New neurons for aging brains

Some wise person once said, “Half of all we teach medical students is wrong. The only problem is figuring out which half. ” I have contributed my share of misinformation by teaching generations of medical students that “you are born with all the neurons you will ever have, the only thing that can happen after that is for the number of neurons to decrease for various reasons. ” In the last few years, however, it has become clear that this dogma is incorrect. Neurogenesis does take place throughout life in the olfactory and in the dentate gyrus of the hippocampus. This neurogenesis in the hippocampus is age dependent, decreasing as the animals age. Gage and his colleagues have been among the leaders in the study of neurogenesis in the hippocampus and have asked such questions as the following: What are the cellular mechanisms underlying neurogenesis? Are there factors that promote neurogenesis? and Are these cells functional in hippocampal systems? Previous studies have indicated that physical activity has a strong upregulation of adult hippocampal neurogenesis in mice. In the report by Kempermann and colleagues, the investigators ask whether exposure to an enriched environment over the long term is associated with sustained effects on neurogenesis. To answer this, they raised 10-month-old mice for 10 months in an environment enriched by larger cages and various “toys” as well as a running wheel. The controls were placed in standard, smaller stages, without these enriching elements. After 10 months, cellular proliferation was marked by BrdU labeling, which indicates all proliferating cells, glia, neurons, and those not identifiable. After a short incubation time, there were twice as many BrdU-labeled cells in the dentate gyrus of mice living under the enriched conditions as compared with the controls, with a modest increase in the percentage of neurons. Interestingly, 4 weeks later there was no difference in the number but a marked difference in the distribution of new cells, with neurons three times more prevalent than glia in the enriched as compared with the control animals. This finding suggests that there was not a continuing proliferation of new cells but rather a change in the distribution of newly formed cells. In other words, there was a phenotypic shift from gliogenesis to neurogenesis. A recent publication from this same laboratory reported that astrocytes play a role in controlling the destiny of hippocampal stem cells, directing them to develop along neuronal pathways. In addition, not all astrocytes do this; unlike astrocytes from the hippocampus, astrocytes from spinal cords have limited ability to influence neuronal fate. Perhaps it is the regionally specific astrocytes that respond to physical activity or social enhancement. Another bit of dogma gone—astrocytes are more than “brain glue. ” One must wonder whether these added neurons have any physiological role. Studies indicate that these newly formed neurons have electrophysical properties indistinguishable from older pre-existing granule cells. They also may be healthier, having less lipofuscin, a pigment associated with oxidative damage to cells. Enrichment also was associated with changes in behavior with the enriched mice showing more exploratory behavior and greater locomotor skills. This suggests, but does not prove, that the morphological changes are associated with a similar enhancement in behavior. When one sees enhanced responses in a caged animal, one must ask whether this animal is being brought up to the normal of the animal in the wild or, conversely, whether one actually is driving the brain beyond a baseline level. The authors attempted to get at this by determining levels of glucocorticoids in the control and enriched animals. This was done as a surrogate measure for the effects of stress as well as an indication of the known detrimental effects of corticosterone levels on the hippocampus. Somewhat surprisingly, they found higher levels of glucocorticoids in the enriched animals than in the control animals. Thus, the question of what would be the level of neurogenesis in an animal in the wild is not answered. However, if it turns out that physical activity and/or enrichment of the environment produce a rehabilitation effect on hippocampus this is still a very interesting finding. How do we relate these novel findings to what is occurring in humans? In studies of an aging population, it was noted that those who preserve cognitive function were doing three things. One, they were being physically active. Two, they were being mentally active. And three, they were maintaining a positive self-image of themselves. The enhancement of neurogenesis by physical activity and an enriched environment in the mice correlate with the first two of these human activities. It is not clear how these mice felt about themselves. Previous attempts to explain the effects of physical activity or mental activity on preservation of cognitive function have focused on such issues as increased blood flow, greater synaptic plasticity, or perhaps some effects of trophic factors on neuronal maintenance. The present studies suggest EDITORIAL