Hypothalamic Subependymal Niche: A Novel Site of the Adult Neurogenesis

The discovery of undifferentiated, actively proliferating neural stem cells (NSCs) in the mature brain opened a brand new chapter in the contemporary neuroscience. Adult neurogenesis appears to occur in specific brain regions (including hypothalamus) throughout vertebrates’ life, being considered an important player in the processes of memory, learning, and neural plasticity. In the adult mammalian brain, NSCs are located mainly in the subgranular zone (SGZ) of the hippocampal dentate gyrus and in the subventricular zone (SVZ) of the lateral ventricle ependymal wall. Besides these classical regions, hypothalamic neurogenesis occurring mainly along and beneath the third ventricle wall seems to be especially well documented. Neurogenic zones in SGZ, SVZ, and in the hypothalamus share some particular common features like similar cellular cytoarchitecture, vascularization pattern, and extracellular matrix properties. Hypothalamic neurogenic niche is formed mainly by four special types of radial glia-like tanycytes. They are characterized by distinct expression of some neural progenitor and stem cell markers. Moreover, there are numerous suggestions that newborn hypothalamic neurons have a significant ability to integrate into the local neural pathways and to play important physiological roles, especially in the energy balance regulation. Newly formed neurons in the hypothalamus can synthesize and release food intake regulating neuropeptides and they are sensitive to the leptin. On the other hand, high-fat diet positively influences hypothalamic neurogenesis in rodents. The nature of this intriguing new site of adult neurogenesis is still so far poorly studied and requires further investigations.     

Locating and labeling neural stem cells in the brain

The phenomenon of adult neurogenesis has been demonstrated in most mammals including humans. At least two regions of the adult brain maintain stem cells throughout life; the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the subventricular zone (SVZ) of the lateral ventricle wall. Both regions continuously produce neurons that mature and become integrated into functional networks that are involved in learning and memory and odor discrimination, respectively. Apart from these well‐studied regions neurogenesis has been reported in a number of other brain regions, such as amygdala and cortex. However, these studies have been contested and there is currently no well‐postulated function for non‐SVZ/SGZ neurogenesis. The studies of the regional localization of neurogenesis in the brain have been made possible due to several methods for detecting adult neurogenesis including; bromodeoxyuridine labeling (BrdU) together with markers of mature neurons, genetic labeling, by mouse transgenesis, or with the use of viral vectors. These techniques are already put to creative use and will be essential for the discovery of the nature of the adult neural stem cells. In this mini‐review, we will discuss the localization of neural stem/progenitor cells in the brain and their implications as well as discussing the pro's and con's of stem cell labeling techniques. J. Cell. Physiol. 226: 1–7, 2010. © 2010 Wiley‐Liss, Inc.     

For the long run: maintaining germinal niches in the adult brain

The adult mammalian brain retains neural stem cells that continually generate new neurons within two restricted regions: the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus subgranular zone (SGZ) of the hippocampus. Though these cellular populations are spatially isolated and subserve different brain systems, common themes begin to define adult neurogenic niches: (1) astrocytes serve as both stem cell and niche cell, (2) a basal lamina and concomitant vasculogenesis may be essential components of the niche, and (3) "embryonic" molecular morphogens and signals persist in these niches and play critical roles for adult neurogenesis. The adult neurogenic niches can be viewed as "displaced" neuroepithelium, pockets of cells and local signals that preserve enough embryonic character to maintain neurogenesis for life.     

Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain

Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.     

