The rodent subventricular/subependymal zone (SVZ/SEZ) houses neural stem cells (NSCs) that generate olfactory bulb interneurons. It is unclear how the SVZ environment sustains neuronal production into adulthood. We discovered that the adapter molecule Ankyrin-3 (Ank3) is specifically upregulated in radial glia destined to become SVZ ependymal niche cells, but not in NSCs, and is required for SVZ assembly through progenitor lateral adhesion. Furthermore, we found that Ank3 expression is controlled by Foxj1, a transcriptional regulator of multicilia formation, and genetic deletion of this pathway led to complete loss of SVZ niche structure. In its absence, radial glia continued to transition into postnatal NSCs. However, inducible ependymal deletion of Foxj1-Ank3 after SVZ niche assembly resulted in dramatic depletion of neurogenesis. Targeting a novel pathway regulating ependymal organization/assembly and showing its requirement for new neuron production, our results have important implications for environmental control of adult neurogenesis and harvesting NSCs for replacement therapy.
Postnatal/adult neural stem cells (NSCs) within the rodent subventricular/subependymal zone (SVZ/SEZ) generate Doublecortin (DCX)+ neuroblasts that migrate and integrate into olfactory bulb circuitry1,2. Continuous production of neuroblasts is controlled by SVZ microenvironmental niche3,4. It is generally believed that enhancing neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear if there are conditions that favor astrogenesis over neurogenesis in the SVZ niche, and if astrocytes produced there exhibit different properties from others in the brain. We have uncovered that SVZ-generated astrocytes express high levels of Thrombospondin-4 (Thbs4)5,6, a secreted homopentameric glycoprotein, in contrast to cortical astrocytes which are Thbs4low. We found that localized photothrombotic/ischemic cortical injury initiates a marked increase in Thbs4hi astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-CreERtm4 lineage-tracing demonstrated that it is these SVZ-generated Thbs4hi astrocytes, and not DCX+ neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation, modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production7. Consequently, Thbs4KO/KO animals showed severe defects in cortical injury-induced SVZ astrogenesis, instead producing cells expressing DCX from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular hemorrhage into the brain parenchyma of Thbs4KO/KO animals. Taken together, these findings have significant implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members play important roles8,9.
subventricular zone; astrogenesis; brain injury; Thbs4; Notch; tsp
The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice—albeit with NSCs nearer ependymal cells—and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of α6β1 integrin, syndecan-1, and lutheran, and in vivo blocking of β1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.
Neurogenesis in the postnatal brain depends on maintenance of three biological events: proliferation of progenitor cells, migration of neuroblasts, as well as differentiation and integration of new neurons into existing neural circuits. For postnatal neurogenesis in the olfactory bulbs, these events are segregated within three anatomically distinct domains: proliferation largely occurs in the subependymal zone (SEZ) of the lateral ventricles, migrating neuroblasts traverse through the rostral migratory stream (RMS), and new neurons differentiate and integrate within the olfactory bulbs (OB). The three domains serve as ideal platforms to study the cellular, molecular, and physiological mechanisms that regulate each of the biological events distinctly. This paper describes an organotypic slice assay optimized for postnatal brain tissue, in which the extracellular conditions closely mimic the in vivo environment for migrating neuroblasts. We show that our assay provides for uniform, oriented, and speedy movement of neuroblasts within the RMS. This assay will be highly suitable for the study of cell autonomous and non-autonomous regulation of neuronal migration by utilizing cross-transplantation approaches from mice on different genetic backgrounds.
Neurogenesis in the adult brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle, olfactory bulb (OB) and the dentate subgranular zone, and survival of adult-born cells in the OB is influenced by factors including sensory experience. We examined, in mice, whether survival of adult-born cells is also regulated by the rate of precursor proliferation in the SVZ. Precursor proliferation was decreased by depleting the SVZ of dopamine after lesioning dopamine neurons in the substantia nigra compacta with 6-hydroxydopamine. Subsequently, we examined the effect of reduced SVZ proliferation on the generation, migration and survival of neuroblasts and mature adult-born cells in the SVZ, rostral migratory stream (RMS) and OB. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 47% or 36%, respectively, 7 days after dopamine depletion, and by 29% or 31% 42 days after dopamine depletion, compared to sham-treated animals. Neuroblast generation in the SVZ and their migration along the RMS were not affected, neither 7 nor 42 days after the 6-hydroxydopamine injection, since the number of doublecortin-immunoreactive neuroblasts in the SVZ and RMS, as well as the number of neuronal nuclei-immunoreactive cells in the OB, were stable compared to control. However, survival analysis 15 days after 6-hydroxydopamine and 6 days after BrdU injections showed that the number of BrdU+ cells in the SVZ was 70% higher. Also, 42 days after 6-hydroxydopamine and 30 days after BrdU injections, we found an 82% increase in co-labeled BrdU+/γ-aminobutyric acid-immunoreactive cell bodies in the granular cell layer, while double-labeled BrdU+/tyrosine hydroxylase-immunoreactive cell bodies in the glomerular layer increased by 148%. We conclude that the number of OB interneurons following reduced SVZ proliferation is maintained through an increased survival of adult-born precursor cells, neuroblasts and interneurons.
