Effects of neurogenesis on cerebral ischemic recovery
There are definitive physiological changes that occur during the recovery from a stroke. However, is the recovery from cerebral ischemia more a function of brain plasticity or the contribution of newly born cells?
To attempt to answer this question, Raber et al. form an experimental design where they disrupt neurogenesis and see whether it has a negative impact on recovery from cerebral ischemia. From previous work, it was found that there is a dose-related depression of neurogenesis after subjects are treated with whole-brain x-irradiation. In order to see whether this depression of neurogenesis in the dentate gyrus has a negative effect on recovery from stroke, they treated gerbils with x-ray radiation and then subjected the gerbils to five minutes of bilateral common carotid artery occlusion (BCCAO). BCCAO shuts off blood supply to the brain and simulates the effects of cerebral ischemic trauma, so based on the recovery the researchers hoped to find an answer to their question. They also used 5-bromo-2-deoxyuridine-5-monophosphate (BrdU) to analyze the phenotype and survival ratio of newborn cells. This is a very common method to investigate the proliferation of newly inserted cells that relies on a substitution of the thymide nucleotide so that all newly replicated cells can be identified.
The team separated the gerbils into four groups: controls, x-ray irradiation only, BCCAO only, and x-ray irradiation followed by BCCAO. The key group difference that they were looking for was a functional difference in learning performance between the gerbils subjected to just BCCAO and gerbils subjected to x-ray irradiation followed by BCCAO, because this would determine whether neurogenesis is responsible for some of the recovery following cerebral ischemia.
What they found were strong results on the functional side. The gerbil group subjected to x-ray irradiation and then BCCAO performed dramatically worse on a water maze test, which simulates a learning exercise, with p<.01. However, when they used the results from the BrdU test to analyze the number of neurons in the subgranular zone of the dentate gyrus, they found no statistically significant difference in the number of new neurons in the four treatment groups. Since neurogenesis in this region is supposed to be the mechanism for the difference in learning, this discrepancy poses some tough questions. There are, however, a few ways to address the discrepancy:
1) Cells from other regions besides the dentate gyrus might be involved in functional outcomes, since ischemia affects other regions as well.
2) New neuron cells (from adult neurogenesis) may have contributed from regions other than the dentate subgranular zone. This is a fairly radical suggestion, but one that may deserve consideration.
3) Although the new neuron cells in the dentate gyrus may have been negligible in number, they may have been crucial in their connections to other neurons. It is difficult to tell what role individual neurons could play in the functional whole (that may be the understatement of the year), but it is possible that these new granule cells played crucial roles in coordinating the timing of action potentials of other neurons.
Their paper is concise and informative, and it has some good data showing that neurogenesis is a key mechanism behind the recovery from cerebral ischemic trauama.
Reference
Raber J, et al. 2004 Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Annals of Neurology 55: 381-389. doi: 10.1002/ana.10853.