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Menini A, editor. The Neurobiology of Olfaction. Boca Raton (FL): CRC Press/Taylor & Francis; 2010.

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The Neurobiology of Olfaction.

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Chapter 11Neurogenesis in the Adult Olfactory Bulb

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For over a century, a central paradigm in the field of neuroscience has been that the capacity of germinal layers to generate neurons was restricted to the embryonic period, and that new neurons are not added to the adult mammalian brain (Ramon y Cajal 1913). Occasional early reports of neurogenesis in the adult central nervous system (CNS) (Allen 1912; Levi 1898) were ignored, probably because of the impossibility to determine with certainty the neuronal nature of the cells presenting mitotic figures. In more recent times, the pioneering work of Altman (1962), followed by the studies of Kaplan and Hinds (1977), have reproposed, this time with more compelling evidences, that new neurons are added in discrete regions of the adult brain, the olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus (for a historical review, see Kaplan 2001). These reports were initially ignored, then followed by negative reactions and critical publications that did not confirm the existence of newborn neurons in adults (for a review of the controversy, see Gross 2000). After the finding that in reptiles new neurons continue to be added to most of the telencephalon throughout life (for a review, see Garcia-Verdugo et al. 2002), the paradigm shift leading to the acceptance of the notion of adult neurogenesis in higher vertebrates has known an important acceleration thanks to the discovery of neurogenesis in birds, related to the appearance of seasonal song (for review, see Nottebohm 1989). Nevertheless, these initial discoveries confronted the persistent assumption that adult neurons did not undergo proliferation, the last trench being dug at the level of the mammalian brain (Rakic 1985). The turning point of the collective perception about neurogenesis occurred with the demonstration that adult mammalian brain neurons are also capable of mitosis, and that newborn neurons can migrate and integrate into existing circuitries (for review, see Gross 2000). Interestingly, this particular new form of structural brain plasticity is specific to discrete brain regions and most investigations concern the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus (for a review, see Lledo et al. 2006). Although, in the past, occasional reports have appeared suggesting neurogenesis also at the cortical level (Gould et al. 1999), an elegant paper appeared a few years ago (Bhardwaj et al. 2006) providing almost definite proof that, contrary to other cell types in the brain parenchyma, no new cortical neurons are generated after the perinatal period. Taking advantage of the integration of C-14 generated by nuclear bomb tests and by analyzing neocortical tissue of patients who received bromodeoxyuridine (BrdU), the study provides compelling evidence that there is no biologically significant neocortical neurogenesis in adult humans.


11.2.1. Development and Role of the Subventricular Zone (SVZ)

The SVZ (Boulder Committee 1970), which develops from residual progenitors of the lateral ganglionic eminence (LGE) (Bayer et al. 1994), is one of the major germinal layers during embryogenesis, giving rise to most neurons and glial cells in the forebrain. At late stages of embryonic development, it generates cells destined for the adjacent basal ganglia and for other structures in the brain, including the diencephalon (Rakic and Sidman 1969) and cortex (Anderson et al. 1997; de Carlos et al. 1996). Contrary to other germinal layers, the SVZ persists after birth, lining most of the lateral wall of the lateral ventricle, and, together with the hilar region of the hippocampus, remains one of the two districts in the mammalian brain where neurogenesis persists throughout life (Alvarez-Buylla and Lim 2004), although, compared with the LGE from which it originates, the postnatal SVZ shows a more restricted lineage potentiality (Stenman et al. 2003; Wichterle et al. 2001).

Until recently, it was believed that the germinative zone in the adult was restricted to the wall of the lateral ventricle facing the striatum (lateral wall) in which postnatal proliferation is more easily observed. However, the rostral migratory stream (RMS) and parts of the lateral ventricular wall facing the septum (medial wall), or the corpus callosum or pallium (dorsal wall), contain proliferative cells that act as stem cells in vitro (Doetsch et al. 1999; Gritti et al. 2002) and in vivo (Merkle et al. 2007), so together these regions might be considered a unique large proliferative zone. Further findings that the region involved in adult neurogenesis in the OB might extend well beyond the SVZ comes from the work of Ventura and Goldman (2007), which provides a direct demonstration of a contribution of the dorsal radial glia, formerly believed to senesce postnatally, to the generation of interneurons in the adult OB. Nevertheless, for simplicity, in the following we will generically speak of SVZ.

As originally described by Altman (1969), SVZ stem cells give rise to neuroblasts that migrate tangentially along the RMS into the OB, where they migrate radially to complete their differentiation into different types of interneurons (Luskin 1993; see below).

11.2.2. Progression of Cell Types within the Adult Subventricular Zone (SVZ)

Since the first description of neural stem cells in the adult SVZ (Reynolds and Weiss 1992; Richards et al. 1992), much work has been done to identify these stem cells, and to characterize their progression toward the mature neuronal phenotype, and factors involved in regulating stem cell maintenance and behavior.

The identity of the stem cells in the adult SVZ has been extensively debated. The prevailing model, based on a variety of approaches, including cell lineage, heterochronic and heterotrophic transplantation, and morphological and immunocytochemistry analysis, suggests that a distinct group of astrocytes expressing glial fibrillary acidic protein (GFAP) and exhibiting certain radial glial properties, are neural stem cells that function as primary precursors in the SVZ (type B cells; Alvarez-Buylla and Lim 2004). These slowly proliferating cells, lying adjacent to the ependymal layer, were first identified as astrocytes on the basis of their morphology, ultrastructure, proliferation markers (Doetsch et al. 1999), and capability to form neurospheres giving rise both to neurons and glia (Laywell et al. 2000), an identity that has been further confirmed using a transgenic approach (Garcia et al. 2004). These multipotent neural progenitors produce clusters of rapidly dividing immature precursors (Dlx2+ transit fast amplifying, or type C cells), which, in turn, produce young polysialic acid neural cell adhesion molecule (PSA-NCAM+) neurons, also known as neuroblasts (type A cells) (Doetsch et al. 1999; Doetsch and Alvarez-Buylla 1996).

However, other adult SVZ stem/progenitor cells have been proposed, whose placement into the lineage model outlined above is still a matter of debate.

The adult derivatives of the embryonic forebrain germinal zones consist of two morphologically distinct cell layers surrounding the lateral ventricles: the ependyma and the subependyma. Ependymal cells, which form a multiciliated single cell layer lining the ventricles and are in close proximity to the cells of the SVZ, have been proposed as stem cells (Johansson et al. 1999). However, other studies have challenged this initial report, proposing the subependymal cells as stem cells (Capela and Temple 2002; Chiasson et al. 1999; Doetsch et al. 1999). A recent study reports that, in the adult mouse forebrain, immunoreactivity for a neural stem cell marker, prominin-1/CD133, is exclusively localized to the ependyma, although not all ependymal cells are CD133(+) (Coskun et al. 2008). Using transplantation and genetic lineage tracing approaches, these authors demonstrate that CD133(+) ependymal cells continuously produce new neurons destined for the OB, and propose that these cells may represent an additional—perhaps more quiescent—stem cell population in the mammalian forebrain, which add to the GFAP+ adult neural stem cells (Coskun et al. 2008).

