Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
Signals Regulating Neurogenesis in the Adult Olfactory Bulb
Arvid-Carlsson-Institute for Neuroscience, Department of Clinical Neuroscience, Sahlgrenska University Hospital, Gothenburg, Sweden
Correspondence to be sent to: H. Georg Kuhn, e-mail: georg.kuhn{at}neuro.gu.se
Key words: cell death, granule cells, neuronal progenitor cells, periglomerular neurons, proliferation, subventricular zone
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Introduction |
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 Top Introduction Elimination as well as...Sensory stimulation of olfactory...Molecular regulators of...References |
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Most mammalian brain cells develop from neural progenitor or stem cells that reside in the ventricular and subventricular zone. Interestingly, in rodents and primates, neurogenesis does not end when the olfactory bulb reaches adult size but rather continues throughout life (Kaplan et al., 1985
;
Kuhn et al., 1996;
Pencea et al., 2001). For
neurons at two locations in the olfactory bulb, the granule cell layer and glomerular
layer, a persistent proliferative activity of progenitor cells can be observed in the
subventricular zone (SVZ) of the lateral ventricles. The committed neuronal progenitor
cells migrate rostrally through the remnant of the embryonic olfactory ventricle wall,
the so-called rostral migratory stream (RMS), towards the olfactory bulb. Once the
olfactory bulb is reached, the majority of cells disperse throughout the granule cell
layer to develop into GABAergic granule cells. A small percentage, however, moves into
the periglomerular region to develop into interneurons of mostly GABAergic and
dopaminergic phenotype. |
Elimination as well as long-term survival of young neurons |
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TopIntroductionElimination as well as...Sensory stimulation of olfactory...Molecular regulators of...References |
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The continuous addition of new neurons to the olfactory bulb leads to substantial growth of the structure over the adult life of a rodent, which is achieved mostly through an increase in neuronal density (Kaplan et al., 1985
). Yet, the amount of proliferating and migrating cells appears
to outnumber the growth rate of the olfactory bulb, and therefore, we investigated cell
death within the neurogenic regions of the adult brain and found an up to 100-fold higher
incidence of apoptotic cell death within the SVZ, RMS and olfactory bulb compared with
non-neurogenic regions (Biebl et al.,
2000).
The coexistence of neurogenesis and cell death in the olfactory bulb leads to the
question, whether old cells are replaced or whether the number of developing neurons is
adjusted to the necessary amount. After injecting rats at 2 months of age with
bromodeoxyuridine (BrdU), we quantified the newly generated cells over a period of 19
months (Winner et al.,
2002). A peak of new neurons is reached in the olfactory bulb 1 month after
BrdU injection, when the labeled cells have finished migration from the ventricle wall.
At this point the majority of new cells (>90%) express the mature neuronal
marker NeuN, although the first cells begin expressing NeuN already as early as
7–10 days after birth. Thereafter, we observed a reduction of BrdU-positive cells
to ~50%. We confirm by dUTP-nick end labeling (TUNEL) that progenitors and young
neurons undergo programmed cell death. Nevertheless, cells that survived the first
3 months after BrdU injection were detectable as granule cells for up to 19 months.
A similar elimination of newly generated neurons was observed for the periglomerular
interneurons (Winner et al.,
2002). Rather than replacing old neurons, these results suggest that new
neurons are added to the adult olfactory bulb and that apoptotic elimination of young
neurons is used to control the growth of these neuronal populations in the olfactory
bulb.
