Sci. Aging Knowl. Environ., 4 June 2003
Vol. 2003, Issue 22, p. pe13
[DOI: 10.1126/sageke.2003.22.pe13]


Creating New Neurons in Old Brains

Phyllis M. Wise

The author is in the Department of Neurobiology, Physiology, and Behavior, Division of Biological Sciences, University of California, Davis, Davis, CA 95616, USA. E-mail: pmwise{at};2003/22/pe13

Key Words: Neurogenesis • growth factor • fibroblast growth factor • heparin-binding epidermal growth factor-like growth factor • injury

The dogma that new neurons are born only during development and not in the adult version of the mammalian brain was accepted without much question for over a century. Neurogenesis, or the birth of new neurons, had been thought to occur during fetal development and, perhaps, during the early postnatal period (1). Yet many recent papers clearly demonstrate that neurons continue to be born, migrate, differentiate, and perhaps function normally during adulthood (2) (see "Newborn Neurons Search for Meaning"). It appears, then, that the birth of new neurons is one of many mechanisms that the adult brain uses to maintain normal function. In addition, the brain responds to injury with cellular and molecular mechanisms that involve increased neurogenesis leading to self-repair (3). More recently, the concept that the brain may remain able to undergo impressive repair as we age has emerged, as several papers attest to the fact that, during aging, the brain may decrease the basal level of neurogenesis but responds to injury with neurogenesis that is comparable to that observed in young mammals (4-6).

It has been documented that neurogenesis decreases in the brains of aged rodents as compared to those of young adult rodents. In addition, previous studies have shown that the administration of growth factors increases basal neurogenesis in the young adult rodent brain, but whether the aging brain can still respond to growth factors remains in question. As the average life span of humans increases, the number of people who suffer from age-related neurodegeneration is likely to increase. The possibility that the aging brain remains responsive to therapeutic interventions that enhance neurogenesis raises hopes that normal brain function can be maintained into old age. It is thus important to determine whether age-related changes that inhibit the ability of these cells to proliferate occur in neuronal stem/progenitor cells and/or in the local and systemic environment. If changes do occur in the cellular environment, researchers then must ask whether this environment can be corrected to maintain normal young adult levels of neurogenesis.

The current work of Jin and colleagues (7) in the June 2003 issue of the journal Aging Cell adds substantially to our understanding of the mechanisms of neurogenesis in the aging brain. It corroborates and extends the work of Lichtenwalner et al. (4), who showed that insulin-like growth factor 1 increases neurogenesis in young, middle-aged, and old rats. The results of the present study clearly establish that two growth factors--fibroblast growth factor 2 (FGF-2) and heparin-binding epidermal growth factor-like growth factor (HB-EGF)--enhance neurogenesis in two brain regions of aged mice: the subgranular zone of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ). The hippocampal region is a part of the brain involved in learning and memory, and the SVZ is the site where new neurons are born that migrate to the olfactory bulb and the cerebral cortex. The cortex is also involved in learning and memory. FGF-2 and HB-EGF had previously been shown to stimulate neurogensis in the brains of young adult rodents.

In order to ask whether the brains of old mice retain the ability to respond to growth factors, Jin et al. infused FGF-2 and HB-EGF individually into the lateral cerebral ventricles of the brains of young (3 months) and aged (20 months) mice. Then they assessed neurogenesis by measuring bromodeoxyuridine (BrdU) labeling in the DG and SVZ. BrdU, which is incorporated into newly synthesized DNA and thus provides a measure of DNA replication, was administered for 3 days with and without concomitant administration of growth factors. Animals were killed 1 week later, and the numbers of BrdU-labeled cells in the DG and SVZ were compared using immunohistochemistry. Thus, the investigators assessed whether cell proliferation was induced during the period of growth factor administration and whether these cells survived for several days thereafter. They also assessed the phenotype of the new cells by colabeling with doublecortin, a marker of neuronal precursors. Whether BrdU incorporation truly reflects the birth of new neurons or just marks DNA synthesis is still a matter of discussion (8); nevertheless, an increasing number of investigators use this method as an index of cell proliferation (9).

From these experiments, Jin et al. found that basal neurogenesis was decreased ~90% in the DG and ~50% in the SVZ of old mice as compared to young adult mice. However, the aged brain remained remarkably responsive to the neurogenesis-stimulating effects of the growth factors FGF-2 and HB-EGF. The number of BrdU-labeled cells in the DG of old mice increased upon HB-EGF treatment from 10 to 25% of that in the young adult mice; similarly, for FGF-2, the increase was from 10 to 20%. In the SVZ of old mice, the infusion of both growth factors resulted in an increase in BrdU labeling to a level similar to that observed in the SVZ of young adult mice. Interestingly, the investigators found that the number of brain cells that divide in response to the administration of growth factor to only one side of the brain was the same on both sides of the brain, except in the SVZ of the 20-month-old mice. In other words, even when growth factor is administered only to the left side of the brain, new neuron-like cells are born on both the left and right sides of the brain. This result was not expected, as one would think that only the part of the brain that was bathed in the growth factor would respond. Because the growth factors were administered intracerebroventricularly, it is possible that they diffused to the opposite side of the brain, but the result was still unanticipated.

The authors also determined that the BrdU-labeled cells expressed the proteins NeuroD, which is found in immature neurons (Fig. 1), and nestin, which exists in neuroepithelial progenitor cells, confirming that the new cells are of the neuronal lineage. Whether these newborn neuronlike cells ultimately differentiate, migrate to the proper regions of the brain, establish normal synaptic contacts with the proper neighboring neurons, function normally, and respond to stimuli in the proper fashion remains unknown. Clearly this knowledge is essential before we can assume that growth factor-induced neurogenesis in aging animals is a viable therapeutic strategy for the neurodegeneration observed in age-related diseases such as Alzheimer's and Parkinson's. Future studies also will have to address the difficult question of whether these studies using animal models are relevant to maintaining brain function in elderly humans.

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Fig. 1. BrdU- and NeuroD-labeled cells in the DG and SVZ of the aged mouse brain. Old male mice were treated for 3 days with intraperitoneal BrdU and killed 1 week later. Tissue sections were double-labeled with antibodies against BrdU (red) and NeuroD (green; stains immature neurons) and were analyzed by laser-scanning confocal microscopy. [Photo courtesy of (7)]


June 4, 2003
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Citation: P. M. Wise, Creating New Neurons in Old Brains. Sci. SAGE KE 2003, pe13 (4 June 2003);2003/22/pe13

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