Brain ischemia, neurogenesis, and neurotrophic receptor expression in primates

Generation of new neurons persists in the normal adult mammalian brain, with neural stem/progenitor cells residing in at least two brain regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG). Adult neurogenesis is well documented in the rodent, and has also been demonstrated in vivo in nonhuman primates and humans. Brain injuries such as ischemia affect neurogenesis in adult rodents as both global and focal ischemic insults enhance the proliferation of progenitor cells residing in SGZ or SVZ. We addressed the issue whether an injury triggered activation of endogenous neuronal precursors also takes place in the adult primate brain. We found that the ischemic insult increased the number of progenitor cells in monkey SGZ and SVZ, and caused gliogenesis in the ischemia-prone hippocampal CA1 sector. To better understand the mechanisms regulating precursor cell division and differentiation in the primate, we analyzed the expression at protein level of a panel of potential regulatory molecules, including neurotrophic factors and their receptors. We found that a fraction of mitotic progenitors were positive for the neurotrophin receptor TrkB, while immature neurons expressed the neurotrophin receptor TrkA. Astroglia, ependymal cells and blood vessels in SVZ were positive for distinctive sets of ligands/receptors, which we characterized. Thus, a network of neurotrophic signals operating in an autocrine or paracrine manner may regulate neurogenesis in adult primate SVZ. We also analyzed microglial and astroglial proliferation in postischemic hippocampal CA1 sector. We found that proliferating postischemic microglia in adult monkey CA1 sector express the neurotrophin receptor TrkA, while activated astrocytes were labeled for nerve growth factor (NGF), ligand for TrkA, and the tyrosine kinase TrkB, a receptor for brain derived neurotrophic factor (BDNF). These results implicate NGF and BDNF as regulators of postischemic glial proliferation in adult primate hippocampus.     

Functional evaluation of neural stem cell differentiation by single cell calcium imaging

Neurogenesis in the adult mammalian brain occurs in two specific brain areas, the subventricular zone (SVZ) bordering the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. Although these regions are prone to produce new neurons, cultured cells from these neurogenic niches tend to be mixed cultures, containing both neurons and glial cells. Several reports highlight the potential of the self-healing capacity of the brain following injury. Even though much knowledge has been produced on the neurogenesis itself, brain repairing strategies are still far away from patients cure. Here we review general concepts in the neurogenesis field, also addressing the methods available to study neural stem cell differentiation. A major problem faced by research groups and companies dedicated to brain regenerative medicine resides on the lack of good methods to functionally identify neural stem cell differentiation and novel drug targets. To address this issue, we developed a unique single cell calcium imaging-based method to functionally discriminate different cell types derived from SVZ neural stem cell cultures. The unique functional profile of each SVZ cell type was correlated at the single cell level with the immunodetection of specific phenotypic markers. This platform was raised on the basis of the functional response of neurons, oligodendrocytes and immature cells to depolarising agents, to thrombin and to histamine, respectively. We also outline key studies in which our new platform was extremely relevant in the context of drug discovery and development in the area of brain regenerative medicine.     

Activation of neural precursors in the adult neurogenic niches

The generation of new neurons within the dentate gyrus of the mature hippocampus is critical for spatial learning, object recognition and memory, whereas new neurons born in the subventricular zone (SVZ) contribute to olfactory function. Adult neurogenesis is a multistep process that begins with the activation and proliferation of a pool of stem/precursor cells. Although the presence of self-renewing and multipotent neural precursors is well established in the SVZ, it is only recently that the existence of such a precursor population has been demonstrated in the hippocampus, the region of the brain involved in learning and memory. Determining how this normally latent pool can be activated therefore offers considerable potential for the development of targeted neurogenic-based therapeutics to ameliorate the cognitive decline associated with hippocampal dysfunction in several neurodegenerative diseases. In this review, we summarize the effects of neural activity, various molecular factors and pharmaceutical agents, as well as voluntary exercise, in activating endogenous neural precursors in the two neurogenic niches of the adult brain, and highlight the role of activation-driven enhancement of neurogenesis for the treatment of psychiatric illness and aging dementia.     

Brain micro-ecologies: neural stem cell niches in the adult mammalian brain

Neurogenesis persists in two germinal regions in the adult mammalian brain, the subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal formation. Within these two neurogenic niches, specialized astrocytes are neural stem cells, capable of self-renewing and generating neurons and glia. Cues within the niche, from cell-cell interactions to diffusible factors, are spatially and temporally coordinated to regulate proliferation and neurogenesis, ultimately affecting stem cell fate choices. Here, we review the components of adult neural stem cell niches and how they act to regulate neurogenesis in these regions.     