Distinct olfactory bulb (OB) interneurons are thought to become specified depending on from which of the different subregions lining the lateral ventricle wall they originate, but the role of region-specific transcription factors (TFs) in the generation of OB interneurons diversity is still poorly understood. Despite the crucial roles of the Dlx family of TFs for patterning and neurogenesis in the ventral telencephalon during embryonic development, their role in adult neurogenesis has not yet been addressed. Here we show that in the adult brain, Dlx 1 and Dlx2 are expressed in progenitors of the lateral but not the dorsal subependymal zone (SEZ), thus exhibiting a striking regional specificity. Using retroviral vectors to examine the function of Dlx2 in a cell-autonomous manner, we demonstrate that this TF is necessary for neurogenesis of virtually all OB interneurons arising from the lateral SEZ. Beyond its function in generic neurogenesis, Dlx2 also plays a crucial role in neuronal subtype specification in the OB, promoting specification of adult-born periglomerular neurons (PGNs) toward a dopaminergic fate. Strikingly, Dlx2 requires interaction with Pax6, because Pax6 deletion blocks Dlx2-mediated PGN specification. Thus, Dlx2 wields a dual function by first instructing generic neurogenesis from adult precursors and subsequently specifying PGN subtypes in conjunction with Pax6.
neurogenesis; subependymal zone; olfactory bulb; transcription factor; tyrosine hydroxylase; stem cell
Ischaemia leads to increased proliferation of progenitors in the subependymal zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1 h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5 weeks and 1 year after the insult. Neural stem cells (NSCs) responded differently from their downstream progenitors to MCAO, with NSCs being activated only transiently whilst progenitors remain activated even at 1 year post-injury. Importantly, mitotic activation was observed only in the affected areas of the niche and specifically in the dorsal half of the SEZ. Analysis of the topography of mitoses, in relation to the anatomy of the lesion and to the position of ependymal cells and blood vessels, suggested an interplay between lesion-derived recruiting signals and the local signals that normally control proliferation in the chronic post-ischaemic phase.
•Neural stem cells respond transiently to ischaemia.•Progenitors respond chronically to ischaemia.•Neural stem/progenitor cells of the subependymal zone respond only in areas of damage to the niche.•Ischaemia affects the cytoarchitecture of mitoses in the ageing niche.•Density of microglia is decreased in the ageing niche.
Neurogenesis; Neural stem cells; Progenitors; Subependymal zone/subventricular zone; Stroke; Ischaemia; Proliferation
In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a novel function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21-null cells induces replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19Arf and p53. Our results show a novel regulation of NSC expansion driven by a p21/Sox2/p53 axis.
neurogenesis; senescence; DNA damage; DDR; p53; p19; replicative stress; transcription
Establishment of a neural stem cell niche in the postnatal subependymal zone (SEZ) and the rostral migratory stream (RMS) is required for postnatal and adult neurogenesis in the olfactory bulbs (OB). We report the discovery of a cellular lineage in the SEZ-RMS-OB continuum, the specification of which is dependent on the expression of the forkhead transcription factor Foxj1 in mice. Spatially- and temporally- restricted Foxj1+ neuronal progenitors emerge during embryonic periods, surge during perinatal development, and are active only for the first few postnatal weeks. We show that the development of the unique Foxj1-derived lineage is dependent on Foxj1 expression, and is required for overall postnatal neurogenesis in the OB. Strikingly, the production of neurons from Foxj1+ progenitors significantly declines after the early postnatal weeks, but Foxj1-derived neurons in the OB persist during adult periods. Our study for the first time identifies the time-and region-specific activity of a perinatal progenitor domain that is required for transition and progression of OB neurogenesis from the embryonic-to-postnatal periods.
