Neurogenic Niches

An increasing number of "potential" neurogenic zones have been discovered during the last decade, in accordance with the fact that neural stem cells can be isolated from several areas in adult brain (Gould 2007). However, the only zones where neurogenesis has been consistently found are the SGZ and the SVZ. Indeed, the microenvironments of the SGZ and SVZ contain specific factors that are permissive for adult neurogenesis, whereas the lack of these factors as well as inhibitory molecules restricts differentiation to neural lineages in other brain regions. The existence of specific neurogenic niches where a number of mechanisms direct the differentiation, proliferation, and survival of newborn cells has underlined the role of the glial environment, astrocytes, and oligodendrocytes and other cell types such as ependymal or endothelial cells and neuroblasts (Doetsch 2003; Ma et al. 2005; Ninkovic and Gotz 2007; Riquelme et al. 2008). For instance, a number of trophic factors such as vascular endothelial growth factor (VEGF), brain derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) have been shown to modulate one or several phases of adult neurogenesis after intracerebral or peripheral infusions (Schmidt and Duman 2007). Interestingly, neurogenesis appears to occur in intimate association with angiogenesis, and both processes can be activated by similar stimuli (Palmer et al. 2000).

More diffusible factors such as hormones, peptides, and neurotransmitters may act and interact to affect adult neurogenesis (Ming and Song 2005; Hagg 2005; Vaidya et al. 2007). Indeed, the neurogenic regions are richly innervated by neurotransmitter systems of local and distant origins. For instance, glucocorti-coids, which mediate some of the deleterious effects of stress, have inhibitory effects on hippocampal neurogenesis both directly and indirectly by activating the glutamatergic transmission (Mirescu and Gould 2006). In contrast to its role as an inhibitory neurotransmitter on mature cells, GABA released locally depolarizes neural progenitors and early newborn neurons. Thus, GABA was shown to inhibit proliferation and promote maturation and differentiation of these cells (Ge et al. 2007). In the SVZ, GABA serves as a feedback regulator of neural production and migration (Bordey 2007), and in the SGZ, GABA-ergic mechanisms regulate differentiation and the timing of synaptic integration of new neurons (Markwardt and Overstreet-Wadiche 2008). As already mentioned, glutamatergic signaling, mainly through N-methyl-d-aspartate (NMDA) receptors, regulates adult neurogenesis. However, the role of NMDA receptor activation is complex since the progenitor cells do not express functional NMDA receptors (Nacher et al. 2007). Increases in cell proliferation have been observed after both NMDA (Joo et al. 2007) and NMDA antagonist administration (Nacher and McEwen 2006), depending on the delay posttreatment. One hypothesis is that this effect could be mediated by GABA, whose release by hippocampal interneurons requires NMDA activation (Matsuyama et al. 1997). Indeed, interactions between various neurotransmitters or between neurotransmitters and hormones or trophic factors released near or into the neurogenic niches may account for complex in vivo regulation of adult neurogenesis.

Every monoaminergic input (dopaminergic [DA], noradrenergic [NA], and serotonergic [5-HT] afferents) affects proliferation and neurogenesis in both neu-rogenic region (Hagg 2005; Vaidya et al. 2007). The strong DA innervation of the striatum has triggered a number of studies investigating the DA control of cell proliferation and neurogenesis in the SVZ-OB system (Borta and Hoglinger 2007), with the hope of using the pool of progenitors to replace the DA content lost in patients with Parkinson disease (Geraerts et al. 2007). However, conflicting data have been reported since DA depletion leads to an increase (Liu et al. 2006; Aponso et al. 2008), or a decrease in cell proliferation in the SVZ (Baker et al. 2004; Hoglinger et al. 2004; Freundlieb et al. 2006), followed by a shift in differentiation of dopaminergic cells in the OB (Winner et al. 2006). Activation of DA-D2 receptors has been shown to inhibit (Kippin et al. 2005) or to rescue and stimulate cell proliferation in the SVZ, an effect mediated by CNTF (ciliary neurotrophic factor) (Hoglinger et al. 2004; Yang et al. 2008). Further, DA-D3 receptors strongly expressed at the SVZ level are also positively involved in the regulation of cell proliferation in rats (Coronas et al. 2004; Van Kampen et al. 2004) but not in mice (Baker et al. 2005), suggesting the influence of genetic background.

By contrast, data concerning NA control of adult neurogenesis are rather scarce, but all suggest a positive implication of this catecholamine. Chronic increase in NA level produces significant enhancement in cell proliferation in the SGZ (Malberg et al. 2000), while NA depletion induces the opposite effect without affecting survival and differentiation (Kulkarni et al. 2002). However, by using an a2-adrenergic receptor antagonist leading to a general increase in NA transmission and a blockade of postsynaptic a2-noradrenergic receptors, a selective increase in cell survival and differentiation was also shown in the hippocampus (Rizk et al. 2006), and in the OB (Bauer et al. 2003). These results suggest that various adrenergic receptor subtypes have specific involvement in NA regulation of neurogenesis phases.

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