Neurogenesis and brain injury: managing a renewable resource for repair

As observed by the pioneering neuroscientist Santiago Ramon y Cajal, the mature CNS was distinguished from the developing nervous system by the lack of growth and cellular regeneration.The fixed neuronal population of the adult brain was understood to be necessary to maintain the functional stability of adult brain circuitry.This explanation has also been offered to account for the lack of endogenous CNS repair following injury or disease.Ever perceptive, Cajal left open the possibility for future advances to alter this "harsh decree," and in the last several decades, mounting evidence has led to the view of the CNS as a dynamic, plastic organ, endowed with some potential for self-repair and regeneration.Recent progress in understanding continued neurogenesis in the adult brain has raised hopes that selfrenewal leading to structural repair by new neurons may even be possible in the mature CNS.Nevertheless, under normal conditions, neurogenesis in the adult brain appears to be restricted to the discrete germinal centers: the subventricular zone and the hippocampal dentate gyrus (2) (Figure 1).While some reports indicate that neurogenesis in the adult CNS may be more widespread and include the cerebral cortex (3, 4), other reports cast doubt on these observations (5-7).More study is needed to establish the origin, extent, survival, and function of new neurons in these other regions.This Spotlight summarizes our current understanding of the regulation of adult neurogenesis and its relevance to structural brain repair.We propose strategies for harnessing the potential of neural stem cells for brain repair and consider how to apply these strategies to the aging brain. Plasticity in adult neurogenesisNeurogenesis in the adult brain can be divided into three phases in accordance with the sequence of neurogenesis during CNS development: (a) proliferation, when new cells are generated; (b) migration toward target areas; and (c) terminal differentiation into distinct phenotypes (Figure 1).The use of the term "neurogenesis" implies progression through differentiation and should not be used in cases where only proliferation is studied.It is not yet fully known whether these phases in adult neurogenesis are regulated by the same mechanisms that regulate development, or even whether the same mechanisms regulate neurogenesis in the two adult germinal centers.Nevertheless, new, functional neurons are generated in these areas, expanding the definition of plasticity in the adult brain to now include cellular addition to circuitry (8).New hippocampal neurons may participate in the processing of memory in the hippocampus (9), while new olfactory bulb neurons appear to participate in processing olfactory input (10).Newly generated hippocampal neurons may also contribute to the response of the nervous system to antidepressant administration (11).Interestingly, adult neurogenesis is not static, but its rate may fluctuate in response to environmental change, even subtle macroenvironmental alterations (2).Examples of positive regulators of neurogenesis