Taken together, these findings emphasize the complexity of the issue about the identity of neural stem cells in vivo, and call for further investigations to tie up the many loose ends, for example, the placement of LeX+ (Aguirre et al. 2004; Capela and Temple 2002; Platel et al. 2009) or nestin+ (Beech et al. 2004; Burns et al. 2009; Lagace et al. 2007) adult SVZ stem/progenitor cells into the current lineage model. Conceivably, there might be several sources of neural stem cells in the adult SVZ that might get involved in different situations, as occurs in the adult olfactory epithelium, where distinct cell populations mediate normal neuronal turnover and neuronal replacement under special circumstances (Leung et al. 2007).

11.2.3. Regionalization of Neuronal Stem Cells

Neuronal progenitors bound to the OB originate from all rostrocaudal sectors of the SVZ (Doetsch and Alvarez-Buylla 1996; Kirschenbaum and Goldman 1995). It has long been held that neural stem cells in the SVZ are a homogeneous population of multipotent, plastic progenitors, and that neuroblasts born in the SVZ might be equivalent until they reach the OB and begin to differentiate. However, it has first been shown that a certain degree of molecular heterogeneity already exists in migrating SVZ neuroblasts before reaching the OB (Baker et al. 2001; De Marchis et al. 2004; Jankovski and Sotelo 1996), and then that neural stem cells in the SVZ are organized in a multiple restricted and diverse population of progenitors (Beech et al. 2004; Hack et al. 2005; Kelsch et al. 2007; Kohwi et al. 2005; Merkle et al. 2007; Waclaw et al. 2006; Young et al. 2007).

By taking advantage of the regionally restricted embryonic expression of different transcription factors (Kriegstein and Gotz 2003), transgenic mice (Nkx2.1-Cre, Gsh2-Cre, Emxl-Cre, Dbxl-Cre, and Emxl-CreERT2) were crossed with Cre reporter mice in fate-mapping experiments (Kohwi et al. 2007; Young et al. 2007). BrdU and staining for cell-type-specific markers was used to identify adult-generated cells. Descendants of the embryonic LGE and cortex settle in ventral and dorsal aspects of the dorsolateral SVZ, respectively. Both generate RMS neuroblasts and are responsible for generating olfactory interneurons throughout life. However, these two stem cell populations make unequal contributions to adult neurogenesis. Cortex-derived stem cells (Emxl+), generate primarily calretinin-positive (CalR+) and tyrosine hydroxylase (TH)+ periglomerular (PG) cells, but none of the calbindin-positive (CalB+) interneurons. LGE-derived stem cells (Gsh2+) generate all of the adult-born CalB+ interneurons for the olfactory glomerulus (Kohwi et al. 2007; Young et al. 2007).

In a systematic study carried out by Merkle et al. (2007), the radial glia was labeled in a regionally specific manner by stereotaxical injection of small volumes of adenovirus-expressing Cre-recombinase in neonatal (P0) LacZ/eGFPG reporter mice (Novak et al. 2000). Injected mice were then analyzed 4 weeks later and labeled OB interneurons were stained for cell-type-specific markers (Kosaka et al. 1995). Fifteen different populations of neuronal stem cells were targeted in the SVZ at different rostrocaudal and dorsoventral levels, including the RMS, the medial (septal) wall, and the cortical wall of the lateral ventricle. They found that OB interneurons are produced from the entire SVZ, including regions of the cortical walls located beyond the accepted boundary of the adult neurogenic zone. However, each region gives rise to only a very specific subset of interneuron subtypes. This is particularly evident for PG cells that, on the basis of their neurochemical properties, can be subdivided into nonoverlapping populations subserving different functions in the bulbar circuitry, basically calretinin- and calbindin-expressing cells, and dopaminergic (DA) cells (Kosaka et al. 1995; Parrish-Aungst et al. 2007). Anterior and dorsal regions produce PG cells in a region-specific manner. So, for example, DA neurons and CalB+ cells originate from stem cells located in the dorsal and ventral regions, respectively. An analogous regionalization is also observed for granule cell precursors: each targeted region produces granule cells, but dorsal regions tend to produce superficial granule cells, whereas ventral regions produce mostly deep granule cells. Finally, CalR+ cells, either PG or granule cells, originate in the same areas, RMS and medial (septal) wall. Interestingly, the site of origin within the adult SVZ not only determines the specific markers and final position of postnatally generated interneurons within the OB, but also the specific projection of their dendrites (Kelsch et al. 2007); see below.

It is of some interest to observe how stem cells colonizing different parts of the SVZ and generating different neuronal progeny, have different embryonic origins, suggesting that some characteristic of embryonic patterning is maintained in the adult SVZ. Under this aspect, the diversity of adult-generated bulbar interneurons seems to originate from a process more akin to that of cortical interneurons, deriving from distinct progenitor pools (Wonders and Anderson 2006), rather than to that of cerebellar interneurons, originating from multipotent precursors that acquire their mature identities under the influence of local instructive cues (Leto et al. 2006).

11.2.4. Timing

Neonatal and adult SVZ progenitors differentially contribute to neurochemically and functionally distinct types of interneurons following a precise timing.

In one study, mice were given a single pulse of BrdU at different time points, and BrdU-labeled nuclei in the granule cell layer (GrL) were quantified after 20–28 days (Lemasson et al. 2005). Cells labeled at P3 or P7 were more likely to integrate in the superficial GrL and survive, compared to cells born at later ages.

Another group injected the SVZ with dye or grafted it at different ages and suggested that different subtypes of PG cells might be preferentially produced at different ages (De Marchis et al. 2007). Labeled PG cells are more likely to be CalB+ if derived from the neonate, and more likely to be CalR+ or TH+ if derived from the adult-labeled SVZ. Also, embryonic or neonatal cells grafted into the neonatal or adult brain produce different cell types: again, younger tissues produce a higher percentage of CalB+ cells and a lower percentage of CalR+ cells than older tissues. Some of these findings have received further support from a more recent study (Batista-Brito et al. 2008).

Taken together, apart from some difference between these studies, it is becoming clear that different cell types are preferentially produced at different ages. This might be relevant because, since these different cell types integrate into different OB circuits, the temporal pattern of their production might regulate the functional maturation of the OB.