Olfactory Bulb Development; Stem Cell Niche; Adult Neurogenesis; Foxj1; Subependymal Zone; Subventricular Zone; Neural Progenitors; Neural Stem Cells; Mouse
Progenitor cells isolated from adult brain tissue are important tools for experimental studies of remyelination. Cells harvested from neurogenic regions in the adult brain such as the subependymal zone have demonstrated remyelination potential. Multipotent cells from the progenitor fraction have been isolated from the adult olfactory bulb (OB) but their potential to remyelinate has not been studied.
We used the buoyant density gradient centrifugation method to isolate the progenitor fraction and harvest self-renewing multipotent neural cells grown in monolayers from the adult green-fluorescent protein (GFP) transgenic rat OB. OB tissue was mechanically and chemically dissociated and the resultant cell suspension fractionated on a Percoll gradient. The progenitor fraction was isolated and these cells were plated in growth media with serum for 24 hrs. Cells were then propagated in N2 supplemented serum-free media containing b-FGF. Cells at passage 4 (P4) were introduced into a demyelinated spinal cord lesion. The GFP+ cells survived and integrated into the lesion, and extensive remyelination was observed in plastic sections. Immunohistochemistry revealed GFP+ cells in the spinal cord to be glial fibrillary acidic protein (GFAP), neuronal nuclei (NeuN), and neurofilament negative. The GFP+ cells were found among primarily P0+ myelin profiles, although some myelin basic protein (MBP) profiles were present. Immuno-electron microscopy for GFP revealed GFP+ cell bodies adjacent to and surrounding peripheral-type myelin rings.
We report that neural cells from the progenitor fraction of the adult rat OB grown in monolayers can be expanded for several passages in culture and that upon transplantation into a demyelinated spinal cord lesion provide extensive remyelination without ectopic neuronal differentiation.
Neurogenesis, the production of neural cell-types from neural stem cells (NSCs), occurs during development as well as within select regions of the adult brain. NSCs in the adult subependymal zone (SEZ) exist in a well-categorized niche microenvironment established by surrounding cells and their molecular products. The components of this niche maintain the NSCs and their definitive properties, including the ability to self-renew and multipotency (neuronal and glial differentiation).
We describe a model in vitro NSC niche, derived from embryonic stem cells, that produces many of the cells and products of the developing subventricular zone (SVZ) and adult SEZ NSC niche. We demonstrate a possible role for apoptosis and for components of the extracellular matrix in the maintenance of the NSC population within our niche cultures. We characterize expression of genes relevant to NSC self-renewal and the process of neurogenesis and compare these findings to gene expression produced by an established neural-induction protocol employing retinoic acid.
The in vitro NSC niche shows an identity that is distinct from the neurally induced embryonic cells that were used to derive it. Molecular and cellular components found in our in vitro NSC niche include NSCs, neural progeny, and ECM components and their receptors. Establishment of the in vitro NSC niche occurs in conjunction with apoptosis. Applications of this culture system range from studies of signaling events fundamental to niche formation and maintenance as well as development of unique NSC transplant platforms to treat disease or injury.
The mammalian subependymal zone (SEZ; often called subventricular) situated at the lateral walls of the lateral ventricles of the brain contains a pool of relatively quiescent adult neural stem cells whose neurogenic activity persists throughout life. These stem cells are positioned in close proximity both to the ependymal cells that provide the cerebrospinal fluid interface and to the blood vessel endothelial cells, but the relative contribution of these 2 cell types to stem cell regulation remains undetermined. Here, we address this question by analyzing a naturally occurring example of volumetric scaling of the SEZ in a comparison of the mouse SEZ with the larger rat SEZ. Our analysis reveals that the number of stem cells in the SEZ niche is correlated with the number of ependymal cells rather than with the volume, thereby indicating the importance of ependymal-derived factors in the formation and function of the SEZ. The elucidation of the factors generated by ependymal cells that regulate stem cell numbers within the SEZ is, therefore, of importance for stem cell biology and regenerative neuroscience.
