug commonly used in treating breast cancer – when the time was right.
Understanding the Role of Adult Neurogenesis
After being given this drug for eight days, an otherwise normal adult mouse had more than 80 percent fewer new neural stem cells, so neurogenesis was greatly reduced. With fewer neurons, the mice failed to perform satisfactorily on common behavioral spatial memory tasks, clearly demonstrating the role of neurogenesis in the acquisition and storage of memory.
“The development of this new, inducible “knockout” mouse model provides a new and powerful tool to understand better the role of adult neurogenesis in normal behavior and disease,” Gage says.
Gage was delighted that he and his team could selectively block TLX to prevent stem cell proliferation without killing the cell. That is important, he says, because to really understand what role neurogenesis may play in neurodegenerative illnesses such as Parkinson’s disease and Alzheimer’s disease, we must first understand its normal function in the healthy brain.
This work contributes to other efforts in Gage’s lab that may eventually lead to methods of replacing or enhancing brain and spinal cord tissues lost or damaged due to neurodegenerative disease or other trauma. This particular study suggests the possibility that researchers may one day be able to trigger neurogenesis with orally active drugs to stimulate memory function in aged and damaged brains.
In addition to the major findings from this investigation, Gage was surprised to learn that TLX plays such a strong role in maintaining the pool of proliferation of cells all by itself.
“We demonstrate very directly that TLX, inside the stem cell, is acting to maintain the ability of the cell to divide. It doesn’t require anything at all from the outside,” he says. “I couldn’t imagine that.”
The Impact of Exercise
Yet another interesting discovery occurred when Gage took the “knockout” mice with stunted memory and put them onto a running wheel. Evidently, as a result of increased physical exercise, the neurons in even these mutant mice were stimulated to grow and divide more rapidly and extensively than when they were sedentary.
“That was actually quite exciting,” Gage says.
Gage had demonstrated the importance of exercise and an enriched environment in stimulating neurogenesis in earlier research with young and old animals. Here was yet another example that mobility increases neurogenesis, bringing cells back to a proliferating state – even in mice with 80 percent fewer neural stem cells than normal mice. Of special interest is that while the initial studies in this field have involved work with songbirds, monkeys, and mice, we know now that human adult brains can grow new neurons throughout life too.
What is important for us to understand about the rate and success of neurogenesis, Gage says, is not only that neurogenesis plays a role in learning and memory, but that it is literally dependent upon our interactions with the environment.
“Neurogenesis is not just a static event,” he repeats. “Physical movement and environmental enrichment can aid in that process.”
The accumulated medical research in this field has already been applied to humans in nursing homes and hospitals, where physical therapy is being used as a vehicle for activating brain activity in people with stroke and Parkinson’s and Alzheimer’s diseases.
Fred H. Gage, Ph.D. is a member of the Alliance for Aging Research Scientific Advisory Board.