11.2.5. Factors Regulating Adult Neurogenesis

Neuronal stem cells’ self-renewal and differentiation are regulated by a specialized microenvironment— conventionally referred to as the germinal niche—in which these cells reside (Doetsch 2003; Moore and Lemischka 2006). A large assortment of intrinsic genetic programs (Hack et al. 2005; Kohwi et al. 2005; Waclaw et al. 2006) and extrinsic environmental cues (Hack et al. 2005) direct or regulate the balance of self-renewal and differentiation in all stem cells within niches and on their way to the OB. Stem cells, their progeny, and elements of their microenvironment make-up an anatomical structure that coordinates normal homeostatic production of functional mature cells. Cellular Niches

In vertebrates, adult-born neurons are the progeny of precursor cells residing within specialized brain regions, termed neurogenic niches (Doetsch 2003; Garcia-Verdugo et al. 2002; Ma et al. 2005); for a review see Moore and Lemischka (2006). In ecology, a niche is a term describing the relational position of an organism or population in its ecosystem, what it does, and how it interacts with its close environment. Accordingly, a neurogenic niche is an interactive structural unit, organized to facilitate the complex local interactions occurring between neuronal stem cells and their close environment, in order to produce cell-fate decisions in a proper spatiotemporal manner. The cellular and extracellular elements that make up neurogenic niches not only support the precursor cells structurally, but also functionally regulate their activity and the development of their progeny (Doetsch 2003; Ma et al. 2005; Shen et al. 2004; Song et al. 2002). Glial cells are key components of the neurogenic niches of adult vertebrates, acting both as the precursor cells and in the support and regulation of neurogenesis (Doetsch 2003; Garcia et al. 2004; Garcia-Verdugo et al. 2002; Ma et al. 2005; Seri et al. 2004; Song et al. 2002). These cells also guide and regulate the migration of newborn cells to the regions of the brain in which they differentiate into neurons (Bolteus and Bordey 2004; Lois et al. 1996). Additional important niche elements include a close association with the vasculature and the presence of specialized basal lamiae (Doetsch 2003; Garcia-Verdugo et al. 2002; Ma et al. 2005; Mercier et al. 2002; Palmer et al. 2000, 2002).

Striking similarities have been described between adult neurogenesis in the invertebrate brain (in freshwater crayfish) and what is known about the origin of new neurons in adult vertebrate brain (Sullivan et al. 2007). In the adult avian and mammalian brain, the precursor cells reside within a specialized niche supporting self-renewal and differentiation. Precursor cells for adult neurogenesis in crayfish are also glial cells that reside within a niche containing specialized basal lamina and vasculature (Sullivan et al. 2007). Furthermore, like neurogenic astrocytes in the mammalian brain, these glial cells appear to function not only as precursors, but also as support cells to guide the directional migration of neuroblasts. As has been observed (Alvarez-Buylla 2007), it is intriguing that common strategies are used across such phylogenetically distant species, and it will be interesting to widen the range of species studied to understand whether these similarities are a result of a common evolutionary origin for adult neural stem cells or of convergence. Intrinsic Factors

Intrinsic factors can be defined as the ensembles of signals expressed by stem cells and progenitors that control different neurogenic phases, as opposed to external factors, which are produced by surrounding tissues to act on stem cells and progenitors. Intrinsic factors can be phenotypic-independent or phenotypic-specific. A list of intrinsic factors is shown in Table 11.1.

TABLE 11.1. Intrinsic Factors Involved in Neurogenesis and Morphogenesis in the SVZ.

TABLE 11.1

Intrinsic Factors Involved in Neurogenesis and Morphogenesis in the SVZ. Extrinsic and Epigenetic Factors

The processes of newborn neuron proliferation, migration, maturation, targeting, and survival are all subject to modulation by environmental signals, like neurotransmitters, growth factors, hormones, and a variety of environmental factors, including various injuries, summarized in Table 11.2. Also a complement of epigenetic factors, including mitogenic or antiproliferative factors in the local environment, have been shown to control the duration of the cell cycle or the number of cells cycling and the speed of neuroblasts migration prior to their integration into the OB circuitry (for reviews, see Bordey 2006; Hagg 2005).

TABLE 11.2. Extrinsic Factors Involved in Neurogenesis in SVZ-OB System.

TABLE 11.2

Extrinsic Factors Involved in Neurogenesis in SVZ-OB System.

For the near future, it will be worth keeping an eye on recent patents concerning novel small molecules, identified from screening collections, which would stimulate or otherwise regulate stem cell differentiation and neurogenesis. Several recent patents claim newly discovered neural stem cells differentiation modulating the activity of previously marketed drugs, suggesting perhaps a previously unknown mechanism of action of these drugs and/or implicating the target enzyme and receptor pathways as key players in neurogenesis (Rishton 2008).

11.2.6. The Subventricular Zone (SVZ) in Humans

Although, to date, the notion of an active neurogenesis from neural progenitors continuing throughout life in discrete regions of the CNS of mammals can be considered as firmly established, the point at which neurogenesis studies can be extrapolated to humans is still a matter for discussion (Breunig et al. 2007).

In humans, as in rodents, the SVZ contains cells that proliferate in vivo, and behave as multipotent progenitor cells in vitro (Bédard and Parent 2004; Bernier et al. 2000; Johansson et al. 1999; Kirschenbaum et al. 1994; Kukekov et al. 1999; Nunes et al. 2003; Palmer et al. 2001; Roy et al. 2000; Sanai et al. 2004). The existence of the equivalent of the SVZ-RMS was reported also in primates (macaque; Kornack and Rakic 2001), and it was therefore with some surprise that, in 2004, an investigation based on a large number of postmortem and biopsy samples reported that the RMS—or an equivalent structure—was missing in humans (Sanai et al. 2004; see also comment by Rakic 2004), an observations that seemed to confirm a previous report showing that migratory neuronal precursors are present in humans during infancy, but seem to disappear during childhood (Weickert et al. 2000).

A more recent report, however, realigns findings from rodents concerning the potential for neurogenesis in the adult mammalian brain with human structures (Curtis et al. 2007). For its importance, this paper deserves some space in this context. Briefly, the authors, as in the study of Sanai, have obtained postmortem samples of the adult human brain, and used a combination of basic and specific stains to locate and identify the complex SVZ-RMS-OB in adult humans, and to characterize the cells within the area. The work first illustrates, through proliferating cell nuclear antigen (PCNA is a marker for proliferating cells) staining and a Nissl counterstain, the presence of an RMS-like pathway between the cerebral ventricles and the OB; this network of cells streams in a caudal-ventral direction, before turning rostral along the olfactory tract toward the OBs. Next, ultrastructural studies verify that the human SVZ and all levels of the RMS contain cells with migratory-like (type A) morphology, and stain positive for PSA-NCAM, β III-tubulin, and doublecortin. The authors further show a gradient of expression of markers of cell differentiation (Pax6, 01ig2, and DCX) all along the pathway from the cerebral ventricles to the OB. Next, the work shows that the human RMS is organized around a tubular extension of the lateral ventricle that reaches the OB via cross sections from postmortem human tissue and MRI scans of the forebrain/OB region. Finally, using double staining for BrdU and NeuN, they show that progenitor cells become mature neurons in the OB.