In the developing brain, cell migration is a crucial process for structural organization, and is therefore highly regulated to allow the correct formation of complex networks, wiring neurons, and glia. In the early postnatal brain, late developmental processes such as the production and migration of astrocyte and oligodendrocyte progenitors still occur. Although the brain is completely formed and structured few weeks after birth, it maintains a degree of plasticity throughout life, including axonal remodeling, synaptogenesis, but also neural cell birth, migration and integration. The subventricular zone (SVZ) and the dentate gyrus of the hippocampus (DG) are the two main neurogenic niches in the adult brain. Neural stem cells reside in these structures and produce progenitors that migrate toward their ultimate location: the olfactory bulb and granular cell layer of the DG respectively. The aim of this review is to synthesize the increasing information concerning the organization, regulation and function of cell migration in a mature brain. In a normal brain, protein involved in cell-cell or cell-matrix interactions together with secreted proteins acting as chemoattractant or chemorepellant play key roles in the regulation of neural progenitor cell migration. In addition, recent data suggest that gliomas arise from the transformation of neural stem cells or progenitor cells and that glioma cell infiltration recapitulates key aspects of glial progenitor migration. Thus, we will consider glioma migration in the context of progenitor migration. Finally, many observations show that brain lesions and neurological diseases trigger neural stem/progenitor cell activation and migration towards altered structures. The factors involved in such cell migration/recruitment are just beginning to be understood. Inflammation which has long been considered as thoroughly disastrous for brain repair is now known to produce some positive effects on stem/progenitor cell recruitment via the regulation of growth factor signaling and the secretion of a number of chemoattractant cytokines. This knowledge is crucial for the development of new therapeutic strategies. One of these strategies could consist in increasing the mobilization of endogenous progenitor cells that could replace lost cells and improve functional recovery.
The adult mouse subependymal zone (SEZ) harbours neural stem cells that are thought to generate exclusively GABAergic interneurons of the olfactory bulb. Here we describe the adult generation of glutamatergic juxtaglomerular neurons, with dendritic arborizations that project into adjacent glomeruli identifying them as short-axon cells. Fate mapping revealed that these originate from Neurogenin2- and Tbr2-expressing progenitors located in the dorsal region of the SEZ. Progenitors of these glutamatergic interneurons recapitulate the sequential expression of transcription factors that hallmark glutamatergic neurogenesis in the developing cerebral cortex and adult hippocampus. Indeed, the molecular specification of these SEZ progenitors allows for their recruitment into the cerebral cortex upon lesion. Taken together, our data show that SEZ progenitors not only produce a novel population of adult-born glutamatergic juxtaglomerular neurons, but may also provide a new source of progenitors for endogenous repair.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder due to mutations in either TSC1 or TSC2 that affects many organs with hamartomas and tumors. TSC-associated brain lesions include subependymal nodules, subependymal giant cell astrocytomas and tubers. Neurologic manifestations in TSC comprise a high frequency of mental retardation and developmental disorders including autism, as well as epilepsy. Here, we describe a new mouse model of TSC brain lesions in which complete loss of Tsc1 is achieved in multiple brain cell types in a stochastic pattern. Injection of an adeno-associated virus vector encoding Cre recombinase into the cerebral ventricles of mice homozygous for a Tsc1 conditional allele on the day of birth led to reduced survival, and pathologic findings of enlarged neurons, cortical heterotopias, subependymal nodules, and hydrocephalus. The severity of clinical and pathologic findings as well as survival was shown to be dependent upon the dose and serotype of Cre virus injected. Although several other models of TSC brain disease exist, this model is unique in that the pathology reflects a variety of TSC-associated lesions involving different numbers and types of cells. This model provides a valuable and unique addition for therapeutic assessment.
The microenvironment of the subependymal zone (SEZ) neural stem cell niche is necessary for regulating adult neurogenesis. In particular, signaling from the microvasculature is essential for adult neural stem cell maintenance, but microvascular structure and blood flow dynamics in the SEZ are not well understood. In this work, we show that the mouse SEZ constitutes a specialized microvascular domain defined by unique vessel architecture and reduced rates of blood flow. Additionally, we demonstrate that hypoxic conditions are detectable in the ependymal layer that lines the ventricle, and in a subpopulation of neurons throughout the SEZ and striatum. Together, these data highlight previously unidentified features of the SEZ neural stem cell niche, and further demonstrate the extent of microvascular specialization in the SEZ microenvironment.
Here we show that conditional deletion of PTEN in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to the constitutive neurogenesis in the olfactory bulb. As a result, the Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, contrary to olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis.
