Neural Stem Cell Death In The Adult

With the recent identification of neural stem cells in the adult brain, consideration of regulated cell death pathways in these cells is warranted. The molecules that regulate neural stem cell death in the embryo may not have similar functions in adult stem cell populations for several reasons, making the studies of adult neural stem cell death pathways particularly exciting. First, the expression patterns of many regulatory death molecules change during neurogenesis in the embryo. The expression levels of apoptosis-associated molecules in adult neural stem cells are unknown but will surely influence cell death responsiveness. Second, the microenvironment of the adult brain is markedly different from that of the embryo, and extrinsic regulators of neural stem cell death that are present in the embryo may be absent or altered in the adult. Furthermore, adult neural stem cells, given their multipotency and proliferative potential, may become oncogenic if cell death pathways are dysregulated. Finally, recent attempts at transplantation of neural stem cells into injured or degenerating adult brain have been hampered by a significant amount of cell death of neural stem cell grafts.

There is clear evidence for adult neurogenesis in the dentate gyrus of the hippocampus and in the olfactory bulb (119-121). These neurons arise from neural stem cells in the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle. Recently, claims for neurogenesis in the adult neocortex have challenged the long accepted hypothesis that cortical neurogenesis in the adult mammalian brain is minor (122,123).

Cell Death of Newly Generated Neurons in the Dentate Gyrus

New neurons in the dentate gyrus originate in the subgranular zone, located between the dentate gyrus and the hippocampal hilus (120). These neurons attain both morphological and functional characteristics of dentate granule neurons, and may have roles in hippocampal memory formation or mood homeostasis. Many of these cells seem to die soon after birth (122,124,125). In the rodent, strain-dependent factors may influence survival of newly generated neurons in the dentate gyrus (126). The number of newly generated neurons may be increased by cognitive tasks, but it is not entirely clear whether this effect is due to prevention of programmed cell death or to a generalized increase in hippocampal neurogenesis (122,127). A percentage of newly generated neurons in the adult dentate gyrus do appear pyknotic and exposure to alcohol or nicotine increases pyknosis, TUNEL positivity, and activated caspase-3 immunoreactivity in the dentate gyrus (128,129).

A significant number of reports indicate that newly generated neurons in the dentate gyrus decrease in number over time. Many authors have suggested that this decline may be due to death of neural stem cells. However, an analysis of the particular program of cell death engaged by these dying cells has not, to our knowledge, been completed. It will be interesting to determine the molecular requirements for adult hippocampal neural precursor death in both the rodent and primate.

Cell Death of Newly Generated Neurons in the Olfactory Bulb

In the rodent, newly generated granule and periglomerular neurons in the olfactory bulb originate in the rostral region of the lateral ventricle and migrate to the olfactory bulb (119). This rostral migratory stream provides newly generated neurons to the olfactory bulb, where they play roles in odor discrimination and odor memory. The ultimate fate of these neurons is thought to be cell death, although the precise mechanism of death is unclear (130,131). In untreated adolescent rats, apoptotic figures and TUNEL positivity have been demonstrated along the rostral migratory stream and in laminar regions of the olfactory bulb (132,133). Significant numbers of TUNEL positive cells are also seen in the adult subventricular zone, rostral migratory stream, and olfactory bulb (134,135).

Neurons in the rodent olfactory bulb are dependent on sensory input for survival. Deafferation of the olfactory receptor neurons induces a reduction of epithelial thickness and cell death in the olfactory epithelium (136). This apoptotic stimulus results in increased pyknosis in the olfactory bulb and increased TUNEL positivity in lateral ventricle, rostral migratory stream, and the olfactory bulb, suggesting that sensory withdrawal-induced death in these populations is apoptotic (133,137-139). Similar results have been shown using anosmic mice, which express mutated cyclic nucleotide-gated channels in olfactory receptor neurons (140,141). In these mice, an increase in TUNEL positivity can be seen in the granule cell layer of the olfactory bulb (142). It is not clear whether cell death in the olfactory bulb occurs solely in postmitotic olfactory receptor neurons or whether neural precursor cells are also subjected to cell death in the adult.

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