Certainly, caution must be used in evaluating all these data, as authoritatively and appropriately reminded (Breunig et al. 2007; Rakic 2002), but, on the basis of the experimental evidence available to date, it seems not inappropriate to conclude that neurogenesis does exists in the human SVZ, producing new neurons to the OB following modalities that are similar to those described in rodents, and equally robust in quantitative terms.


Neuroblasts born in the SVZ migrate to the OB where they differentiate into local interneurons (Altman 1969; Belluzzi et al. 2003; Carleton et al. 2003; Lois and Alvarez-Buylla 1994; Luskin 1993). The neuroblasts migrate within the rostral extension of the SVZ along the RMS within tubelike structures formed of GFAP-positive astrocytes. These glial cells, all along the RMS and up to the OB, possess neurogenic potential themselves: multipotential (neuronal-astroglial-oligodendroglial) precursors with stem cell features have been isolated not only from the SVZ, but also from the entire rostral extension, including the distal portion within the OB (Aguirre and Gallo 2004; Gritti et al. 2002). Stem cells isolated from the proximal RMS generate significantly more oligodendrocytes than neurons or astrocytes, and those from the distal RMS proliferate significantly more slowly than stem cells derived from the SVZ and other RMS regions (Gritti et al. 2002).

A recent paper shows that there are significant differences at the translational level between neural progenitor cells from SVZ and RMS/OB (Maurer et al. 2008). Protein expression profiles differ not only in the quantity of single proteins (more numerous in SVZ vs OB), but also in their quality: some protein species are expressed in only one of the two groups (e.g., in the OB proteins involved in differentiation and microenvironmental integration, in SVZ GFAP), others in both groups (neuronal progenitor cell marker nestin, and the mature neuronal markers, Tubulin-β-III). A possible explanation is that microenvironmental stimuli, such as growth factors, neurotransmitters, and cell surface molecules, influence the proteome in a spatial and temporally restricted manner (Maurer et al. 2008).

Neuroblasts migration is a critical event in the process of adult neurogenesis, and perhaps one of the most complex and far-reaching forms of neuronal migration. In rodents, newborn neurons first migrate in the SVZ, and then join the RMS, which leads them into the core of the OB. The newly generated cells migrate rostrally, up to 5 mm in rodents and up to 20 mm in monkeys, to reach the OB (Doetsch and Alvarez-Buylla 1996; Kornack and Rakic 2001; Lois and Alvarez-Buylla 1994). This migration follows, without dispersion, the RMS, and requires 4–10 days in rodents (Hu et al. 1996; Lois and Alvarez-Buylla 1994; Luskin 1993; Winner et al. 2002). The dynamic analysis of the migratory process, realized with time-lapse videomicrography, revealed that individual cells migrate very rapidly, from 30 μm/h (personal unpublished observation) to 122 Ltm/h (Wichterle et al. 1997). A number of factors are known to regulate this process (see below).

Although in normal conditions the migrating neuroblasts are directed only to the OB, it has been shown that after lesions to the cerebral cortex, striatum, or corpus callosum, newborn SVZ neuroblasts can migrate from the SVZ to injured regions (Arvidsson et al. 2002; Goings et al. 2004; Sundholm-Peters et al. 2005). There is no agreement on whether such emigration is due to redirection of SVZ cells from the OB to the injured regions, or on increased neurogenesis, but it seems that epidermal growth factor (EGF) is the signal inducing SVZ emigration (Sundholm-Peters et al. 2005). Finally, a recent paper should be cited in this context, as it reignites the vexata quaestio of whether or not, in normal conditions, the neuroblasts originating from the SVZ are destined only to the OB (Breunig et al. 2007; Rakic 2002): based on thorough BrdU birthdating and retrovirus-based experiments, a significant migration of 5-HT3-positive cells is reported from postnatal SVZ into numerous forebrain regions, including the cortex, striatum, and nucleus accumbens (Inta et al. 2009).

11.3.1. The Rostral Migratory Stream (RMS)

The adult SVZ and the RMS are organized as an extensive network of tangentially oriented arrays, or chains, of migrating neuroblasts (Halliday and Cepko 1992; O’Rourke et al. 1995). These arrays contain closely apposed, elongated neuroblasts connected by membrane specializations (Lois et al. 1996). The network of individual arrays is not static, but may change over time (Yang et al. 2004). Neuroblasts can move from array to array in vitro (Wichterle et al. 1997) and form new arrays in vivo (Alonso et al. 1999). In vitro studies of SVZ explants show that neuroblasts lose and reform contacts with neighbors in longitudinal arrays (Wichterle et al. 1997). Within the SVZ and the RMS, the chains of migrating cells are ensheathed by a meshwork of astrocytes originating from longitudinally oriented glial tubes that continue into the OB, wherein single neuroblasts spread radially (Jankovski and Sotelo 1996; Lois et al. 1996; Peretto et al. 1997). Chain formation is not directly linked to glial tube assembly, as it generally precedes the occurrence of complete glial ensheathment (Peretto et al. 2005).

Heterochronic and heterotopic transplantation have shown that the SVZ-OB pathway is not a “passive generic guidance” for all classes of premigratory neurons, as early postnatal (P2–13) cerebellar progenitor cells, implanted in the SVZ-OB pathway of adult mice do not migrate to the OB and acquire the phenotype of cerebellar neurons (Jankovski and Sotelo 1996).

When studied via time-lapse imaging of fluorescently labeled cells in acute brain slices, the process of cell migration in the SVZ has shown that cells move unidirectionally toward the OB with a typical leading process elongation—nuclear translocation sequence (De Marchis et al. 2001; Kakita and Goldman 1999; Suzuki and Goldman 2003).

However, a more recent paper has shown that the dynamic features of neuroblast motility in the SVZ and RMS are probably more complex than normally thought. For example, migratory morphology is not predictive of actual motility, one-third of motile neuroblasts move locally in complex exploratory patterns, and not in a fast, well-oriented way as they do for long-distance migration, and not all migrating neuroblasts are doublecortin positive (Nam et al. 2007). Tangential migration is controlled by multiple factors, including PSA-NCAM (Cremer et al. 1994; Hu et al. 1996; Ono et al. 1994; Rousselot et al. 1995; Tomasiewicz et al. 1993), extracellular matrix molecules, i.e., tenascin-C (Garcion et al. 2001; Jankovski and Sotelo 1996), and members of the ErbB and Eph family of tyrosine kinase receptors and their ligands (Anton et al. 2004; Conover et al. 2000); see Table 11.2.