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Sensory stimulation of olfactory neurogenesis |
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TopIntroductionElimination as well as...Sensory stimulation of olfactory...Molecular regulators of...References |
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It is well established that during embryonic brain development a large proportion of neural progenitors and young neurons are eliminated by programmed cell death unless the cells receive synaptic input or trophic support (for a review, see Oppenheim, 1991
). Newly generated
neurons in the adult brain depend on sensory stimulation as demonstrated by decreased
neurogenesis due to increased cell death after naris closure (Corotto et al., 1994), whereas sensory
stimulation through exposure to novel odorants had the opposite effect (Rochefort et al., 2002). On the other
hand, exposure to an enriched environment and physical activity, such as voluntary wheel
running, increase neurogenesis in the dentate gyrus of adult mice and rats (Kempermann et al., 1997;
Nilsson et al., 1999); but
no difference in SVZ progenitor proliferation or neurogenesis in the olfactory bulb was
detectable under these conditions (Brown et
al., 2003). Conversely, odorant enrichment was ineffective in raising
the hippocampal neurogenesis level (Rochefort
et al., 2002), thus arguing for local, yet unidentified mechanisms
that specify neurogenic signals in the adult brain. Using anosmic mice, Alvarez-Buylla
and colleagues found that sensory input was critical for the survival of young granule
cells during maturation, and once synaptically connected, their survival depended on the
level of activity that they received (Petreanu
and Alvarez-Buylla, 2002). |
Molecular regulators of olfactory neurogenesis |
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TopIntroductionElimination as well as...Sensory stimulation of olfactory...Molecular regulators of...References |
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Direct mitogenic stimulation of progenitor cells in the adult brain appears to be mediated via growth factors and trophic factors. It is still unclear to what extend endogenous production of several candidate growth factors, such as FGF-2 and BDNF, play a role in the ongoing spontaneous olfactory bulb neurogenesis. Possible mechanisms include local expression or direct action of factors passing through the blood-brain barrier. But other mechanisms, such as angiogenesis, could also be triggered, which have a secondary positive effect on neurogenesis (Palmer et al., 2000
;
Louissaint et al., 2002;
Shen et al., 2004). In this
context it is important to note, that several blood-derived growth factors such as
erythropoietin and vascular endothelial growth factor (VEGF) are potent stimulators of
neurogenesis, when applied directly into the ventricular system (Shingo et al., 2001;
Jin et al., 2002;
Schänzer et al.,
2004).
The effect of neurotransmitter systems on adult neurogenesis has been extensively
studied in the hippocampus. Glutamatergic input from the entorhinal cortex has a negative
impact on granule cell production (Cameron et
al., 1995;
Bernabeu and Sharp, 2000;
Kitamura et al., 2003;
Nacher et al., 2003),
whereas the serotonergic input from the raphé nuclei is an activator of
hippocampal neurogenesis. Treatments with the antidepressants, which act as stimulators
of the serotonergic system, have demonstrated a positive influence neurogenesis
(Malberg et al., 2000;
Czeh et al., 2001;
Santarelli et al., 2003). In
a recent study we were able to demonstrate that neurogenesis in the olfactory bulb as
well as in the dentate gyrus is reduced after lesion of the cholinergic basal forebrain
system using immunotoxin lesions (Cooper-Kuhn
et al., 2004). These studies indicate that the extracellular milieu
in the neurogenic regions can be substantially influenced by the release of
neurotransmitters. However, it remains to be shown, whether and at what stage the
immature cells express neurotransmitters receptors in order become directly responsive to
these signals.
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References |
|---|
|
TopIntroductionElimination as well as...Sensory stimulation of olfactory...Molecular regulators of...References |
|---|
Bernabeu, R. and Sharp, F.R. (2000) NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J. Cereb. Blood Flow Metab., 20, 1669–1680.[CrossRef][Web of Science][Medline]
Biebl, M., Cooper, C.M., Winkler, J. and Kuhn, H.G. (2000) Analysis of neurogenesis and programmed cell death reveals a self- renewing capacity in the adult rat brain. Neurosci. Lett., 291, 17–20.[CrossRef][Web of Science][Medline]
Brown, J.P., Cooper-and, C.M., Kempermann, G., van Praag, H., Winkler, J., Gage, F.H. and Kuhn, H.G. (2003) Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur. J. Neurosci., 17, 2042–2046.[CrossRef][Web of Science][Medline]
Cameron, H.A., McEwen, B.S. and Gould, E. (1995) Regulation of adult neurogenesis by excitatory input and NMDA receptor activation in the dentate gyrus. J. Neurosci., 15, 4687–4692.[Abstract]
Cooper-Kuhn, C.M., Winkler, J. and Kuhn, H.G. (2004) Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J. Neurosci. Res., 77, 155–165.[CrossRef][Web of Science][Medline]
Corotto, F.S., Henegar, J.R. and Maruniak, J.A. (1994) Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse. Neuroscience, 61, 739–744.[CrossRef][Web of Science][Medline]
Czeh, B., Michaelis, T., Watanabe, T., Frahm, J., de Biurrun, G., van Kampen, M., Bartolomucci, A. and Fuchs, E. (2001) Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc. Natl Acad. Sci. USA, 98, 12796–801.
