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Neurogenesis Demonstrated in Human Olfactory Bulb

In the rodent brain, the subventricular zone (SVZ) generates thousands of new olfactory bulb neurons every day. Three years ago, a paper in Nature announced the existence of adult neural stem cells in the SVZ lining the lateral ventricles of the human brain, but the authors could find no evidence of a pathway linking the SVZ to the olfactory bulb as in the rodent brain, so they concluded that this phenomenon was unique to the human brain (2004;427:740–744). That same year, Andreanne Bedard and Andre Parent discovered newly generated neurons in the human olfactory bulb, but they could not find the path they took to get there (Brain Res Dev Brain 2004;151:159–168).

Now, scientists in New Zealand and Sweden have identified the path by which new neurons travel from the SVZ of the human brain, where they are born, to the olfactory bulb, demonstrating that this type of neurogenesis, so vigorous in rodents, occurs in humans, too. The findings were published online Feb. 15 in Science Express in advance of the print publication of Science.

Experts say the discovery could prompt the development of new therapies in such neurodegenerative diseases as Parkinson disease (PD), multiple sclerosis, and Huntington disease.

This pathway from the SVZ, known as the rostral migratory stream, or RMS, has a different shape in humans than in rodents, which made it difficult to find.

“The structure is relatively small in humans, but four times as long as the rodent RMS,” lead author Maurice A. Curtis, PhD, of the University of Gothenburg, told Neurology Today in an e-mail. “Therefore rigorous serial sagittal sectioning of whole forebrains is required to see the long axis of it. Also, because the human forebrain is enlarged and rotated forward compared to the rodent brain, and the olfactory system lies beneath it, there is an S-shaped bend in the human RMS, which has made the structure difficult to track. Previous groups appear not to have taken this variation into account.”

STUDY PROTOCOLS

The scientists found evidence of the stream by staining human brain specimens with proliferating cell nuclear antigen and using a high-powered microscope to follow cells that took up the stain from the SVZ to the olfactory bulb in the base of the forebrain. This demonstrated the presence of new cells that were in the process of dividing.

They had dissected the olfactory bulb from cancer patients who, before they died, had received bromodeoxyuridine to detect the presence of rapidly dividing cancer cells. The scientists confirmed the finding of newly formed neuronal cells. Dissection also revealed a hollow ventricle in the olfactory bulb. MRI of six living patients indicated that these ventricles were filled with fluid. The cells migrate in the tissue surrounding these fluid-filled ventricles.

“By better understanding how and why cells migrate from the SVZ to certain brain regions, we hope to direct the newly formed cells into brain regions that are affected by neurodegeneration, such as Parkinson disease and Huntington disease,” Dr. Curtis said. “Furthermore, the discovery of this pathway may offer some clues as to the anosmia in Parkinson disease.”

The loss of smell that many PD patients experience may seem logical at first, since both disorders — anosmia and PD — result from the degeneration of neurons, but the occurrence of both together poses a paradox: while the neurons in the midbrain that produce dopamine deteriorate in PD, dopamine neurons in the olfactory system proliferate (Mov Disord 2004;19:687–692). Some researchers suspect that the extra dopamine produced by these cells may inhibit transmission in the olfactory system, but the mechanism that produces anosmia is unknown.

EXPERTS COMMENT

Ole Isacson, MD, PhD, professor of neurology (neuroscience) at Harvard Medical School and director of the Center for Neuroregeneration Research Laboratories at McLean Hospital, said members of his lab were excited about the paper not only because it shows the existence of the RMS in humans, but also because it makes research on rodents clearly relevant to humans.

“The authors demonstrate that everything we have learned about the olfactory system in rodents showing how new neurons are born, migrate, take up positions in the olfactory bulb, and start getting integrated into sensory experience, is probably transferable to humans,” he said. “The anatomy is different, but everything seems to be evolutionarily conserved.”

In 1913, the Nobel-laureate Spanish neuroanatomist Santiago Ramon y Cajal declared that adult nerve pathways “are immutable.” That remained the standard view for decades to follow. Then, in 1983, Steven A. Goldman, MD, PhD, of the University of Rochester, discovered that neurogenesis takes place in the ventricular zone of adult female canaries (Proc Natl Acad Sci 1983;80:2390–2394). In 1998, neurogenesis was found to occur in the dentate gyrus of the hippocampus of mammals as well. Now it is also known to occur in the SVZ of mammals.

Human neurogenesis holds out the tantalizing promise of therapies that could halt and possibly reverse degenerative diseases such as Parkinson disease and multiple sclerosis, and repair other forms of brain damage, said Dr. Isacson. Stem cell transplants from other sources could possibly achieve the same result, but they carry the danger of rejection, he noted. Regenerating stem cells from a patient's own brain — a therapy that neurogenesis makes imaginable — would get around that problem, although the neurons born in the SVZ might not work, he said.

“Olfactory dopamine neurons are not adapted to function in the striatum, which receives dopamine from midbrain neurons lost or damaged in PD,” he said. “If you don't get the right cells in the right place, they tend not to work as well, but any dopamine-producing cell is better than having none at all. My lab is trying to stimulate the SVZ to make new olfactory dopamine neurons, and then draw them into the striatum to replace the loss of dopamine in PD.”

The fact that the human brain generates new olfactory neurons may provide clues to the hyposmia, odor discrimination, and identification deficits found in schizophrenia and bipolar disorder, as well as in PD, said Lise Rioux, PhD, who studies molecular neuropathology and genetic mechanisms of olfactory deficits in schizophrenia at Drexel University College of Medicine in Philadelphia.

“These deficits may be due to a developmental insult, or they may be of genetic origin,” said Dr. Rioux, who believes the root problem produces a disruption of synaptic transmissions in the olfactory system (Schizophr Res 2005;77:229–239). These new findings make it possible to study more extensively the developmental stages of olfactory bulb neuron renewal and address the role of candidate genes that could affect this process.

Dr. Curtis said this discovery “offers huge potential to study progenitor cell migration in the human brain. We can see how they do it and learn from those cells that are already equipped to do it.”

Fred H. Gage, PhD, a professor in the Laboratory of Genetics at the Salk Institute for Biological Studies and the University of California-San Diego, who was one of the pioneers in the study of human neurogenesis, agrees that these findings offer “great potential,” but he also pointed out that they offer no direct applications at the moment. “It confirms human adult neurogenesis and extends it to another brain region besides the hippocampus,” he said.

ARTICLE IN BRIEF

Scientists in New Zealand and Sweden have identified the path by which new neurons travel from the subventricular zone of the human brain, where they are born, to the olfactory bulb, demonstrating that this type of neurogenesis, so vigorous in rodents, occurs in humans, too.

References

• Curtis MA, et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 2007: E-pub 2007 Feb. 15.
    • Rioux L, Gelber EI, Parand L, Kazi HA, Yeh J, Wintering R, Bilker W, Arnold SE. Characterization of olfactory bulb glomeruli in schizophrenia. Schizophr Res 2005;77:229–239.
    • Bedard A, Parent A. Evidence of newly generated neurons in the human olfactory bulb. Brain Res Dev. Brain Res 2004;151:159–168.
      • Huisman E, Uvlings HBM, Hoogland PV. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov Disord 2004;19:687–692.