11.3.2. Signaling Driving the Migration

An interesting question is: How do migrating neuroblasts avoid getting lost over such a long distance and through the tangle of glial and neuronal cell bodies and processes that compose the adult brain parenchyma? It has been proposed that directional migration toward the OB is regulated by the cooperation of chemorepulsive Slit proteins expressed in the septum (Hu 1999; Hu and Rutishauser 1996) and choroid plexus (Nguyen-Ba-Charvet et al. 2004; Wu et al. 1999), and chemoattractive cues produced by the OB (Liu and Rao 2003), such as the secreted molecules netrin-1, prokineticin2, and GDNF (Murase and Horwitz 2002; Paratcha et al. 2006).

However, how can a chemorepulsive signal originating in structures separated from the SVZ by the lateral ventricle, filled with cerebrospinal fluid (CSF), and by its epithelial lining, the ependyma, orient neuroblasts migration? An elegant explanation is provided by Sawamoto et al. (2006), who show that new neurons follow the stream of CSF in the adult brain: the coordinated whiplike beating of ependymal cilia, setting in motion the CSF in a precise direction, creates a concentration gradient providing the vectorial information for guidance of the young, migrating neurons.

Although a role of the OB as a chemoattractant structure has been suggested, its involvement in proliferation and guidance of the newly born cells remains unclear. Indeed, whereas OB removal (Kirschenbaum et al. 1999) or disconnection of the olfactory peduncle (Jankovski et al. 1998) does not prevent SVZ precursors from proliferating and migrating toward the OB, a cut through the RMS (Alonso et al. 1999) or a removal of the rostral OB (Liu and Rao 2003) impedes neuroblasts migration. Thus, it has been proposed that a diffusible attractant is secreted in specific layers in the OB, including the glomerular layer, but not the GrL (Liu and Rao 2003).

After reaching the middle of the OB, the newborn cells detach from chains, migrate radially, and progress into one of the overlying cell layers, whereupon they undergo terminal differentiation. Neuroblast detachment from chains is initiated by reelin and tenascin-C, whereas radial migration depends on tenascin-R (Hack et al. 2002; Saghatelyan et al. 2004).

In the adult OB, radial glia, which guide radial migration earlier in development, are no longer present, and this poses the problem of neuroblasts guidance in this last phase of migration. A recent paper (Bovetti et al. 2007) provides a tantalizing answer: neuronal precursors would follow blood vessels, in a new form of guidance, dubbed “vasophilic.” The authors provide electronmicroscopy evidence that half of the radially migrating cells associate with the vasculature in the GrL of the OB, and show in vivo time-lapse imaging demonstrating that migrating cells use blood vessels as a “scaffold” for their journey, through an interaction with the extracellular matrix and perivascular astrocyte end feet (Bovetti et al. 2007) (Table 11.3).

TABLE 11.3. Factors Involved in Neuronal Migration.

TABLE 11.3

Factors Involved in Neuronal Migration.


Neurogenesis in the adult brain is confronted by two seemingly conflicting aims. On the one hand, it must maintain behavior and thus preserve the underlying circuitry, and on the other hand, it must allow circuits to adapt to environmental challenges. How are these conflicting objectives pursued in the OB?

11.4.1. Life and Death of the Newly Born Cells

The number of cells added daily to the OB ranges from 10,000 to 30,000 (Lois and Alvarez-Buylla 1994) to 80,000 (Kaplan et al. 1985; Peterson and Peterson 2000). This would mean some 1% of the about seven million olfactory granule cell population per day in young adult rodent (Biebl et al. 2000; Kaplan et al. 1985). In contrast, neurogenesis in the SGZ of the hippocampus occurs at a considerably lower rate, about 9000 new cells per day in adult rats (Alvarez-Buylla et al. 2001), corresponding to 0.03% of the total hippocampal dentate neuronal population (Kempermann et al. 1997).

Although limited volumetric enlargement of the OB throughout lifetime has been reported in the rat (Kaplan et al. 1985), the prevailing view is that the size of the OB does not substantially change throughout life (Biebl et al. 2000; Petreanu and Alvarez-Buylla 2002; Rosselli-Austin and Altman 1979), contrary to the DG in adult rats, where neurogenesis contributes to the increase in neuronal number of granule cells (Bayer et al. 1982; Crespo et al. 1986; Imayoshi et al. 2008). The continuous generation of new neurons in the OB, in a frame of substantial stability of the total number of cells, implies that neurogenesis must be counterbalanced by an accompanying cell loss, and, in fact, programmed cell death has been shown to be a prominent regulatory feature in neurogenic regions of the OB (Biebl et al. 2000). Massive cell death has been observed during the first two months after a BrdU pulse (Winner et al. 2002). This elimination mechanism is prominent in the OB compared with the RMS and the SVZ (Belvindrah et al. 2002; Biebl et al. 2000; Petreanu and Alvarez-Buylla 2002) and may maintain a constant OB cell number by a continuous cell turnover, as was suggested during earlier development (Oppenheim 1991).

Therefore, more than the total number of newly generated cells arriving in the OB each day, what really counts is the number of newly born cells that survive and take their place in the bulbar network. In the GrL, 1 month after a BrdU pulse, this number has been estimated to range from 60,000 (Biebl et al. 2000) to 120,000 (Winner et al. 2002). In the latter case, it was shown that 50% of the newly generated neurons (i.e., about 80,000 in the GrL and 800 in the PG layer) that survived the initial period of cell death, survived for at least 19 months (Winner et al. 2002), confirming earlier work (Kaplan et al. 1985). With the use of retroviral labeling of precursors in the SVZ, it was confirmed that one-half of the labeled cells died shortly after their arrival in the OB (between 15 and 45 days after neuronal birth), and that most dying cells were mature, harboring dendritic arborization, and receiving connections (Petreanu and Alvarez-Buylla 2002). In this study, it was further shown that survival of the newly generated granule cells depends on sensory input.

