Neurogenesis in Adult Mammalian Brains: Problems and Progress

The recent general acceptance that new neurons are generated in adult mammalian nervous systems, contrary to long-established dogma, has generated much speculation about possible functions of such neurons and aroused hopes for therapeutic applications, but controversy still surrounds these findings. The Journal of Neuroscience presents a series of mini-reviews by experts in this field in the number for February 1, 2002. Most of the reviews are about five pages long, with extensive references. A reader interested in this topic but who has not been following it in detail will find here much information and leads for further study.

Gage (2002), in the introductory mini-review, provides a brief overview of the field and raises some of the main questions that other reviewers discuss in more detail.

How can one identify new neurons in the adult nervous system and distinguish them from glial cells? The difficulties, problems and progress in this field are reviewed both by Rakic (2002), who has been critical of studies in this area, and by Gould and Gross (2002), who have published strong claims of adult neurogenesis. Rakic, for example, points out that much evidence for adult neurogenesis involves use of the agent bromodeoxyuridine (BrdU), a thymidine analog which labels dividing cells. But BrdU does not prove cell division but only synthesis of DNA which may occur for other reasons, such as cell repair. Rakic also notes that BrdU is mutagenic. Gould and Gross (2002) cite evidence that BrdU gets into the brain less efficiently in adults than in fetuses, possibly because the blood-brain barrier is further developed, and that low doses of BrdU probably lead to underestimations of neurogenesis. Also, the toxicity or lack of specificity of labeling found in developing rats do not apply to adult rats.

Alvarez-Buylla and Garcia-Verdugo (2002) study adult neurogenesis in the subventricular zone (called ventricular zone in the text; see Figure 7.4) and migration of new cells into the olfactory bulb. They suggest that this may provide a model system for study of the origin and migration of neurons. For example, they identify ventricular zone astrocytes as neural stem cells.

Kempermann (2002) asks what might be the functions for new neurons in the hippocampus. Because activity and experience favor neurogenesis in the adult hippocampus but it requires a few days for the new neurons to become functionally integrated into the hippocampus, it seems obvious that the new connections cannot benefit the events, such as environment stimulation or physical exercise, that triggered neurogenesis. Rather, Kempermann proposes that if the hippocampus acts as the gateway to memory, neurogenesis provides "new gatekeepers."

Kintner (2002) compares neurogenesis in the embryo and the adult. He asks how some transcription factors known as proneural proteins function in both cases. Investigating the comparisons may suggest strategies that could increase the neurogenic potential of neural stem cells for determination and differentiation.

Unlike the other authors, Nottebohm (2002) specializes in research on songbirds, in which neurogenesis is relatively common in the adult brain. Even in songbirds, however, with about 12 interconnected brain nuclei in the song system and 24 neural types, only three kinds of neurons continue to be produced in adulthood. Nottebohm proposes that the replacement of older neurons, whose function may be fixed and no longer plastic, may offer a mechanism for constant rejuvenation and new learning in the nervous system. He also advocates the study of adult neurogenesis and neural replacement in a diversity of free-ranging animals leading normal lives to find how nature uses these phenomena.

References:

Alvarez-Buylla, A. and García-Verdugo, J.M. (2002). Neurogenesis in Adult Subventricular Zone. Journal of Neuroscience, 22: 629-634.

Gage, F. (2002). Neurogenesis in the Adult Brain. Journal of Neuroscience, 22: 612-613.

Gould, E. and. Gross , C.G. (2002). Neurogenesis in Adult Mammals: Some Progress and Problems. J. Neurosci. 22: 619-623.

Kempermann , G. (2002). Why New Neurons? Possible Functions for Adult Hippocampal Neurogenesis. J. Neurosci. 22: 635-638.

Kintner , C. (2002). Neurogenesis in Embryos and in Adult Neural Stem Cells. J. Neurosci. 22: 639-643.

Nottebohm , F. (2002). Why Are Some Neurons Replaced in Adult Brain? J. Neurosci. 22: 624-628.

Rakic , P. (2002). Adult Neurogenesis in Mammals: An Identity Crisis. J. Neurosci. 22: 614-618.