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.     

Ogt controls neural stem/progenitor cell pool and adult neurogenesis through modulating Notch signaling

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GABA and glutamate signaling: homeostatic control of adult forebrain neurogenesis

The neurotransmitter GABA exerts a strong negative influence on the production of adult-born olfactory bulb interneurons via tightly regulated, non-synaptic GABAergic signaling. After discussing some findings on GABAergic signaling in the neurogenic subventricular zone (SVZ), we provide data suggesting ambient GABA clearance via two GABA transporter subtypes and further support for a non-vesicular mechanism of GABA release from neuroblasts. While GABA works in cooperation with the neurotransmitter glutamate during embryonic cortical development, the role of glutamate in adult forebrain neurogenesis remains obscure. Only one of the eight metabotropic glutamate receptors (mGluRs), mGluR5, has been reported to tonically increase the number of proliferative SVZ cells in vivo, suggesting a local source of glutamate in the SVZ. We show here that glutamate antibodies strongly label subventricular zone (SVZ) astrocytes, some of which are stem cells. We also show that some SVZ neuroblasts express one of the ionotropic glutamate receptors, AMPA/kainate receptors, earlier than previously thought. Collectively, these findings suggest that neuroblast-to-astrocyte GABAergic signaling may cooperate with astrocyte-to-neuroblast glutamatergic signaling to provide strong homeostatic control on the production of adult-born olfactory bulb interneurons. An erratum to this article can be found at     

Multifaceted control of adult SVZ neurogenesis by the vascular niche

The subventricular zone is one of the 2 germinal niches of the adult brain where neural stem cells (NSC) generate new neurons and glia throughout life. NSC behavior is controlled by the integration of intrinsic signals and extrinsic cues provided by the surrounding microenvironment, or niche. Within the niche, the vasculature has emerged as a critical compartment, to which both neural stem cells and transit-amplifying progenitors are closely associated. A key function of the vasculature is to deliver blood-borne and secreted factors that promote proliferation and lineage progression of committed neural progenitors. We recently found that, in contrast to the established role of soluble cues, juxtacrine signals on vascular endothelial cells maintain neural stem cells in a quiescent and undifferentiated state through direct cell-cell interactions. In this perspective, we discuss how, through these apparently opposing signals, the vascular niche might coordinate stem cell decisions between maintenance and proliferation.     

Embryonic stem cell neurogenesis and neural specification

The prospect of using embryonic stem cell (ESC)‐derived neural progenitors and neurons to treat neurological disorders has led to great interest in defining the conditions that guide the differentiation of ESCs, and more recently induced pluripotent stem cells (iPSCs), into neural stem cells (NSCs) and a variety of neuronal and glial subtypes. Over the past decade, researchers have looked to the embryo to guide these studies, applying what we know about the signaling events that direct neural specification during development. This has led to the design of a number of protocols that successfully promote ESC neurogenesis, terminating with the production of neurons and glia with diverse regional addresses and functional properties. These protocols demonstrate that ESCs undergo neural specification in two, three, and four dimensions, mimicking the cell–cell interactions, patterning, and timing that characterizes the in vivo process. We therefore propose that these in vitro systems can be used to examine the molecular regulation of neural specification. J. Cell. Biochem. 111: 535–542, 2010. © 2010 Wiley‐Liss, Inc.     

The how and why of adult neurogenesis

Brain plasticity refers to the brain’s ability to change structure and/or function during maturation, learning, environmental challenges, or disease. Multiple and dissociable plastic changes in the adult brain involve many different levels of organization, ranging from molecules to systems, with changes in neural elements occurring hand-in-hand with changes in supportive tissue elements, such as glia cells and blood vessels. There is now substantial evidence indicating that new functional neurons are constitutively generated from endogenous pools of neural stem cells in restricted areas of the mammalian brain, throughout life. So, in addition to all the other known structural changes, entire new neurons can be added to the existing network circuitry. This addition of newborn neurons provides the brain with another tool for tinkering with the morphology of its own functional circuitry. Although the ongoing neurogenesis and migration have been extensively documented in non-mammalian species, its characteristics in mammals have just been revealed and thus several questions remain yet unanswered. Is adult neurogenesis an atavism, an empty-running leftover from evolution? What is adult neurogenesis good for and how does the brain ‘know’ that more neurons are needed? How is this functional demand translated into signals a precursor cell can detect? Adult neurogenesis may represent an adaptive response to challenges imposed by an environment and/or internal state of the animal. To ensure this function, the production, migration, and survival of newborn neurons must be tightly controlled. We attempt to address some of these questions here, using the olfactory bulb as a model system.     