A recent paper from Imayoshi et al. (2008) is a quantum leap in our knowledge of adult neurogenesis. Adopting a skillful transgenic strategy, the authors permanently label newborn neural stem cells and their progeny with a fluorescent marker, and then selectively kill new neurons at a chosen timepoint. In particular, the authors generated a mouse in which tamoxifen-inducible Cre recombinase (CreEPJ2) was expressed under the promoter for the neural precursor marker, nestin. By crossing their mice with a conditional LacZ reporter line, they first answer the questions of how many new stem cell-derived neurons are added to the adult brain, and whether newly generated neurons constitute a small population of neurons that are repeatedly replaced or whether they constitute a large population (Lledo et al. 2006). They find that almost the whole population of deep granule cells is replaced by new neurons over a 12-month period, whereas only half of the granule cells are replaced in the superficial layers. Other authors have also described a preferential target of adult-born granule cells to the deepest layers (ring effect; Lemasson et al. 2005; Mouret et al. 2008). This suggests that there is at least one subpopulation of persistent granule cells in the OB, which Imayoshi et al. propose might regulate the long-term memory of the smell (see below). The rate of neuronal replacement was nearly linear for the first six months, with a decrease in the pace of addition at older ages. Unfortunately, a similar quantitative analysis has not been performed for PG cells. This is probably due to the fact that PG cells constitute such a heterogeneous population that it would have required a relatively long series of double markers, so it is understandable that in a paper so rich with different approaches, this aspect has been left behind, but, nevertheless, it is a pity that this piece of information is still missing.

Next, the authors conditionally killed newborn neurons by expressing diphtheria toxin (DTA) in cells derived from nestin+ progenitors of the adult SVZ. When these new neurons were killed by DTA activation, a significant depletion of the granule cell population was observed as early as three weeks later, more evident after 12 weeks, while in controls this population remained fairly constant over time. This clearly proves that cell death is not a consequence of neuron addition, but rather is an independent process occurring even in the absence of neurogenesis. Adult neurogenesis is required to maintain a constant population of OB granule neurons in the face of normal population turnover. Granule cells produced before the disruption of neurogenesis continued to disappear from the OB at a rate similar to that in controls, suggesting that the addition of new neurons does not elicit the death of those already present in the GrL.

11.4.2. Role of Neurotransmitters

Survival and integration of newborn cells is under the control of a variety of neurotransmitter-mediated signaling systems, e.g., acetylcholine (ACh), glutamate, and gamma-aminobutyric acid (GABA).

Nicotine has been shown to be detrimental to the survival of newborn granule cells in the adult OB: knockout mice lacking β2 ACh receptors, the prevalent form of brain high-affinity nicotinic receptors, display nearly 50% more newborn neurons and significantly fewer apoptotic cells than control mice (Mechawar et al. 2004). Conversely, in vivo chronic nicotine exposure significantly decreases the number of newborn granule cells in wildtype but not knockout (KO) adult mice. Interestingly, KO mice, with an increased number of granule cells, have a less robust short-term olfactory memory than their wildtype counterparts (Mechawar et al. 2004).

In the hippocampus during a short critical period after neuronal birth (the third week), survival is regulated competitively by stimulation via N-methyl D-aspartate (NMDA) receptors (Tashiro et al. 2006). In the OB, there is no evidence for a similar NMDA receptor-mediated survival/death ruling, but a decrease in NMDA-mediated response in newborn PG cells seems to be important for establishing synaptic contacts with the olfactory nerve (Grubb et al. 2008).

During brain development, GABA has depolarizing activity in cerebrocortical neural precursors, controlling cell division and contributing to neuronal migration and maturation. In the adult forebrain, the SVZ and the SGZ are exposed to synaptic and nonsynaptic GABA release. Neural stem cells and neuronal progenitors express GABA receptors in SVZ. GABA effects in these cells are very similar to those found in embryonic cortical precursor cells, and therefore it is possible that this amino acid plays important roles during adult brain plasticity (reviewed in Salazar et al. 2008). Furthermore, neuronal activity accelerates neuronal differentiation and alters the mechanism of GABA synthesis in newly generated neurons (Gakhar-Koppole et al. 2008) (Figure 11.1).

FIGURE 11.1. A newborn eGFP+ PG cell (green) around a glomerulus at P109, 3 weeks after virus injection.


A newborn eGFP+ PG cell (green) around a glomerulus at P109, 3 weeks after virus injection. Calretinin-labeled (red) and tyrosine hydroxylase-labeled (blue) PG cells outline the glomerulus. Scale bar: 20 μm. (From Belluzzi, O. et al. J. Neurosci. (more...)

11.4.3. Granule Cells

The majority (about 75%) of the SVZ-derived cells differentiate into GABA-containing granule cells (Betarbet et al. 1996; Carleton et al. 2003; Kato et al. 2001; Petreanu and Alvarez-Buylla 2002; Winner et al. 2002). The sequence of maturation steps marking this differentiation has been studied using a GFP-encoding retrovirus injected into the adult SVZ (Carleton et al. 2003; Petreanu and Alvarez-Buylla 2002). Before becoming a fully mature granule cell, the neuroblasts pass by a series of stages that have been well characterized electrophysiologically and morphologically (Carleton et al. 2003). In short, tangentially migrating neurons express extrasynaptic GABA(A) receptors and then α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. As early as 6 days after their birth, some new neurons reach the bulb, start radial migration to their final positions, and begin to express NMDA receptors. Fourteen days after virus injection, they already display dendritic spines, suggesting they might already receive synaptic inputs. In fact, spontaneous synaptic currents have been recorded shortly after migration is complete. However, at the earlier stages of differentiation, newborn neurons remain unable to fire action potentials (Carleton et al. 2003). This delay in excitability timing, which may be finalized to protecting circuits from uncontrolled neurotransmitter release and neural network disruption, marks an interesting difference with respect to what happens during developmental neurogenesis, where spiking activity is acquired much earlier (Lledo et al. 2004). Thus, the maturation of synaptic inputs in the adult bulb does not seem to recapitulate events during embryogenesis, a difference to that which occurs in the hippocampus (Esposito et al. 2005).

An interesting problem is the mechanisms regulating the way dendrites of adult-born neurons are steered at their target and compelled to establish connections with specific cell types. In principle, this could be determined either by the local environment of the neuronal circuit in the target area, or dictated by some predetermined property of the immature neurons, inherent to their particular lineage. The problem has recently been studied by Kelsh et al. (2007): using retroviral fate mapping, they studied the lamina-specific dendritic targeting of granule cells as defined by their morphology and intrinsic electrophysiological properties in neonatal and adult neurogenesis. Fate mapping revealed the existence of two separate populations of granule cell precursors, giving rise to the same neuronal type, but with two distinct patterns of dendritic targeting, innervating either a deep or superficial lamina of the external plexiform layer, where they connect to different types of principal neurons. Furthermore, using heterochronic and heterotopic transplantation and lineage tracing of neuronal precursor cells from the SVZ directly to the OB, they have elegantly revealed that the cells at an early stage of their development have a predetermined fate that is not altered by placing them in their neighboring environment. These results demonstrate that the pattern of dendritic targeting of neonatal and adult-born granule cells is a cell-autonomous property, predetermined from the moment that a neuron is born (Kelsch et al. 2007) (Figure 11.2).

