. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007 Mar 2;315(5816):1243-9. PubMed.

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  1. It has been only a few years that we have known about the existence of adult neurogenesis in the brain of mammals. Presently, the majority of researchers in the field unequivocally accept that the generation of new neurons is continuously taking place in the subventricular zone (SVZ), subadjacent to the lateral ventricles, and in the subgranular zone (SGZ) of the hippocampus. Functionally, these newborn neurons may take over functions in olfactory learning, hippocampus-dependent learning, and mood regulation under physiological conditions. Under certain pathological conditions, such as stroke, Alzheimer disease, Huntington disease, or multiple sclerosis, repair mechanisms involving SVZ- or SGZ-derived neural precursors have been reported (Arvidsson et al., 2002; Jin et al., 2004; Picard-Riera et al., 2002; Curtis et al., 2003). A recent interesting finding was that precursor cell proliferation in the SVZ and SGZ of the adult brain can be stimulated by pharmacological means (Höglinger et al., 2004; Hagg, 2005). This opens up the exciting perspective that we might be able to learn one day how to use endogenous adult neurogenesis for the purpose of controlled brain repair in neurodegenerative conditions.

    This concept, however, was deeply challenged by Sanai et al. (2004). This report suggested that although the adult human SVZ contains stem cells with the capacity to create new neurons, the capacity of the neuroblasts in the human brain would be profoundly compromised with regard to migration and integration when compared to the rodent brain. This present study by Curtis et al. now provides a careful anatomic evaluation of the adult human SVZ with its rostral extension into the olfactory bulb. It demonstrates that the human system has conserved a remarkable degree of similarity with the rodent system. These findings do enforce the concept that there is stem cell activity maintained in the adult human brain, and they encourage research into how this activity may be utilized to counteract neurodegenerative disorders such as Alzheimer disease.

    References:

    . Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002 Sep;8(9):963-70. PubMed.

    . Increased cell proliferation and neurogenesis in the adult human Huntington's disease brain. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9023-7. PubMed.

    . Molecular regulation of adult CNS neurogenesis: an integrated view. Trends Neurosci. 2005 Nov;28(11):589-95. PubMed.

    . Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci. 2004 Jul;7(7):726-35. PubMed.

    . Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. PubMed.

    . Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13211-6. PubMed.

    . Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004 Feb 19;427(6976):740-4. PubMed.

  2. Comment by Ole Isacson and Antoine de Chevigny

    New neurons take similar routes to reach olfactory system in humans and rodents
    Olfaction is a faculty that is remarkably sensitive to changes in function and may even be an early sign of ongoing neurodegeneration (Huisman et al., 2003, Hawkes et al., 2003). There have been debates about the way the subventricular zone (SVZ) sends new neurons to the olfactory bulb in humans. A highly publicized Nature paper suggested that there was not a so-called rostral migratory stream (RMS) in humans (Sanai et al., 2004). Now, this paper by Curtis and colleagues finds that indeed there is a form of RMS also in humans. Moreover, it demonstrates how this RMS structure is a close homologue to other mammalian olfactory systems.

    This study shows for the first time that the adult human brain contains a rostral migratory stream of neuroblasts extending from the subventricular zone (SVZ) to the olfactory bulb. The authors further demonstrate that, unlike rodents and primates but more like rabbits, the human RMS is organized around a lateral ventricular extension reaching the core of the olfactory bulb. They also provide a characterization of the 3D-architecture of the human ventriculo-olfactory neurogenic system (VONS) containing the SVZ, the RMS, and the olfactory tract and bulb.

    Human RMS neuroblasts express PSANCAM, DCX, and Tuj1, and they have ultrastructural characteristics reminiscent of those of neuroblasts from other mammalian species studied (Alvarez-Buylla and Garcia-Verdugo, 2002). The neuroblasts have a migratory morphology, and the orientation of their leading and trailing processes indicates that they migrate from the SVZ to the olfactory bulb. Finally, this study demonstrates that, as shown in rodents (Hack et al., 2005; Kohwi et al., 2005), the expression of the transcription factor Pax6—known to induce neuroblast differentiation—is increased in the human olfactory bulb as compared to the RMS. In contrast, Olig2 expression—known to inhibit olfactory neuron differentiation—is decreased in the olfactory bulb, as compared to the RMS. Such data suggest that factors and mechanisms controlling olfactory precursor cell fate specification are conserved between rodents and humans. In conclusion, this work contrasts with the findings and interpretation of a previous study (Sanai et al., 2004), and in fact demonstrates a remarkable similarity between the human and rodent olfactory systems. Therefore, the presence and function of adult olfactory bulb neurogenesis seems to be conserved from lower mammals to humans.

    The new article by Curtis et al. closes by mentioning the reduced SVZ progenitor cell proliferation observed in animal models and patients with Parkinson disease. However, the authors do not discuss the paradox in Parkinson disease, which is that dopamine neurons progressively degenerate in the midbrain of patients, while dopamine neurons in the olfactory system, in fact, increase in numbers (Huisman et al., 2003). There is no consistent explanation for this increase relative to other neuron types in the Parkinson disease olfactory bulb. A possible explanation for the reduced olfaction is that dopamine somehow inhibits transmission in the olfactory system, and so the paradoxical increase in dopamine neurons in the olfactory bulb in Parkinson disease patients may, in fact, explain this olfactory impairment. While the demonstration of RMS in humans may at first appear peripheral to experimental attempts to eventually deliver new therapies based on adult neurogenesis to patients with neurodegenerative diseases (Cooper and Isacson et al., 2004, Hack et al., 2005), Curtis et al. provides substantial evidence that work using rodent models to study adult neurogenesis also in the olfactory system can be directly transferable to humans.

    References:

    . Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 2007 Mar 2;315(5816):1243-9. PubMed.

    . Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb. Exp Neurol. 2006 Jan;197(1):113-21. PubMed.

    . Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons. J Neurosci. 2004 Oct 13;24(41):8924-31. PubMed.

    . Olfaction in neurodegenerative disorder. Adv Otorhinolaryngol. 2006;63:133-51. PubMed.

    . Olfactory function in patients with Parkinson's disease. J Chronic Dis. 1975 Oct;28(9):493-7. PubMed.

    . Neurogenesis in adult subventricular zone. J Neurosci. 2002 Feb 1;22(3):629-34. PubMed.

    . Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci. 2005 Jul;8(7):865-72. PubMed.

    . Pax6 is required for making specific subpopulations of granule and periglomerular neurons in the olfactory bulb. J Neurosci. 2005 Jul 27;25(30):6997-7003. PubMed.

    . Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature. 2004 Feb 19;427(6976):740-4. PubMed.

    . A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov Disord. 2004 Jun;19(6):687-92. PubMed.