A novel stem cell type at the basal side of the subventricular zone maintains adult neurogenesis

According to the current consensus, murine neural stem cells (NSCs) apically contacting the lateral ventricle generate differentiated progenitors by rare asymmetric divisions or by relocating to the basal side of the ventricular–subventricular zone (V‐SVZ). Both processes will ultimately lead to the generation of adult‐born olfactory bulb (OB) interneurons. In contrast to this view, we here find that adult‐born OB interneurons largely derive from an additional NSC‐type resident in the basal V‐SVZ. Despite being both capable of self‐renewal and long‐term quiescence, apical and basal NSCs differ in Nestin expression, primary cilia extension and frequency of cell division. The expression of Notch‐related genes also differs between the two NSC groups, and Notch activation is greatest in apical NSCs. Apical downregulation of Notch‐effector Hes1 decreases Notch activation while increasing proliferation across the niche and neurogenesis from apical NSCs. Underscoring their different roles in neurogenesis, lactation‐dependent increase in neurogenesis is paralleled by extra activation of basal but not apical NSCs. Thus, basal NSCs support OB neurogenesis, whereas apical NSCs impart Notch‐mediated lateral inhibition across the V‐SVZ.     

Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory

The fetal and even the young brain possesses a considerable degree of plasticity. The plasticity and rate of neurogenesis in the adult brain is much less pronounced. The present study was conducted to investigate whether housing conditions affect neurogenesis, learning, and memory in adult rats. Three‐month‐old rats housed either in isolation or in an enriched environment were injected intraperitoneally with bromodeoxyuridine (BrdU) to detect proliferation among progenitor cells and to follow their fate in the dentate gyrus. The rats were sacrificed either 1 day or 4 weeks after BrdU injections. This experimental paradigm allows for discrimination between proliferative effects and survival effects on the newborn progenitors elicited by different housing conditions. The number of newborn cells in the dentate gyrus was not altered 1 day after BrdU injections. In contrast, the number of surviving progenitors 1 month after BrdU injections was markedly increased in animals housed in an enriched environment. The relative ratio of neurogenesis and gliogenesis was not affected by environmental conditions, as estimated by double‐labeling immunofluorescence staining with antibodies against BrdU and either the neuronal marker calbindin D28k or the glial marker GFAp, resulting in a net increase in neurogenesis in animals housed in an enriched environment. Furthermore, we show that adult rats housed in an enriched environment show improved performance in a spatial learning test. The results suggest that environmental cues can enhance neurogenesis in the adult hippocampal region, which is associated with improved spatial memory. © 1999 John Wiley & Sons, Inc. J Neurobiol 39: 569–578, 1999     

Impact of diet on adult hippocampal neurogenesis

Research over the last 5 years has firmly established that learning and memory abilities, as well as mood, can be influenced by diet, although the mechanisms by which diet modulates mental health are not well understood. One of the brain structures associated with learning and memory, as well as mood, is the hippocampus. Interestingly, the hippocampus is one of the two structures in the adult brain where the formation of newborn neurons, or neurogenesis, persists. The level of neurogenesis in the adult hippocampus has been linked directly to cognition and mood. Therefore, modulation of adult hippocampal neurogenesis (AHN) by diet emerges as a possible mechanism by which nutrition impacts on mental health. In this study, we give an overview of the mechanisms and functional implications of AHN and summarize recent findings regarding the modulation of AHN by diet.     

TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation

In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process.     

p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis

Throughout life, neural stem cells (NSCs) in the adult hippocampus persistently generate new neurons that modify the neural circuitry. Adult NSCs constitute a relatively quiescent cell population but can be activated by extrinsic neurogenic stimuli. However, the molecular mechanism that controls such reversible quiescence and its physiological significance have remained unknown. Here, we show that the cyclin‐dependent kinase inhibitor p57^kip2 (p57) is required for NSC quiescence. In addition, our results suggest that reduction of p57 protein in NSCs contributes to the abrogation of NSC quiescence triggered by extrinsic neurogenic stimuli such as running. Moreover, deletion of p57 in NSCs initially resulted in increased neurogenesis in young adult and aged mice. Long‐term p57 deletion, on the contrary, led to NSC exhaustion and impaired neurogenesis in aged mice. The regulation of NSC quiescence by p57 might thus have important implications for the short‐term (extrinsic stimuli‐dependent) and long‐term (age‐related) modulation of neurogenesis.     

Mesodermal cell types induce neurogenesis from adult human hippocampal progenitor cells

Neurogenesis in the adult human brain occurs within two principle neurogenic regions, the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. Recent reports demonstrated the isolation of human neuroprogenitor cells (NPCs) from these regions, but due to limited tissue availability the knowledge of their phenotype and differentiation behavior is restricted. Here we characterize the phenotype and differentiation capacity of human adult hippocampal NPCs (hNPCs), derived from patients who underwent epilepsy surgery, on various feeder cells including fetal mixed cortical cultures, mouse embryonic fibroblasts (MEFs) and PA6 stromal cells. Isolated hNPCs were cultured in clonal density by transferring the cells to serum-free media supplemented with FGF-2 and EGF in 3% atmospheric oxygen. These hNPCs showed neurosphere formation, expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1 and Olig2, the NSC markers Nestin and Musashi1, the proliferation marker Ki67 and significant activity of telomerase. The phenotype was CD15low/-, CD34-, CD45- and CD133-. After removal of mitogens and plating them on poly D-lysine, they spontaneously differentiated into a neuronal (MAP2ab+), astroglial (GFAP+), and oligodendroglial (GalC+) phenotype. Differentiated hNPCs showed functional properties of neurons, such as sodium channels, action potentials and production of the neurotransmitters glutamate and GABA. Co-culture of hNPCs with fetal cortical cultures, MEFs and PA6 cells increased neurogenesis of hNPCs in vitro, while only MEFs and PA6 cells also led to a morphological and functional neurogenic maturation. Together we provide a first detailed characterization of the phenotype and differentiation potential of human adult hNPCs in vitro. Our findings reinforce the emerging view that the differentiation capacity of adult hNPCs is critically influenced by non-neuronal mesodermal feeder cells.     

Neural stem cells: involvement in adult neurogenesis and CNS repair

Recent advances in stem cell research, including the selective expansion of neural stem cells (NSCs) in vitro, the induction of particular neural cells from embryonic stem cells in vitro, the identification of NSCs or NSC-like cells in the adult brain and the detection of neurogenesis in the adult brain (adult neurogenesis), have laid the groundwork for the development of novel therapies aimed at inducing regeneration in the damaged central nervous system (CNS). There are two major strategies for inducing regeneration in the damaged CNS: (i) activation of the endogenous regenerative capacity and (ii) cell transplantation therapy. In this review, we summarize the recent findings from our group and others on NSCs, with respect to their role in insult-induced neurogenesis (activation of adult NSCs, proliferation of transit-amplifying cells, migration of neuroblasts and survival and maturation of the newborn neurons), and implications for therapeutic interventions, together with tactics for using cell transplantation therapy to treat the damaged CNS.     

Quantitative analysis reveals dominance of gliogenesis over neurogenesis in an adult brainstem oscillator

Neural stem/progenitor cells in the neurogenic niches of the adult brain are widely assumed to give rise predominantly to neurons, rather than glia. Here, we performed a quantitative analysis of the resident neural progenitors and their progeny in the adult pacemaker nucleus (Pn) of the weakly electric fish Apteronotus leptorhynchus. Approximately 15% of all cells in this brainstem nucleus are radial glia‐like neural stem/progenitor cells. They are distributed uniformly within the tissue and are characterized by the expression of Sox2 and Meis 1/2/3. Approximately 2–3% of them are mitotically active, as indicated by expression of proliferating cell nuclear antigen. Labeling of proliferating cells with a single pulse of BrdU, followed by chases of up to 100 days, revealed that new cells are generated uniformly throughout the nucleus and do not undergo substantial migration. New cells differentiate into S100+ astrocytes and Hu C/D+ small interneurons at a ratio of 4:1, reflecting the proportions of the total glia and neurons in this brain region. The continuous addition of new cells leads to a diffuse growth of the Pn, which doubles in volume and total cell number over the first 2 years following sexual maturation of the fish. However, the number of pacemaker and relay cells, which constitute the oscillatory neural network, remains constant throughout adult life. We hypothesize that the dominance of gliogenesis is an adaptation to the high‐frequency firing of the oscillatory neurons in this nucleus. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 934–952, 2014     