FIGURE 11.2. Synaptic properties of newly generated PG cells.


Synaptic properties of newly generated PG cells. (A) Spontaneous excitatory synaptic currents in a newborn cell in the glomerular layer (P27, 12 days survival). This activity was blocked by picrotoxin, but not by kynurenate. (B) Action potentials in response (more...)

11.4.4. Periglomerular (PG) Cells

Neuronal precursor cells from the SVZ differentiate into bulbar granule and PG cells with a 3:1 ratio (Kato et al. 2000; Luskin 1993; Zigova et al. 1996). Although it is certainly true that new granule cells outnumber new PG cells in the OB, the amount of the new granule cells is sometimes overestimated, as the more internal layer contains cells in the process of migration toward the glomerular layer.

Within two weeks after generation, newly generated neurons in the rat brain acquire electrophysiological properties typical of fully functional PG cells, i.e., they can fire action potentials, have well-developed, voltage-gated sodium and potassium conductances, and fully enter into synaptic relationship with other elements of the network (Belluzzi et al. 2003). This indicates that the morphological and functional differentiation of PG cells occurs rapidly and nearly concurrently within the glomerular layer.

The sequence of the development of voltage-dependent currents and synaptic connections marks the major difference between newly generated PG and granule cells. In PG cells, the maturation of voltage-dependent sodium current, and, consequently, the capacity of the newly generated cells to fire action potentials, seems to precede the appearance of synaptic contacts (Belluzzi et al. 2003), whereas in granule cells, a full development of the sodium current is observed only after the establishment of synaptic connections (Carleton et al. 2003). This difference may indicate that the pattern of functional integration of new neurons is cell-type-specific. An interesting aspect of the electrophysiological properties of newly generated cells, both PG and granule cells, is that they tend to have a sodium current significantly larger than that in controls, with a steeper conductance-voltage relationship and more negative activation voltages. This difference, as well as the higher gNa/gK ratio in new cells, may result in greater excitability to better respond to immature excitatory synaptic inputs (Belluzzi et al. 2003; Carleton et al. 2003).

DA PG cells constitute a significant fraction of the interneurons added in adulthood to the glomerular layer (Baker et al. 2001; Betarbet et al. 1996; Winner et al. 2002; for a thorough recent review, see Cave and Baker 2009). Actually, only a minority of TH-positive cells is generated in the embryo/neonate, as the production of most of them occurs in the postnatal/adult OB (McLean and Shipley 1988; Winner et al. 2002). In the OB, DA neurons are restricted to the glomerular layer (Halász et al. 1977), but using transgenic mice expressing eGFP under the TH promoter, the presence of TH-GFP+ cells has also been detected in the mitral and external plexiform layers (Baker et al. 2001; Saino-Saito et al. 2004). Thorough studies conducted by the group of H. Baker have shown that, in some intermitral and inframitral interneurons, there is a transcription of the TH gene that is not followed by translation (Baker et al. 2001), and lead to the hypothesis that these could be adult-generated neurons committed to become DA, but not yet entirely differentiated. Accordingly, TH-GFP+ cells outside the glomerular layer exhibit functional properties (appearance of pacemaker currents, synaptic connection with the olfactory nerve, intracellular chloride concentration, and other) marking a gradient of maturity toward the DA phenotype along the mitral-glomerular axis. The establishment of a synaptic contact with the olfactory nerve seems to be the key event allowing these cells to complete their differentiation toward the DA phenotype and to reach their final destination (Pignatelli et al. 2008) (Figure 11.3).

FIGURE 11.3. Maturation of voltage-dependent currents in newborn PG cells.


Maturation of voltage-dependent currents in newborn PG cells. Recording from cells at different stages of maturation from the positions indicated by arrows. (A) P32, 9 days survival. RMS. (B) P28, 10 days survival, just above the mitral cell layer. (C) (more...)


A key question that has been associated with these studies since the initial reports that the adult brain contains stem cells that generate new neurons is whether or not adult neurogenesis is a functionally relevant process. A substantial body of work has shown that adult-born neurons can integrate into active neural circuits, but then, once they have survived, reached their target, become mature neurons, which is their function? And why is neurogenesis present only in the OB and hippocampus, and not in other areas of the brain?

The first attempts to answer these questions have been at cellular and network level, and now some enlightening answer has also been given at a higher (information processing) level.

At cellular level, differences in voltage-dependent conductance have been reported in newborn vs older PG and granule cells (Belluzzi et al. 2003; Carleton et al. 2003). However, both these reports were made in OB slices of rat, where patch-clamp recordings are very difficult after 1.5 months, so there is no evidence that these differences are maintained at older times. Other differences between adult-born and pre-existing olfactory granule neurons is in synaptic plasticity, not surprisingly much higher in newborn vs older neurons (Saghatelyan et al. 2005), and in a greater immediate earlygene (IEG) response to novel odors of adult-born granule neurons vs mature, pre-existing neurons (Magavi et al. 2005).

At network level, there is little more than plausible hypothesis (Lledo et al. 2006). Possibly, the boundaries within which effective explanations of adult neurogenesis in the OB should be searched, are defined on the one side by behavioral experiments (e.g., Rochefort et al. 2002), and on the other side by the observation that the total number of neurons in this structure remains constant in time (see above). This latter observation implies that the new neurons are not “added” to the OB, but rather replace other neurons. If one considers the OB a processing unit, then it is tempting to think of neuron swapping as an adaptive adjustment of the bulbar circuitry to better tune it to previously inexperienced external conditions. A strong argument against this possibility, lent from the neurogenesis in the hippocampus (Kempermann 2002), has been that the functional benefit from adult neurogenesis in the OB cannot be acute, because it takes several weeks to generate a functionally integrated new neuron (Ortega-Perez et al. 2007). In this view, the new connection could not benefit the particular functional event that triggered neurogenesis, because this would be long over when the new neurons are in place. However, a recent study on the neurogenesis of DA neurons (Pignatelli et al. 2008) suggests a different way to look at the problem: new cells are continuously produced, migrate into the OB, and start to differentiate toward their final phenotype. They halt their migration in the mitral cell layer, freeze their maturation process in a preterminal state, and wait for a consensus signal that will allow them to complete their migration, and to find their place within the bulbar circuitry. This is the classical scheme also followed during embryonic development: new neurons, produced in excess, need for trophic support or synaptic input, or die (Oppenheim 1991; Oppenheim et al. 2000). In any case, this means that in any given moment there are new cells in the mitral cell layer committed to a DA fate, sending their projection into the glomerular layer and trying to establish synaptic contacts. If this does not occur, the newly generated cell will undergo apoptosis and die, and, in fact, the majority of cells generated in the SVZ are eliminated after reaching the OB (Biebl et al. 2000; Winner et al. 2002). However, if a successful synaptic contact is established, then the cell will complete its differentiation and will migrate to its final destination. It is tempting to think that, through this process, the entire circuitry of the OB can self-adapt to novel external stimuli, tailoring its wiring for optimal processing. This time gap between sensory experience and circuit modifications would be extremely small, as rewiring would require the molding of plastic elements that are already present in situ, and that would not need to be produced in response to the stimulus itself.

