Welcome to the sixth installment of
This week we ponder
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What Do New Neurons Do?
A rat puts some new neurons to work in a Morris water maze. The maze requires the animal to find and remember the location of a platform hidden beneath the surface. The study reviewed below showed that mice solving such a maze used new neurons to create the remembered spatial map. Photo courtesy Wikipedia Commons.
by David Dobbs, Editor, Mind Matters
After a sometimes ferocious debate lasting decades, most neuroscientists now agree that the adult brain makes new neurons. Yet they're far from agreeing on what, if anything, these freshly minted new brain cells actually do. Do they replace worn-out veterans? Provide new memories? Strengthen existing knowledge? Just take up space? These questions hang over every discussion of neurogenesis -- and drive quite a few research agendas.
The paper reviewed here -- "Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus
," by Nohjin Kee, Catia M. Teixeira, Afra H. Wang, and Paul W. Frankland, from Nature Neurosciece
4 Feb 2007 -- suggests some answers. As our experts Doug Fields and Brad Aimone explain, this paper shows that at least some new neurons help us form memories -- and suggests other intriguing possibilities as well.
Join us in a look at how new neurons go to work.
Baby Neurons Making Memories
by R. Douglas Fields
National Institute of Child Health and Development, Bethesda, Md.
Science is like the federal tax code. The rules are rigid -- but they keep changing. At one time a hard-and-fast rule held that neurons, unlike so many other cells in the body, could not divide. The neurons you were born with were the ones you took to your grave. That began changing in the 1980s, however, when Fernando Nottebohm
and others discovered neurons dividing like happy yeast cells in the forebrain dough of canaries. It appeared that neurons divided after all.
People resisted this idea. It clashed with all established facts and belief. But slowly the data moved minds. Now newborn brain cells are popping up like mushrooms after rain. The latest research even shows new neurons hatching in the most hallowed of all brain regions -- the hippocampus, which is the seat of declarative and spatial memory.
A New Neuronal Lease on Life?
, as this neuron creation is known, has ignited interest in all kinds of latent stem cells in the adult brain
, and it comes as an enormous relief to aging baby boomers mourning neurons lost during overexuberant college days. The latest news even shows that the crop of new neurons increases after physical exercise! What a relief to know that you can repent and repair simply by jogging around the blockÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ‚Ã‚Â¦if you wanted to.
Tough-minded scientists, however, have met all this news with a good question: What good are new neurons if they don't somehow wire themselves into the circuitry of the brain. And how are these green neurons going to do that? The difficulty of incorporating new neurons into existing neuronal networks was always one of the rational arguments for why new neurons probobaly didnÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ¢Ã¢Â€ÂžÃ‚Â¢t form in the adult brain. There would be no way to knit the nubile neuronal newbies into the intricate, tightly woven fabric of synaptic connections in the grown-up brain. What good are these cellular neophytes if they are just childish bystanders?
In the last few years, however, new findings from several labs have shown that new neurons do indeed connect up with existing circuitry. As its title suggests, the paper weÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ¢Ã¢Â€ÂžÃ‚Â¢re looking at here, ÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ…Ã¢Â€ÂPreferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus
,ÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ‚Ã‚Â by Nohjin Kee and colleagues at the Frankland Lab
at the University of Toronto, adds to this evidence. It shows that new neurons integrate themselves into functional networks in the hippocampus -- and that these new recruits actually boost memory, or at least participate in making new memories. This is perhaps the clearest demonstration yet that new neurons join existing teams and do real work. How did researchers crack that nut?
The Swim Test
It took a microscope, a tank of water, and a retarded mouse.
First you need to know that to make memories stick, genes must be turned on in the neuron to manufacture proteins that will cement more strongly the synapses the neuron shares with other neurons (see "Making Memories Stick
", Scientific American
, Feb. 2005). Kee and his fellow researchers first trained mice in a standard memory test device called a Morris water maze
. This water maze test consists of plunking a mouse in a vat of milky water where a small platform is hidden somewhere just beneath the surface. The mouse swims in a highly motivated manner until it finds the submerged life saver where it can stand comfortably with its head above water. Put the mouse in the tank again, and it remembers where the platform was and swims to it pronto. With subsequent trials, the mouse gets really good at finding the platform quickly. This is learning -- spatial learning, because the mouse can't see the platform but it has to remember its location by using landmarks on the tank walls or suspended overhead. (Incidentally, this test works well because mice and rats are good swimmers and take naturally to the challenge.)
After training mice in this task, Kee and his colleagues looked to see if this task switched on the genes associated with learning in new hippocampal neurons. They knew they were looking at new neurons because they had injected the mice with a marker for dividing cells -- one of the DNA bases (uridine), that is chemically modified so that it shows up in tissue slides under a microscope. Since cells must make DNA to divide, newly minted cells carry this uridine marker in their nuclei.
