Princeton Weekly Bulletin April 5, 1999
Do brain cells regenerate?
New discoveries about neurogenesis prompt reevaluation of cerebral development
By Ken Howard
For the past several decades, scientists believed that brain cells were a finite resource; that unlike other cells in the body, those in the brain did not regenerate.
(photo by Denise Applewhite)
But psychology professor Elizabeth Gould recently proved such is not the case for the hippocampal formation of the brain in Old World monkeys, primates closely related to man. And Fred Gage at the Salk Institute in La Jolla has showed that adult humans also generate new neurons in their hippocampus. These discoveries, along with Gould's later findings about the relationship between learning and neuronal regeneration, could change the way scientists look at the brain.
The hippocampus is part of the limbic system, a cluster of nuclei in the lower part of the mammalian forebrain that interacts with the cerebral cortex in determining emotions and processing memories. It is a phylogenetically ancient collection of cells found not only in primates but also in birds, rats and lizards. While its specific function and processes are not very well understood, studies of hippocampal-damaged people who experience amnesia indicate that it is involved in learning and memory.
"There is a theory that the hippocampus is a transient memory holder, storing memories temporarily, before they're stored elsewhere in the brain," says Gould. Researchers have described it operating like a sponge: memories are picked up and then squeezed out into other areas of the brain before new information can be stored.
New granule neurons
Gould first reported neurogenesis in an adult primate in spring of 1998, when she observed that a significant number of new granule neurons (which get their name from their small size) were being produced in the hippocampus of adult marmoset monkeys. She followed this discovery the following fall with the same observation in mature macaque monkeys, Old World primates closely related to humans. While scientists, including Gould, had previously observed neurogenesis in other animals, including canaries, rats and tree shrews, Gould's discovery brought the focus to primates and supported Gage's parallel findings in adult humans.
This past March, Gould extended knowledge about neurogenesis when she published research findings that indicate the number of neurons lost and new neurons generated in adult rats might be related to the degree of cognitive challenges an animal encounters. In other words, "use it or lose it" may have grounding in science.
Visible, invisible platform
In a series of experiments, Gould presented rats with both hippocampal-dependent and independent tasks and conditioning. To test the effects of specific learning on new neurons, Gould filled a small circular pool with water and white paint, making it impossible to see below the surface. For hippocampal-dependent learning, a platform was submerged and invisible; for independent learning, it was above the surface, visible. The rats were divided into groups and trained to swim to the platform under different setups.
In the conditioning experiments, a noise and eyelid stimulation were used to elicit an eye-blink response. For hippocampal-dependent conditioning, there was a time interval between the noise and the stimulation. For independent conditioning, the noise and the stimulation were delivered simultaneously.
After testing was complete, the rat's neurons were examined for staining by a chemical that had been injected at the beginning of the experiment; the stain was picked up only by newly-formed cells. Gould found that hippocampal-dependent learning led to an increase in newly generated neurons in the dentate gyrus of the hippocampus, the "gateway" to that region of the brain. Learning independent of the hippocampus did not change the number of neurons, compared to the control.
Alternative cellular mechanism
The discovery of a correlation between learning and neurogenesis could "provide an alternative cellular mechanism for how learning may occur," says Gould. One widely accepted theory holds that learning occurs at the synapses of existing neurons. "The traditional view says that learning must involve changes at the synapse," explains psychology professor Charles Gross. "Elizabeth Gould's demonstration of the existence of new cells and the relationship to learning requires the reevaluation of our previous notions of how the brain develops and how learning takes place and memories are stored."
One possibility is that cell function is tied to cell age, explains Gould. "In the hippocampus, the population of neurons ranges in age from days to years. It is very likely that cells of different ages perform different functions. Perhaps new neurons are more plastic, allowing them to play a unique role in learning. This would be a radical restructuring of our notion of adult primate brains."
Chronic negative regulators of neurogenesis in humans, such as aging and stress, have been associated with impaired hippocampal-dependent learning. Previous research by Gould has suggested that stressful conditions may suppress the production of granule neurons in the hippocampus of tree shrews and rats. These and the more recent discoveries about neurogenesis, she says, may eventually point the way towards treatment of brain trauma and diseases such as Parkinson's or Alzheimer's.