Neurogenesis In The Adult Brain

National Institute Of Mental Health

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Abstract

TTo study the regulation of adult neurogenesis and its role in behavior, we use rats and mice, which show adult neurogenesis similar to that in primates, including humans. During the past year, we have completed two studies using immediate-early gene expression to assess the activation of new hippocampal granule cells at a population level, which allows us to study the maturation and function of these new neurons. These studies involve exposing the animals to learning tasks or other experiences, injecting cell cycle markers to mark newly born cells, and then using immunohistochemistry and confocal microscopy to count cells and assess their expression of immediate-early genes and other markers of cell age or phenotype. In the first study, we showed that exercise, free access to a running wheel, advanced the functional maturation of young neurons, causing them to be incorporated into hippocampal networks significantly faster. In addition, exercise nearly doubled the survival of the young neurons, but had only a small and transient effect on proliferation contrary to what is generally believed to be the mechanism of exercises effect on adult neurogenesis. We found that daily stress had no effect on maturation but caused a transient and unexpected increase in the survival of the young neurons. This finding suggests that repeated stress, with recovery time between stressful episodes, may have very different and more positive effects than chronic increases in glucocorticoids, which are known to inhibit granule cell survival. In a second series of experiments, we compared behaviorally induced activation of granule cells in the dorsal and ventral dentate gyrus to better understand the functional differences between these two subregions. It is becoming widely accepted that hippocampal function varies in a subregion-specific fashion, with spatial processing being more dependent on the dorsal hippocampus and anxiety-related behavior more dependent on the ventral hippocampus. Recently, we found that activation of granule cells born in adulthood by a spatial water maze task is higher in the ventral dentate gyrus than in the dorsal region. This finding is surprising, given that this task is spatial, that granule cells born during development are more activated in the dorsal region, and that more new neurons are born in the dorsal region and suggests that adult-born neurons may play a specific role in anxiety-related behavior or other non-spatial aspects of hippocampal function. We have now followed up this study in aged rats, showing that even though there is 90% less neurogenesis in aged rats, activation of young and older granule cells by spatial water maze learning show the same gradients as in young rats. Together, these studies provide a basis for understanding the mechanisms through which exercise, stress, and aging alter may affect learning, memory, and mood disorders.