When Kee et alia looked through the microscope at the hippocampi of mice who had learned to find the platform, they indeed found that certain "memory" genes known as c-fos and arc were turned on in many of the new neurons. However, as Kee knew, itÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ¢Ã¢Â€ÂžÃ‚Â¢s possible for these genes to get turned on by forms of mental stimulation other than learning. How would they know these new neurons were actually storing memories of where the submerged platform was hidden?
Enter the mutant mouse. As a control, Kee and company also put through the water maze test a mouse that had a disabling mutation in an enzyme (CaMKII) that is essential for making memories. This mouse could find the platform, but it wouldn't carry the memory to the next test; it had to find afresh every time. As it turned out, its hippocampus had as many newborn neurons as the more learned mice did -- but its "memory" gene, c-fos, was not switched on any more than it was in animals that had not been trained. The activation of the memory gene, then, seemed to be what made the learning possible.
The researchers also found that by training the mice at different time intervals after the uridine injection, they could determine how old the new neurons must be before they joined the adult circuits of memory storage. They found that new neurons are not involved in memory until they reach the age of about 4-6 weeks. About the time of a mid-term exam, new neurons may be helping out on the test. Yet, like impressionable children, these new neurons were actually more likely to participate in learning than the adult neurons already established into networks with their peers.
The study might have been strengthened by using an additional mutant of a different type, or various drugs to interfere with memory (see "Erasing Memories
," Scientific American Mind, January 2006) instead of using only the CaMKII mutant mouse. This is because this enzyme is involved in turning on the c-fos gene for reasons unrelated to memory formation. Also, whether or not the gene more closely associated with memory, arc, was switched on in the mutant mice, was not reported.
Yet the study carries substantial significance. It showsthat although most neurons in the adult brain do not divide, about 1-2 percent of the population is new in parts of the brain, including the hippocampus. It now seems clear that these new neurons are preferentially recruited into brain circuits that record new spatial memories. But the reasons for this -- and how plugging new neurons into existing circuits might affect old memories -- are still about as opaque as the instructions for the Federal 1040 tax form.
R. Douglas Fields , a frequent contributor to Scientific American and Scientific American Mind, is chief of the Nervous System Development and Plasticity Section at the National Institute of Child Health and Development, where he investigates neural development and the interactions between neurons and glia.
More than Just an Interesting Phenomenon
by Brad Aimone
University of California at San Diego
The biggest question currently facing neurogenesis researchers is What are these new neurons doing?
While their existence in the hippocampus suggests a role in memory formation, the null hypothesis has been that these new cells simply replace dying cells or are just a functionless evolutionary artifact -- an ÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ…Ã¢Â€ÂappendixÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ‚Ã‚Â of sorts in the brain.
The paper reviewed here, however, supports the idea that these neurons indeed perform a meaningful function. The Kee study does not aim to show the exact role of these new cells, but it does further demonstrate that the animalÃƒÂƒÃ‚Â¢ÃƒÂ¢Ã¢Â€ÂšÃ‚Â¬ÃƒÂ¢Ã¢Â€ÂžÃ‚Â¢s experience makes these new neurons functionally distinct from the existing population of neurons. Because the young neurons are more likely to respond in this manner than fully mature cells, it is difficult to imagine that they are simply replacing dying parts of the circuit.
So what is the function of these new neurons? One possibility is that they serve several different functions as they mature. For instance, last year several colleagues and I proposed
that immature neurons may respond somewhat indiscriminately to different events occurring around the same time, thereby contributing temporal information to new memories.
However, that hypothesis addresses only the role of these neurons as they mature; it does not account for those newborn neurons that survive longer and respond to specific information months later, as shown in the Kee study. It is possible that these longer lasting neurons have a temporally restricted function, such as time coding, early in their development, and then narrow their role so that they respond only to a specific type of information later. The timeline of new neuron learning shown in the Kee paper is consistent with this -- the new neurons begin to integrate into existing networks during the first several weeks after they are born, but only later do they appear to encode the spatial information during training.
Regardless of whether new neurons encode time, spatial maps, or something else entirely, ultimately we need to see a behavioral difference in animals with neurogenesis removed to fully understand the function of these new cells. Beyond the technical difficulties involved in reducing the number of new neurons, the big challenge is determining what types of deficits we should begin to look for in these animals -- and when should we look for them. The Kee study provides some valuable clues for these questions.
Brad Aimone is a graduate student in the Computational Neurobiology program at University of California/San Diego. He is investigating adult neurogenesis in the laboratory of Fred Gage at the Salk Institute for Biological Studies.