侧脑室室管膜下区神经再生的研究进展

神经再生(Neurogenesis)是指具有自我更新能力的神经干细胞(Neural Stem Cells,NSCs)经过迁移、增殖,最终分化为具有特定功能的神经细胞的过程。以往人们认为,神经再生只存在于胚胎期或外周神经系统,近几年发现,在成年动物的中枢神经系统也存在神经再生,研究发现侧脑室室管膜下区(SVZ)是神经再生发生的主要区域之一,产生新的神经元和神经胶质细胞通过RMS通路运输至嗅球进而对嗅觉损伤部分进行修复。本文主要从成年神经再生的发展、神经再生与疾病的关系、神经再生的过程等方面进行综述。     

Neurogenesis in the adult hippocampus

New neurons continue to be generated in two privileged areas of the adult brain: the dentate gyrus of the hippocampal formation and the olfactory bulb. Adult neurogenesis has been found in all mammals studied to date, including humans. The process of adult neurogenesis encompasses the proliferation of resident neural stem and progenitor cells and their subsequent differentiation, migration, and functional integration into the pre-existing circuitry. This article summarizes recent findings regarding the developmental steps involved in adult hippocampal neurogenesis and the possible functional roles that new hippocampal neurons might play.     

The Interesting Interplay Between Interneurons and Adult Hippocampal Neurogenesis

Adult neurogenesis is a unique form of plasticity found in the hippocampus, a brain region key to learning and memory formation. While many external stimuli are known to modulate the generation of new neurons in the hippocampus, little is known about the local circuitry mechanisms that regulate the process of adult neurogenesis. The neurogenic niche in the hippocampus is highly complex and consists of a heterogeneous population of cells including interneurons. Because interneurons are already highly integrated into the hippocampal circuitry, they are in a prime position to influence the proliferation, survival, and maturation of adult-generated cells in the dentate gyrus. Here, we review the current state of our understanding on the interplay between interneurons and adult hippocampal neurogenesis. We focus on activity- and signaling-dependent mechanisms, as well as research on human diseases that could provide better insight into how interneurons in general might add to our comprehension of the regulation and function of adult hippocampal neurogenesis.     

The aging neurogenic subventricular zone

In the adult mouse brain, the subventricular zone (SVZ) is a neurogenic stem cell niche only 4-5 cell diameters thick. Within this narrow zone, a unique microenvironment supports stem cell self-renewal, gliogenesis or neurogenesis lineage decisions and tangential migration of newly generated neurons out of the SVZ and into the olfactory bulb. However, with aging, SVZ neurogenesis declines. Here, we examine the dynamic interplay between SVZ cytoarchitecture and neurogenesis through aging. Assembly of high-resolution electron microscopy images of corresponding coronal sections from 2-, 10- and 22-month-old mice into photomontages reveal a thinning of the SVZ with age. Following a 2-h BrdU pulse, we detect a significant decrease in cell proliferation from 2 to 22 months. Neuroblast numbers decrease with age, as do transitory amplifying progenitor cells, while both SVZ astrocytes and adjacent ependymal cells remain relatively constant. At 22 months, only residual pockets of neurogenesis remain and neuroblasts become restricted to the anterior dorsolateral horn of the SVZ. Within this dorsolateral zone many key components of the younger neurogenic niche are maintained; however, in the aged SVZ, increased numbers of SVZ astrocytes are found interposed within the ependyma. These astrocytes co-label with markers to ependymal cells and astrocytes, form intercellular adherens junctions with neighboring ependymal cells, and some possess multiple basal bodies of cilia within their cytoplasm. Together, these data reveal an age-related, progressive restriction of SVZ neurogenesis to the dorsolateral aspect of the lateral ventricle with increased numbers of SVZ astrocytes interpolated within the ependyma.     

Akhirin regulates the proliferation and differentiation of neural stem cells/progenitor cells at neurogenic niches in mouse brain

Specialized microenvironment, or neurogenic niche, in embryonic and postnatal mouse brain plays critical roles during neurogenesis throughout adulthood. The subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus in the mouse brain are two major neurogenic niches where neurogenesis is directed by numerous regulatory factors. Now, we report Akhirin (AKH), a stem cell maintenance factor in mouse spinal cord, plays a pivotal regulatory role in the SVZ and in the DG. AKH showed specific distribution during development in embryonic and postnatal neurogenic niches. Loss of AKH led to abnormal development of the ventricular zone and the DG along with reduction of cellular proliferation in both regions. In AKH knockout mice (AKH^−/−), quiescent neural stem cells (NSCs) increased, while proliferative NSCs or neural progenitor cells decreased at both neurogenic niches. In vitro NSC culture assay showed increased number of neurospheres and reduced neurogenesis in AKH^−/−. These results indicate that AKH, at the neurogenic niche, exerts dynamic regulatory role on NSC self-renewal, proliferation and differentiation during SVZ and hippocampal neurogenesis.     

Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis,Neural Stem Cell Pool,and Early Neurogenesis in Adult Rats

Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid. TUDCA significantly induced NSC proliferation, self-renewal, and neural differentiation in the SVZ, without affecting DG-derived NSCs. More importantly, expression levels of mitochondrial biogenesis-related proteins and mitochondrial antioxidant responses were significantly increased by TUDCA in SVZ-derived NSCs. Finally, intracerebroventricular administration of TUDCA in adult rats markedly enhanced both NSC proliferation and early differentiation in SVZ regions, corroborating in vitro data. Collectively, our results highlight a potential novel role for TUDCA in neurologic disorders associated with SVZ niche deterioration and impaired neurogenesis.     

RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression

In adult mammalian brains, neurogenesis persists in the subventricular zone of the lateral ventricles (SVZ) and the dentate gyrus (DG) of the hippocampus. Although evidence suggest that adult neurogenesis in these two regions is subjected to differential regulation, the underlying mechanism is unclear. Here, we show that the RNA-binding protein FXR2 specifically regulates DG neurogenesis by reducing the stability of Noggin mRNA. FXR2 deficiency leads to increased Noggin expression and subsequently reduced BMP signaling, which results in increased proliferation and altered fate specification of neural stem/progenitor cells in DG. In contrast, Noggin is not regulated by FXR2 in the SVZ, because Noggin expression is restricted to the ependymal cells of the lateral ventricles, where FXR2 is not expressed. Differential regulation of SVZ and DG stem cells by FXR2 may be a key component of the mechanism that governs the different neurogenic processes in these two adult germinal zones.     

Adult neurogenic process in the subventricular zone‐olfactory bulb system is regulated by Tau protein under prolonged stress

ObjectivesThe area of the subventricular zone (SVZ) in the adult brain exhibits the highest number of proliferative cells, which, together with the olfactory bulb (OB), maintains constant brain plasticity through the generation, migration and integration of newly born neurons. Despite Tau and its malfunction is increasingly related to deficits of adult hippocampal neurogenesis and brain plasticity under pathological conditions [e.g. in Alzheimer''s disease (AD)], it remains unknown whether Tau plays a role in the neurogenic process of the SVZ and OB system under conditions of chronic stress, a well‐known sculptor of brain and risk factor for AD.Materials and methodsDifferent types of newly born cells in SVZ and OB were analysed in animals that lack Tau gene (Tau‐KO) and their wild‐type littermates (WT) under control or chronic stress conditions.ResultsWe demonstrate that chronic stress reduced the number of proliferating cells and neuroblasts in the SVZ leading to decreased number of newborn neurons in the OB of adult WT, but not Tau‐KO, mice. Interestingly, while stress‐evoked changes were not detected in OB granular cell layer, Tau‐KO exhibited increased number of mature neurons in this layer indicating altered neuronal migration due to Tau loss.ConclusionsOur findings suggest the critical involvement of Tau in the neurogenesis suppression of SVZ and OB neurogenic niche under stressful conditions highlighting the role of Tau protein as an essential regulator of stress‐driven plasticity deficits.     

Cellular organization of adult neurogenesis in the Common Marmoset

Adult neurogenesis within the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle (LV) has been most intensely studied within the brains of rodents such as mice and rats. However, little is known about the cell types and processes involved in adult neurogenesis within primates such as the common marmoset (Callithrix jacchus). Moreover, substantial differences seem to exist between the neurogenic niche of the LV between rodents and humans. Here, we set out to use immunohistochemical and autogradiographic analysis to characterize the anatomy of the neurogenic niches and the expression of cell type-specific markers in those niches in the adult common marmoset brain. Moreover, we demonstrate significant differences in the activity of neurogenesis in the adult marmoset brain compared to the adult mouse brain. Finally, we provide evidence for ongoing proliferation of neuroblasts within both the SGZ and SVZ of the adult brain and further show that the age-dependent decline of neurogenesis in the hippocampus is associated with a decrease in neuroblast cells.