Reference 2
NUTRITIONAL MEDICINE RESEARCH
UK

Selected sections from
Nature Medicine
November 1998 Volume 4 Number 11 pp 1313 - 1317

Neurogenesis in the adult human hippocampus
Peter S. Eriksson1, 4, Ekaterina Perfilieva1, Thomas Björk-Eriksson2, Ann-Marie Alborn1, Claes Nordborg3, Daniel A. Peterson4 & Fred H. Gage4
1. Department of Clinical Neuroscience, Institute of Neurology, Sahlgrenska University Hospital, 41345 Göteborg , Sweden
2. Department of Clinical Neuroscience, Department of Oncology, Sahlgrenska University Hospital, 41345 Göteborg , Sweden
3. Department of Clinical Neuroscience, Department of Pathology, Sahlgrenska University Hospital, 41345 Göteborg , Sweden
4. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla , California 92037, USA

The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.
Loss of neurons is thought to be irreversible in the adult human brain, because dying neurons cannot be replaced. This inability to generate replacement cells is thought to be an important cause of neurological disease and impairment. In most brain regions, the generation of neurons is generally confined to a discrete developmental period. Exceptions are found in the dentate gyrus and the subventricular zone of several species that have been shown to generate new neurons well into the postnatal and adult period. Granule neurons are generated throughout life from a population of continuously dividing progenitor cells residing in the subgranular zone of the dentate gyrus in the rodent brain. 'Newborn' neurons generated from these progenitor cells migrate into the granule cell layer, differentiate, extend axons and express neuronal marker proteins

Discussion
Our study demonstrates that cell genesis occurs in human brains and that the human brain retains the potential for self-renewal throughout life. Although earlier studies in adult primates have been unsuccessful in showing neurogenesis in the dentate gyrus, a recent report has demonstrated neurogenesis in three-year-old marmoset monkeys. Although the number of BrdU-labeled cells entering the neuronal lineage seems to be lower in the human hippocampus than in marmosets, those monkeys were considerably younger, even in relative terms, than the humans examined here (average age of 64.4 2.9 years). Therefore, we conclude that, as in rodents, neurogenesis in the human dentate gyrus continues throughout life.
Although our results demonstrate that cells in the adult brain undergo cell division and that some of the newly generated cells can survive and differentiate into cells with morphological and phenotypic characteristics of neurons, we have not proven that these newly generated cells are functional. We also do not yet know the biological significance of cell genesis in the adult human brain. However, this does provide a basis to investigate a newly discovered type of 'neuroplasticity' in humans, one based on addition of neurons, that has not been previously considered. Studies in rodents have shown that the adult hippocampus contains progenitor cells that can be expanded in vitro and grafted back into the adult brain, where they can respond to regional cues by differentiation into site-specific phenotypes, including neurons. The presence of progenitor cells in the human dentate gyrus, reported here, indicates that these cells also may be used for in vitro and in vivo studies of cell differentiation and possibly subsequent transplantation studies. Furthermore, environmental stimulation can influence the rate of neurogenesis in the adult and senescent rodent dentate gyrus. The potential to regulate human neurogenesis should prove to be an interesting area of investigation.

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