But, of course, it is mainly at behavioral level that we would like to have answers about the significance and the implications of adult neurogenesis.

The recent paper of Imayoshi et al. (2008), cited above, provides some key contributions to our understanding of the role played by adult-generated neurons in the hippocampus and, to a lesser extent, in the OB. As already mentioned, in this outstanding paper, the authors selectively killed newborn neurons by conditionally expressing DTA in cells derived from nestin+ progenitors of the adult SVZ. What, then, are the behavioral differences observed in these animals compared to wildtype mice? The selective suppression of adult-generated neurons induced severe deficits in the retention of spatial memories, attributed to the deficits in granule neuron addition to the hippocampus, but, surprisingly enough, it appeared to have little or no effect on olfactory-mediated behaviors. In a simple olfactory discrimination test, mice could still readily discriminate between odors and learn to associate specific odors with a rewarding stimulus, even six months after conditional killing of newborn neurons, when neuronal depletion in the OB was very pronounced.

The authors conclude with what could be defined a “maintenance hypothesis”: in the adult OB, neurogenesis is required for the maintenance and reorganization of the entire interneuron system, but without evident roles in the acquisition of odor-associated memory. The authors, indeed, cautiously smooth their conclusion, pointing out that “more difficult tasks about odor-associated memory could depend on neurogenesis.” In addition, other tasks could critically depend on the continuous rewiring of the OB circuitry ensured by adult neurogenesis, like discrimination and processing of new odors.

In any case, it must be noted that this result is at odds with other evidences suggesting that adult neurogenesis in the OB contributes to odor learning, discrimination, and adaptive behaviors in mating and pregnancy.

Discrimination learning has been reported to increase the number of newborn neurons in the adult OB by prolonging their survival. However, the simple exposure to a pair of olfactory stimuli does not alter neurogenesis, indicating that the mere activation of sensory inputs during the learning task is insufficient to alter neurogenesis (Alonso et al. 2006).

The group of Lledo has subjected NCAM-deficient mice, having severe deficits in the migration of OB neuron precursors, to experiments designed to examine the anatomical and behavioral consequences of such alteration. They found that the deficit is anatomically restricted to the GrL, and that the specific reduction in the turnover of this interneuron population resulted in an impairment of discrimination between odors. In contrast, both the detection thresholds for odors and short-term olfactory memory were unaltered, suggesting that a critical number of bulbar granule cells is crucial only for odor discrimination, but not for general olfactory functions (Gheusi et al. 2000). The link between olfactory training and adult neurogenesis has been investigated more recently by the same group: using a discrimination learning task performed at various times after the birth of new interneurons, they found that olfactory training could increase, decrease, or have no effect on the number of surviving newly generated neurons (Mouret et al. 2008).

In adult life, the survival of newly generated neurons is critically regulated by the degree of sensory input occurring during a precise time window. Yamaguchi and Mori (2005) identified a sensitive period (14–28 days after the formation of the cells) during which sensory experience strongly influences the survival of new granule cells. It is interesting to observe that this is the time at which the new cells begin to receive glutamatergic synaptic contacts. This suggests that sensorial experience and synapse formation might be two faces of the same process, determining the survival of new granule cells during a critical period. Once rescued from death by learning, newborn neurons may remain for extended periods of time, possibly permanently.

Male pheromones stimulate neurogenesis in the adult female mice brain, and it has been shown that neurogenesis induced by dominant-male pheromones correlates with a female preference for dominant males over subordinate males, whereas blocking neurogenesis with a mitotic inhibitor eliminated this preference (Mak et al. 2007). These results suggest that regulation of adult neurogenesis by male pheromones may play an important role in reproductive strategies.

A marked increase in olfactory neurogenesis has been described during pregnancy (Shingo et al. 2003). The process is stimulated by prolactin, and inhibition of prolactin signaling results in a decrease in neurogenesis. Prolactin receptor mutant mice lack pup-induced maternal behavior, suggesting a link between new neuron production and expression of new behaviors (Shingo et al. 2003), although direct evidence that enhanced neurogenesis plays a role (rather than prolactin effecting behavioral changes through a different mechanism) still remains to be found (Temple 2003).


Many problems have to be solved before the fundamental question of the functional significance of adult neurogenesis can be fully answered.

First, we need a better description of the physiological properties of the newborn neurons. Which is, and how evolves, their excitability profile? What are the sources of the inputs these new neurons receive and which are the neurons they target? Do adult-generated neurons form circuits different from those produced during development? Of the two populations of bulbar interneurons interested in adult neurogenesis, we are starting to have good descriptions for granule cells, but not for PG cells. This is probably due to the fact that the latter are much less numerous and, additionally, there are several subtypes of PG cells (Kosaka et al. 1998), against only two, deep and superficial, of granule cells. From the more recent studies on adult neurogenesis, it is emerging that each subpopulation has its own story (Imayoshi et al. 2008), and, therefore, a systematic anatomo-functional analysis will be required to establish the role played by each subtype of newborn neurons in the existing neuronal circuits.

On a different but complementary plane, it will be important to better understand the behavioral implications of adult neurogenesis in the OB. The most obvious focus is on odor memory and discrimination, but it will not be surprising if newborn neurons contribute to these aspects in some, so far, unpredicted way.

Will neural modeling help, even guide, experimental approaches? Expectations in this sense are not missing, although, up to now, it would be difficult to cite significant contributions of computational modeling in unveiling the intimate functioning of this mysterious sense. A simple mathematical model of the OB, based on the known rules of addition of newborn neurons, has shown some capacity to organize its activity in order to maximize the difference between its responses, self-adapting to changing environmental conditions (Cecchi et al. 2001). Possibly, more sophisticated models in the near future will provide interesting working hypothesis.

The challenge posed by the sense of smell is still open, and more than ever enticing, with many of the relevant mechanisms involved in odor recognition still escaping our full understanding. Adult neurogenesis is only the last of a long series of surprises bequeathed by this sense, and promises that the efforts in unveiling its secrets will be all but boring.


This work was supported by a grant from MIUR (PRIN 2007).


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