11 June 2011. Two places in the brain support the regular rise of new neurons. In the dentate gyrus of the hippocampus, neurogenesis is thought to support learning and memory (reviewed in Deng et al., 2010), and in the olfactory bulb, it may allow animals to learn new smells throughout life. To examine the latter firsthand, Yoav Adam spent nine months peering, through glass windows in the skull, into the olfactory bulbs of mice. Adam, a graduate student with Adi Mizrahi at The Hebrew University of Jerusalem, Israel, confirmed what others had proposed: The interneurons of the olfactory bulb undergo regular turnover with consistent adult neurogenesis. As the animals age, there come to be more dopaminergic interneurons in the olfactory bulb, the authors report in the June 1 Journal of Neuroscience.
A team of researchers from the University of Illinois examined the same process in primate hippocampus and found neurogenesis there proceeds at a much slower rate. First author Shawn Kohler and senior author William Greenough report in the June 6 Proceedings of the National Academy of Sciences USA online that the process lasts for six months or longer in Rhesus and crab-eating macaques. Because new maturing neurons are thought to be more plastic than established ones, the study “has many implications,” according to Gerd Kempermann, Center for Regenerative Therapies, Dresden, Germany (see full comment below), including for therapeutics. Kempermann was not involved in the study.
Window on the Olfactory Bulb
Adam wanted to directly image cells developing into neurons in vivo. In both the olfactory bulb and cortex, neurons reside right on the edge of the mouse brain, making them amenable to live imaging. Researchers frequently implant glass windows in the skull around the cortex (see ARF related news story on Hefendehl et al., 2011), but the olfactory bulb is tricky that way: It is capped with a 2 x 3.5 millimeter area of bone, smaller than that over the cortex. It also lies near major blood vessels, so scientists must take exquisite care during surgery. Previously, researchers have used small, open craniotomies, or thinned the bone for imaging. Adam designed his surgery to make a true window and at glue a glass cover slip over an opening in the skull.
“This is a technical feat,” said Martin Wojtowicz of the University of Toronto in Ontario, Canada, who was not involved in the study. “It is good to see with your own eyes that neurons actually appear and disappear.”
Adam saw not only turnover, but also steady growth in the number of new neurons over time. By the end of the nine months, the animals boasted 13 percent more dopaminergic neurons in the olfactory bulb than when the experiment began. Wojtowicz noted the dopaminergic neurons are a small subset of the entire olfactory nerve population.
Next, Adam plans to peer through cranial windows to examine brain function with calcium imaging of neural signals. This technique offers the option to examine aging or ailing tissue, wrote David Scadden of Massachusetts General Hospital in Boston, who was not involved in the study, in an e-mail to ARF. “Rather than just looking at the final outcome, perhaps seeing how the outcome evolves can teach us where to direct our efforts to improve how things turn out.”
It Just Takes a Little Time
Adam was able to observe neurogenesis over and over in his mice, since the process only takes a month in rodents. But the Illinois researchers found that a month was not nearly enough to complete neuron maturation in macaques. They injected animals with the cell division marker BrdU and followed them for up to seven months, looking for molecular and morphological markers of mature neurons. The process was significantly slower than in rodents: At six weeks, only 16 percent of new cells had reached maturity. By 28 weeks, one-third of new cells were finished developing.
In macaques, the period of time it took to attain peak expression of the neuronal marker doublecortin and to produce the mature neuron marker NeuN was more than six times longer than in the rats and mice, according to previous studies (Snyder et al., 2009; Brown et al., 2003; Kempermann et al., 2003; McDonald et al., 2005). Thus, the researchers conclude that the full maturation process for one neuron takes at least six months.
“It was a big surprise for the field,” said study coauthor Judy Cameron of the University of Pittsburgh in Pennsylvania, because most researchers assumed the neurogenesis process would take about the same amount of time across species.
There is thought to be a window during maturation when neurons have a particularly low threshold for long-term potentiation, wrote Kempermann in an e-mail to ARF. Thus, he inferred, “primates might have plastic new neurons for a longer time than rodents.”
The work has implications for drug therapy. Some researchers have suggested that antidepressants, which can take a few weeks to kick in, work by stimulating the growth of new neurons (Santarelli et al., 2003). That idea has been controversial. If neurogenesis takes months, newly matured neurons cannot account for the roughly three-week lag period for antidepressants. The study also implies that potential future treatments to promote neural growth, perhaps eventually for people with a neurodegenerative disease, might take months to produce noticeable effects.
“The overall developmental process is very similar between primates and rodents,” Adam noted. “It is just the time scale which is different.” He suggested that briefer rodent experiments will be able to elucidate much about adult neurogenesis, as long as researchers cross-check their results in primates.—Amber Dance.
Adam Y, Mizrahi A, Long-term imaging reveals dynamic changes in the neuronal composition of the glomerular layer. J Neurosci. 2011 Jun 1;31(22):7967-73. Abstract
Kohler SJ, Williams NI, Stanton GB, Cameron JL, Greenough WT. Maturation time of new granule cells in the dentate gyrus of adult macaque monkeys exceeds six months. Proc Natl Acad Sci USA. 2011 Jun 6. Abstract