11 Jun 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

Comments

1. • Gerd Kempermann
     Center for Regenerative Therapies
   • Posted: 11 Jun 2011
   • Paper: Maturation time of new granule cells in the dentate gyrus of adult macaque monkeys exceeds six months.

   This is indeed an interesting paper. If neuronal maturation in primates takes so much longer than in rodents, this has many implications. The current idea is that there is a time window during this maturation when new cells are particularly sensitive. They are more excitable and show a reduced threshold for synaptic plasticity; their level of LTP is elevated. It has been reported that essentially all LTP that can be elicited in the dentate gyrus under normal conditions is coming from the immature new neurons. The remainder of the neurons, the mature ones, are heavily inhibited. This physiological aspect is not studied here, but the authors examined a number of morphological signs of maturation. The data might indicate that primates have relatively more cells in this critical period because the individual cells remain there longer. This, indeed, has implications for many functional considerations, including the potential role of neurogenesis in depression and antidepressant treatment.

   However, the idea that new neurons would be antidepressants because they replace missing cells is unlikely to be true. There has been a number of arguments against neurogenesis explaining the delay between the initiation of antidepressant medication and the detection of positive effects, including one we recently published (see Klempin et al., 2010). The more important thing is that primates might have plastic new neurons for a longer time than rodents. The details will have to be ironed out, including the physiology, which will be crucial but hard to get from primates.

   References:

   Klempin F, Babu H, De Pietri Tonelli D, Alarcon E, Fabel K, Kempermann G. Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis. Front Mol Neurosci. 2010;3 PubMed.

   View all comments by Gerd Kempermann

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References

News Citations

1. Seeing Is Believing—Plaque Growth Is Slow, Tapers With Age 17 Jan 2011

Paper Citations

1. Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?. Nat Rev Neurosci. 2010 May;11(5):339-50. PubMed.
2. Hefendehl JK, Wegenast-Braun BM, Liebig C, Eicke D, Milford D, Calhoun ME, Kohsaka S, Eichner M, Jucker M. Long-term in vivo imaging of β-amyloid plaque appearance and growth in a mouse model of cerebral β-amyloidosis. J Neurosci. 2011 Jan 12;31(2):624-9. PubMed.
3. Snyder JS, Choe JS, Clifford MA, Jeurling SI, Hurley P, Brown A, Kamhi JF, Cameron HA. Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice. J Neurosci. 2009 Nov 18;29(46):14484-95. PubMed.
4. Brown JP, Couillard-Després S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG. Transient expression of doublecortin during adult neurogenesis. J Comp Neurol. 2003 Dec 1;467(1):1-10. PubMed.
5. Kempermann G, Gast D, Kronenberg G, Yamaguchi M, Gage FH. Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development. 2003 Jan;130(2):391-9. PubMed.
6. McDonald HY, Wojtowicz JM. Dynamics of neurogenesis in the dentate gyrus of adult rats. Neurosci Lett. 2005 Sep 2;385(1):70-5. PubMed.
7. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003 Aug 8;301(5634):805-9. PubMed.

Further Reading

Papers

1. Brill MS, Ninkovic J, Winpenny E, Hodge RD, Ozen I, Yang R, Lepier A, Gascón S, Erdelyi F, Szabo G, Parras C, Guillemot F, Frotscher M, Berninger B, Hevner RF, Raineteau O, Götz M. Adult generation of glutamatergic olfactory bulb interneurons. Nat Neurosci. 2009 Dec;12(12):1524-33. PubMed.
2. Lazarov O, Marr RA. Neurogenesis and Alzheimer's disease: at the crossroads. Exp Neurol. 2010 Jun;223(2):267-81. PubMed.
3. Suh H, Deng W, Gage FH. Signaling in adult neurogenesis. Annu Rev Cell Dev Biol. 2009;25:253-75. PubMed.
4. Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, Mori K, Ikeda T, Itohara S, Kageyama R. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci. 2008 Oct;11(10):1153-61. PubMed.
5. Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011 May 26;70(4):687-702. PubMed.
6. Marker DF, Tremblay ME, Lu SM, Majewska AK, Gelbard HA. A thin-skull window technique for chronic two-photon in vivo imaging of murine microglia in models of neuroinflammation. J Vis Exp. 2010;(43) PubMed.

News

1. Smells Like Neuronal Proliferation! 7 Mar 2003
2. Society for Neuroscience Annual Meeting: Imaging Amyloid Plaques in the Living Mouse 24 Oct 1999
3. Taos: Disease, Drug Development, and Adult Neurogenesis 17 Feb 2011
4. Seeing Is Believing—Plaque Growth Is Slow, Tapers With Age 17 Jan 2011
5. Plaque Growth Gradual, Slowed by Gliosis and Aβ Removal 2 Sep 2009
6. New Methods to Study Adult Neurogenesis and Progenitor Maturation 2 May 2003