SEZ; PTEN; neurogenesis; olfactory; neural repair; post-stroke
Neurogenesis - the production of new neurons - occurs in two specialized niches in the adult brain, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. In the SGZ, neural stem cells (NSCs) give rise to glutamatergic granule neurons that integrate into the granule cell layer. In the SVZ, NSCs generate a more diverse cohort of new neurons, including GABAergic, dopaminergic, and glutamatergic neurons, all of which migrate to the olfactory bulb through the rostral migratory stream. In both adult neurogenic niches, specific transcription factors have been shown to direct fate specification and lineage commitment. This review summarizes current progress on the transcriptional control of glutamatergic neurogenesis in the SGZ and SVZ, highlighting commonalities as well as differences in their transcriptional programs. In particular, we focus on work from our laboratory and others indicating that precise, sequential expression of transcription factors regulates the progression from NSC to lineage-committed progenitor, and ultimately regulates the production and differentiation of adult-born glutamatergic neurons.
adult neurogenesis; neural stem cells; glutamatergic neurons; subventricular zone; subgranular zone; transcription factor
Autism is characterized by a broad spectrum of clinical manifestations including qualitative impairments in social interactions and communication, and repetitive and stereotyped patterns of behavior. Abnormal acceleration of brain growth in early childhood, signs of slower growth of neurons, and minicolumn developmental abnormalities suggest multiregional alterations. The aim of this study was to detect the patterns of focal qualitative developmental defects and to identify brain regions that are prone to developmental alterations in autism. Formalin-fixed brain hemispheres of 13 autistic (4–60 years of age) and 14 age-matched control subjects were embedded in celloidin and cut into 200-μm-thick coronal sections, which were stained with cresyl violet and used for neuropathological evaluation. Thickening of the subependymal cell layer in two brains and subependymal nodular dysplasia in one brain is indicative of active neurogenesis in two autistic children. Subcortical, periventricular, hippocampal and cerebellar heterotopias detected in the brains of four autistic subjects (31%) reflect abnormal neuronal migration. Multifocal cerebral dysplasia resulted in local distortion of the cytoarchitecture of the neocortex in four brains (31%), of the entorhinal cortex in two brains (15%), of the cornu Ammonis in four brains and of the dentate gyrus in two brains. Cerebellar flocculonodular dysplasia detected in six subjects (46%), focal dysplasia in the vermis in one case, and hypoplasia in one subject indicate local failure of cerebellar development in 62% of autistic subjects. Detection of flocculonodular dysplasia in only one control subject and of a broad spectrum of focal qualitative neuropathological developmental changes in 12 of 13 examined brains of autistic subjects (92%) reflects multiregional dysregulation of neurogenesis, neuronal migration and maturation in autism, which may contribute to the heterogeneity of the clinical phenotype.
Autism; Developmental neuropathology; Subependymal nodular dysplasia; Heterotopia; Dysplasia
Newborn inhibitory neurons migrate into existing neural circuitry in the olfactory bulb throughout the lifetime of adult mammals. While many factors contribute to the maturation of neural circuits, intracellular calcium is believed to play an important role in regulating cell migration and the development of neural systems. However, the factors underlying calcium signaling within newborn neurons in the postnatal olfactory bulb are not well understood. Here we show that migrating, immature neurons in the olfactory bulb subependymal layer (SEL) undergo spontaneous and depolarization-evoked intracellular calcium transients mediated by high voltage-activated L-type calcium channels. In contrast to migrating immature neurons in other brain regions, modulation of calcium transients in SEL cells does not alter their rate of migration.
Olfactory bulb; calcium channels; Migration; Interneurons; Development; subventricular zone
Presumably, the 'hard-wired' neuronal circuitry of the adult brain dissuades addition of new neurons, which could potentially disrupt existing circuits. This is borne out by the fact that, in general, new neurons are not produced in the mature brain. However, recent studies have established that the adult brain does maintain discrete regions of neurogenesis from which new neurons migrate and become incorporated into the functional circuitry of the brain. These neurogenic zones appear to be vestiges of the original developmental program that initiates brain formation. The largest of these germinal regions in the adult brain is the subventricular zone (SVZ), which lines the lateral walls of the lateral ventricles. Neural stem cells produce neuroblasts that migrate from the SVZ along a discrete pathway, the rostral migratory stream, into the olfactory bulb where they form mature neurons involved in the sense of smell. The subgranular layer (SGL) of the hippocampal dentate gyrus is another neurogenic region; new SGL neurons migrate only a short distance and differentiate into hippocampal granule cells. Here, we discuss the surprising finding of neural stem cells in the adult brain and the molecular mechanisms that regulate adult neurogenesis.
Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle and subgranular zone (SGZ) of the dentate gyrus (DG). We examined whether cholecystokinin (CCK) through actions mediated by CCK1 receptors (CCK1R) is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 h prior to death or by immunoreactivity against Ki67, were reduced by 37 and 42%, respectively, in female (but not male) mice lacking CCK1Rs (CCK1R−/−) compared to wild-type (WT). Generation of neuroblasts in the SVZ and rostral migratory stream (RMS) was also affected, since the number of doublecortin (DCX)-immunoreactive (ir) neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R−/− mice, BrdU-positive (+), and Ki67-ir cells were reduced by 38 and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R−/− mice was examined. In the OB granule cell layer (GCL), the number of neuronal nuclei (NeuN)-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI) was similar. Compared to WT, the granule cell layer of the DG in female CCK1R−/− mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL) of CCK1R−/− female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is altered.
cholecystokinin 1 receptor; neurogenesis; subventricular zone; rostral migratory stream; olfactory bulb; subgranular zone; interneurons; survival
Neurogenesis in the adult brain, a process once thought to be essentially absent, has now been demonstrated to occur throughout adult mammalian life within several brain regions. Adult neurogenesis normally occurs only within the subventricular zone (SVZ) bordering the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). Neurogenic progenitors within these regions produce distinct neuron types, with progenitors in the SGZ giving rise to glutamatergic neurons that populate the DG granule cell layer and those within the SVZ producing neurons destined for the olfactory bulb. In this review, we highlight recent research on transcription factor expression and function during adult hippocampal neurogenesis. In this regard, recent evidence indicates that adult neurogenesis replicates important aspects of progenitor cell development in the embryonic brain. Specifically, work from our laboratory and others indicates that transcription factor cascades active in progenitor cells during neurogenesis in the embryonic cerebral cortex are also activated in adult hippocampal progenitor cells, where they play an important role in determining neuronal fate and regulating progenitor cell proliferation and maintenance. These findings suggest that conserved transcription factor cascades regulate genetic programs that delineate progenitor cell lineages and control progenitor cell proliferation and differentiation.
Neurogenesis occurs in two neurogenic zones in the adult brain: new neurons are born at the subventricular zone of the lateral ventricles and then migrate to the olfactory bulb, and at the subgranular zone to integrate the granular cell layer of the dentate gyrus. The hippocampus is involved in learning and memory and the generation of new hippocampal neurons has been suggested to be a new form of plasticity implicated in these processes. In the last decades, diverse intrinsic and epigenetic factors have been identified to influence adult neurogenesis but the underlying mechanisms remain unclear. In a recent study, Lafenetre et al. (2010) showed the beneficial influence of physical voluntary activity on adult neurogenesis and cognitive performance in a transgenic mouse, the synRas mouse via brain-derived neurotrophic factor. Here we review how hippocampal neurogenesis can be regulated by environmental factors and the possible role of the newly generated cells in learning and memory.
Ras; exercise; BDNF; object recognition; learning; memory
Adult neurogenesis represents a striking example of structural plasticity in the mature brain. Research on adult mammalian neurogenesis today focuses almost exclusively on two areas: the subgranular zone (SGZ) in the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) of the lateral ventricles. Numerous studies, however, have also reported adult neurogenesis in the hypothalamus, a brain structure that serves as a central homeostatic regulator of numerous physiological and behavioral functions, such as feeding, metabolism, body temperature, thirst, fatigue, aggression, sleep, circadian rhythms, and sexual behavior. Recent studies on hypothalamic neurogenesis have identified a progenitor population within a dedicated hypothalamic neurogenic zone. Furthermore, adult born hypothalamic neurons appear to play a role in the regulation of metabolism, weight, and energy balance. It remains to be seen what other functional roles adult hypothalamic neurogenesis may play. This review summarizes studies on the identification and characterization of neural stem/progenitor cells in the mammalian hypothalamus, in what contexts these stem/progenitor cells engage in neurogenesis, and potential functions of postnatally generated hypothalamic neurons.
Hypothalamus; Neurogenesis; Neural progenitors; Stem cells; Adult; Function; Tanycytes; Development; Metabolism; Energy balance; Ventricular zone