Adult neurogenesis and its promise as a hope for brain repair

Abstract

After the pioneer report by Joseph Altman of adult neurogenesis (AN) in mammals in 1962, the phenomenon of AN was "rediscovered" some 20 years later, first in songbirds and then in mammals. Since the 1990s, interest in AN was fueled by the hope that it could lead to the treatment of neurological deficits by grafting these neurons or their progenitors into brain areas affected by disease or injury. Unfortunately, after 20 years of intense research efforts there is no clear indication that AN can be harnessed for the repair of brain circuits. We argue that the exuberant optimism regarding the potential application of AN for brain repair was misguided by the belief that neurons and their precursors had extensive developmental plasticity. Many of the experiments investigating the potential of AN for brain repair were inspired by the idea that neuronal precursors would be able to adapt, and easily change their developmental fate to replace the lost neurons. However, research during the last 20 years has shown that, in most cases, the fate of neurons is strongly determined and that it rarely changes. Understanding the mechanisms that control neural cell fate may allow for the engineering of adult stem cells so that they can give rise to neurons with properties appropriate for the host circuit to be repaired. The lack of phenotypic flexibility of neuronal progenitors may eventually prove to be advantageous, as this may provide a high degree of predictability (and safety) in the properties of reprogrammed cells. We suggest that AN is still a useful model to understand how neurons integrate into adult brain circuits, and that brain repair will require a thorough understanding of the genetic programs that control neuronal fate and neuronal migration.

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