Embryonic and adult neural stem cell research in China

Neural stem cells(NSCs) are one specific type of multipotential stem cells that have the ability to proliferate for a long time and to differentiate into neural cells,including neurons,astrocytes and oligodendrocytes.These NSCs exist in both the embryonic and adult central nervous system(CNS) of all mammalian species.Progress has been made in the understanding of the developmental regulation of NSCs and their function in neurogenesis.This review discusses recent progress in this area,with emphasis on work d...     

室管膜下区神经干细胞与神经发生的研究进展

室管膜下区(subventricular zone,SVZ)存在着神经干细胞(nueral stem cells,NSCs),是成年哺乳动物脑内重要的神经发生区域。神经发生过程极为复杂,包括一系列的生物学事件。在病理状态下,SVZ区的细胞增殖,新生的神经细胞迁移到病灶处,取代或修复受损的细胞,起到保护脑组织的作用。该文就SVZ区的神经干细胞、神经发生过程及病理状态下神经发生的相关研究做一综述。     

Age‐related changes in stem cell dynamics,neurogenesis, apoptosis,and gliosis in the adult brain: A novel teleost fish model of negligible senescence

Adult neurogenesis, the generation of new neurons in the adult central nervous system, is a reported feature of all examined vertebrate species. However, a dramatic decline in the rates of cell proliferation and neuronal differentiation occurs in mammals, typically starting near the onset of sexual maturation. In the present study, we examined possible age‐related changes associated with adult neurogenesis in the brain of brown ghost knifefish (Apteronotus leptorhynchus), a teleost fish distinguished by its enormous neurogenic potential. Contrary to the well‐established alterations in the mammalian brain during aging, in the brain of this teleostean species we could not find evidence for any significant age‐related decline in the absolute levels of stem/progenitor cell proliferation, neuronal and glial differentiation, or long‐term survival of newly generated cells. Moreover, there was no indication that the amount of glial fibrillary acidic protein or the number of apoptotic cells in the brain was altered significantly over the course of adult life. We hypothesize that this first demonstration of negligible cellular senescence in the vertebrate brain is related to the continued growth of this species and to the lack of reproductive senescence during adulthood. The establishment of the adult brain of this species as a novel model of negligible senescence provides new opportunities for the advancement of our understanding of the biology of aging and the fundamental mechanisms that underlie senescence in the brain. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 74: 514–530, 2014     

Neuronal degeneration and regeneration induced by axotomy in the olfactory epithelium of Xenopus laevis

The olfactory epithelium (OE) has the remarkable capability to constantly replace olfactory receptor neurons (ORNs) due to the presence of neural stem cells (NSCs). For this reason, the OE provides an excellent model to study neurogenesis and neuronal differentiation. In the present work, we induced neuronal degeneration in the OE of Xenopus laevis larvae by bilateral axotomy of the olfactory nerves. We found that axotomy induces specific‐ neuronal death through apoptosis between 24 and 48h post‐injury. In concordance, there was a progressive decrease of the mature‐ORN marker OMP until it was completely absent 72h post‐injury. On the other hand, neurogenesis was evident 48h post‐injury by an increase in the number of proliferating basal cells as well as NCAM‐180– GAP‐43+ immature neurons. Mature ORNs were replenished 21 days post‐injury and the olfactory function was partially recovered, indicating that new ORNs were integrated into the olfactory bulb glomeruli. Throughout the regenerative process no changes in the expression pattern of the neurotrophin Brain Derivate Neurotrophic Factor were observed. Taken together, this work provides a sequential analysis of the neurodegenerative and subsequent regenerative processes that take place in the OE following axotomy. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1308–1320, 2017