Jin, K., Zhu, Y., Sun, Y., Mao, X.O., Xie, L. and Greenberg, D.A. (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl Acad. Sci. USA, 99, 11946–11950.
Kaplan, M.S., McNelly, N.A. and Hinds, J.W. (1985) Population dynamics of adult-formed granule neurons of the rat olfactory bulb. J. Comp. Neurol., 239, 117–125.[CrossRef][Web of Science][Medline]
Kempermann, G., Kuhn, H.G. and Gage, F.H. (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature, 386, 493–495.[CrossRef][Medline]
Kitamura, T., Mishina, M. and Sugiyama, H. (2003) Enhancement of neurogenesis by running wheel exercises is suppressed in mice lacking NMDA receptor epsilon 1 subunit. Neurosci. Res., 47, 55–63.[CrossRef][Web of Science][Medline]
Kuhn, H.G., Dickinson-Anson, H. and Gage, F.H. (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J. Neurosci., 16, 2027–2033.
Louissaint, A., Jr, Rao, S., Leventhal, C. and Goldman, S.A. (2002) Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron, 34, 945–960.[CrossRef][Web of Science][Medline]
Malberg, J.E., Eisch, A.J., Nestler, E.J. and Duman, R.S. (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci., 20, 9104–9110.
Nacher, J., Alonso-Llosa, G., Rosell, D.R. and McEwen, B.S. (2003) NMDA receptor antagonist treatment increases the production of new neurons in the aged rat hippocampus. Neurobiol. Aging, 24, 273–284.[CrossRef][Web of Science][Medline]
Nilsson, M., Perfilieva, E., Johansson, U., Orwar, O. and Eriksson, P.S. (1999) Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J. Neurobiol., 39, 569–578.[CrossRef][Web of Science][Medline]
Oppenheim, R.W. (1991) Cell death during development of the nervous system. Annu. Rev. Neurosci., 14, 453–501.[CrossRef][Web of Science][Medline]
Palmer, T.D., Willhoite, A.R. and Gage, F.H. (2000) Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol., 425, 479–494.[CrossRef][Web of Science][Medline]
Pencea, V., Bingaman, K.D., Freedman, L.J. and Luskin, M.B. (2001) Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain. Exp. Neurol., 172, 1–16.[CrossRef][Web of Science][Medline]
Petreanu, L. and Alvarez-Buylla, A. (2002) Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J. Neurosci., 22, 6106–6113.
Rochefort, C., Gheusi, G., Vincent, J.D. and Lledo, P.M. (2002) Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci., 22, 2679–2689.
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C. and Hen, R. (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301, 805–809.
Schänzer, A., Wachs, F.P., Wilhelm, D., Acker, T., Cooper-Kuhn, C.M., Beck, H., Winkler, J., Aigner, L., Plate, K.H. and Kuhn, H.G. (2004) Direct stimulation of adult neural stem cells in vitro and neurogenesis in vivo by vascular endothelial growth factor. Brain Pathol., 14, 237–248.[Web of Science][Medline]
Shen, Q., Goderie, S.K., Jin, L., Karanth, N., Sun, Y., Abramova, N., Vincent, P., Pumiglia, K. and Temple, S. (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 304, 1338–1340.
Shingo, T., Sorokan, S.T., Shimazaki, T. and Weiss, S. (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J. Neurosci., 21, 9733–9743.
Winner, B., Cooper-Kuhn, C.M., Aigner, R., Winkler, J. and Kuhn, H.G. (2002) Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur. J. Neurosci., 16, 1681–1689.[CrossRef][Web of Science][Medline]
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