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The adaptive significance of adult hippocampal neurogenesis remains unknown. In the laboratory, it is influenced by a variety of environmental and physiological stimuli. In the wild, it may be influenced by the reliance on spatial memory and by environmental stressors. The one common denominator in both settings is that neurogenesis declines markedly with age. Red squirrels are long-lived rodents that store food (thousands of tree cones) to permit survival under harsh winter conditions. We compared a population from the eastern North America that stores its cones singly or in small clusters with one from the west that stores its cones in large stockpiles. The reliance on spatial memory should be much greater in the east than the west, and should not decline with age, as cone storage and recovery is a yearly necessity. We found no difference between the populations in the density of young neurons and both populations showed the same decline with age. Thus, we reject the spatial memory hypothesis for adult neurogenesis in mammals in its original form. Instead, our evidence is consistent with the neurogenic reserve hypothesis in which neuronal cell production early in life leads to enhanced hippocampal function later in life according to environmental demand but without requirement for ongoing cell production as a function of site- and species-specific needs. A more general interpretation of the data leads us to consider a possible role of neurogenesis in novel, flexible episodic memories.

Postnatal hippocampal neurogenesis in wild mammals may play an essential role in spatial memory. We compared two species that differ in their reliance on memory to locate stored food. Yellow-pine chipmunks use a single cache to store winter food; eastern gray squirrels use multiple storage sites. Gray squirrels had three times the density of proliferating cells in the dentate gyrus (determined by Ki-67 immunostaining) than that found in chipmunks, but similar density of young neurons (determined by doublecortin immunostaining). Three explanations may account for these results. First, the larger population of young cells in squirrels may increase the flexibility of the spatial memory system by providing a larger pool of cells from which new neurons can be recruited. Second, squirrels may have a more rapid cell turnover rate. Third, many young cells in the squirrels may mature into glia rather than neurons. The densities of young neurons were higher in juveniles than in adults of both species. The relationship between adult age and cell density was more complex than that has been found in captive populations. In adult squirrels, the density of proliferating cells decreased exponentially with age, whereas in adult chipmunks the density of young neurons decreased exponentially with age.

Adult animals continue to produce new neurons in the dentate gyrus of hippocampus. Until now, the principal method of studying neurogenesis has been to inject either tritiated thymidine or 5'-Bromo-2-deoxyuridine (BrdU) intraperitoneally followed by autoradiographic or immunohistochemical detection methods respectively. However, such exogenous markers may produce toxic effects. Our objective was to determine whether Ki-67, a nuclear protein expressed in all phases of the cell cycle except the resting phase, can be used as an alternative, endogenous marker. Using immunohistochemistry, we examined Ki-67 and BrdU expression pattern in rats. Ki-67 was expressed within the proliferative zone of the dentate gyrus and its expression pattern mimicked that of BrdU when examined soon after exogenous BrdU administration. Quantitative comparison of BrdU and Ki-67-positive cells showed 50% higher numbers of the latter when examined 24 h after the BrdU injection. This was expected, since BrdU can be incorporated into DNA only during the S-phase of the mitotic process, whereas Ki-67 is expressed for its whole duration. Experimental increases (by ischemia) or reductions (by radiation) in the number of mitotic cells produced parallel changes in BrdU and Ki-67 signals. Thus, Ki-67 is an effective mitotic marker and has most of the benefits of BrdU and none of the costs. This study provides evidence for Ki-67 to be used as a marker of proliferation in the initial phase of adult neurogenesis.

The dogma that the adult brain produces no new neurons has been overturned, but the critics are still asking, so what? Is adult neurogenesis a biologically relevant phenomenon, or is it perhaps harmful because it disrupts the existing neuronal circuitry? Considering that the phenomenon is evolutionarily conserved in all mammalian species examined to date and that its relevance has been well documented in non-mammalian species, it seems self-evident that neurogenesis in adult mammals must have a role. In birds, it has been established that neurogenesis varies dramatically with seasonal changes in song production. In chickadees, the learning behaviour related to finding stored food is also correlated with seasonal adult neurogenesis. Such studies are still nonexistent in mammals, but the related evidence suggests that neurogenesis does vary seasonally in hamsters and shows sexual differences in meadow voles. To promote studies on natural populations asking fundamental questions of the purpose and function of neurogenesis, we organized a Workshop on "Hippocampal Neurogenesis in Natural Populations" in Toronto in May 2000. The Workshop highlighted recent discoveries in neurogenesis from the lab, and focused on its functional consequences. The consensus at the Workshop was that demonstration of a role for neurogenesis in natural behaviours will ultimately be essential if we are to understand the purpose and function of neurogenesis in humans.Key words: neurogenesis, hippocampus, dentate gyrus, learning, memory, wild population.Le dogme selon lequel le cerveau adulte ne produit pas de nouveaux neurones ne tient plus, mais les critiques continuent à dire, et alors ? La neurogenèse chez l'adulte est-elle un phénomène biologiquement pertinent, ou peut-elle être dommageable parce qu'elle perturbe le circuit neuronal existant ? Compte tenu du fait que le phénomène a été bien conservé au cours de l'évolution chez tous les mammifères examinés à ce jour et que sa pertinence a été bien documentée chez d'autres espèces, il semble aller de soi que la neurogenèse doit avoir un rôle chez les mammifères adultes. Chez les oiseaux, il est bien établi que la neurogenèse varie considérablement avec les variations saisonnières de la production de chants. Chez les mésanges, le comportement d'apprentissage lié à la découverte de la nourriture entreposée est aussi corrélé avec une neurogenèse saisonnière chez l'adulte. Il n'existe toujours pas d'études de ce genre chez les mammifères, mais les données connexes donnent à penser que la neurogenèse varie effectivement de façon saisonnière et montre des différences sexuelles chez les campagnols des champs et dans les variations du rythme circadien chez les hamsters. Pour encourager les études sur les populations naturelles abordant les questions fondamentales du but et de la fonction de la neurogenèse, nous avons organisé un colloque intitulé " Hippocampal Neurogenesis in Natural Populations ", à Toronto, au mois de mai 2000. Le Colloque a donné un aperçu des récentes découvertes sur la neurogenèse en laboratoire et mis l'accent sur ses conséquences fonctionnelles.. Selon le consensus établi lors du Colloque, il faudra nécessairement démontrer le rôle de la neurogenèse dans les comportements naturels si nous voulons comprendre le but et la fonction de la neurogenèse chez les humains.Mots clés : neurogenèse, hippocampe, corps godronné, apprentissage, mémoire, population sauvage.[Traduit par la Rédaction] [ABSTRACT FROM AUTHOR]