Neurogenesis in the Adult Mammalian Brain

The concept of the CNS cell composition stability has recently undergone significant changes. It was earlier believed that neurogenesis in the mammalian CNS took place only during embryonic and early postnatal development. New approaches make it possible to prove that neurogenesis takes part even in the adult brain. The present review summarizes the data about the neural stem cell. It has been demonstrated that new neurons are constantly formed in adult mammals, including man. In two brain zones, subventricular zone and dentate gyrus, neurogenesis appears to proceed throughout the entire life of mammals, including man. The newly arising neurons are essential for some important processes, such as memory and learning. Stem cells were found in the subependymal and/or ependymal layer. They express nestin and have a low mitotic activity. During embryogenesis, the stem cell divides asymmetrically: one daughter cell resides as the stem cell in the ependymal layer and another migrates to the subventricular zone. There it gives rise to a pool of dividing precursors, from which neural and glial cells differentiate and migrate to the sites of final localization. The epidermal and fibroblast growth factors act as mitogens for the neural stem cell. The neural stem cell gives rise to the cells of all germ layers in vitro and has a wide potential for differentiation in the adult organism. Hence, it can be used as a source of various cell types of the nervous tissue necessary for cellular transplantation therapy.     

Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain

Two decades after the discovery that neural stem cells (NSCs) populate some regions of the mammalian central nervous system (CNS), deep knowledge has been accumulated on their capacity to generate new neurons in the adult brain. This constitutive adult neurogenesis occurs throughout life primarily within remnants of the embryonic germinal layers known as “neurogenic sites.” Nevertheless, some processes of neurogliogenesis also occur in the CNS parenchyma commonly considered as “nonneurogenic.” This “noncanonical” cell genesis has been the object of many claims, some of which turned out to be not true. Indeed, it is often an “incomplete” process as to its final outcome, heterogeneous by several measures, including regional location, progenitor identity, and fate of the progeny. These aspects also strictly depend on the animal species, suggesting that persistent neurogenic processes have uniquely adapted to the brain anatomy of different mammals. Whereas some examples of noncanonical neurogenesis are strictly parenchymal, others also show stem cell niche-like features and a strong link with the ventricular cavities. This work will review results obtained in a research field that expanded from classic neurogenesis studies involving a variety of areas of the CNS outside of the subventricular zone (SVZ) and subgranular zone (SGZ). It will be highlighted how knowledge concerning noncanonical neurogenic areas is still incomplete owing to its regional and species-specific heterogeneity, and to objective difficulties still hampering its full identification and characterization.The central nervous system (CNS) of adult mammals is assembled during developmental neurogenesis, and its architectural specificity is maintained through a vast cohort of membrane-bound and extracellular matrix molecules (Gumbiner 1996; Bonfanti 2006). Although CNS structure is sculpted by experience-dependent synaptic plasticity at different postnatal developmental stages (critical periods) (see Sale et al. 2009) and, to a lesser extent, during adulthood (Holtmaat and Svoboda 2009), the neural networks are rather stabilized in the “mature” nervous tissue (Spolidoro et al. 2009). The differentiated cellular elements forming adult neural circuitries remain substantially unchanged in terms of their number and types, because cell renewal/addition in the CNS is very low. This situation is intuitive because connectional, neurochemical, and functional specificities are fundamental features of the mature CNS in highly complex brains, allowing specific cell types to be connected and to act in a relatively invariant way (Frotscher 1992).Since the discovery of neural stem cells (NSCs) (Reynolds and Weiss 1992), we realized that the aforementioned rules of CNS stability have a main exception in two brain regions: the forebrain subventricular zone (SVZ) (Lois and Alvarez-Buylla 1994) and the hippocampal subgranular zone (SGZ) (Gage 2000). These “adult neurogenic sites” are remnants of the embryonic germinal layers (although indirectly for the SGZ, which forms ectopically from the embryonic germinative matrix), which retain stem/progenitor cells within a special microenvironment, a “niche,” allowing and regulating NSC activity (Kriegstein and Alvarez-Buylla 2009). In addition, the areas of destination (olfactory bulb and dentate gyrus) reached by neuroblasts generated within these neurogenic sites harbor specific, not fully identified yet, environmental signals allowing the integration of young, newborn neurons. These two “canonical” sites of adult neurogenesis have been found in all animal species studied so far, including humans (reviewed in Lindsey and Tropepe 2006; Bonfanti and Ponti 2008; Kempermann 2012; Grandel and Brand 2013). Although in several classes of vertebrates including fish, amphibians, and reptiles, adult neurogenesis is widespread in many areas of the CNS (Zupanc 2006; Chapouton et al. 2007; Grandel and Brand 2013), in mammals, the vast majority of the brain and spinal cord regions out of the germinal-layer-derived neurogenic sites are commonly referred to as “nonneurogenic parenchyma” (Sohur et al. 2006; Bonfanti and Peretto 2011; Bonfanti and Nacher 2012). However, this viewpoint has changed during the last few years. New examples of cell genesis, involving both neurogenesis and gliogenesis, have been shown to occur in the so-called nonneurogenic regions of the mammalian CNS (Horner et al. 2000; Dayer et al. 2005; Kokoeva et al. 2005; Luzzati et al. 2006; Ponti et al. 2008; reviewed in Butt et al. 2005; Nishiyama et al. 2009; Migaud et al. 2010; Bonfanti and Peretto 2011), suggesting that structural plasticity involving de novo neural cell genesis could be more widespread than previously thought. Apart from their temporal persistence (some of them represent examples of delayed developmental neurogenesis, which persist postnatally; see below), neurogliogenic processes vary as to their regional localization, origin, and final outcome. In this review, “noncanonical” neurogenic processes occurring in adult mammals will be reviewed by underlining their heterogeneity across the species and their differences in intensity and outcome with respect to canonical neurogenic sites.

Table 1.

Main sites of noncanonical neurogenesis in the mammalian brain

Neurogenesis in the Diseased Adult Human Brain: New Therapeutic Strategies for Neurodegenerative Diseases

No abstract available.     

The Evidence for Increased L1 Activity in the Site of Human Adult Brain Neurogenesis

Retroelement activity is a common source of polymorphisms in human genome. The mechanism whereby retroelements contribute to the intraindividual genetic heterogeneity by inserting into the DNA of somatic cells is gaining increasing attention. Brain tissues are suspected to accumulate genetic heterogeneity as a result of the retroelements somatic activity. This study aims to expand our understanding of the role retroelements play in generating somatic mosaicism of neural tissues. Whole-genome Alu and L1 profiling of genomic DNA extracted from the cerebellum, frontal cortex, subventricular zone, dentate gyrus, and the myocardium revealed hundreds of somatic insertions in each of the analyzed tissues. Interestingly, the highest concentration of such insertions was detected in the dentate gyrus—the hotspot of adult neurogenesis. Insertions of retroelements and their activity could produce genetically diverse neuronal subsets, which can be involved in hippocampal-dependent learning and memory.     

Cell Proliferation and Neurogenesis in Adult Mouse Brain

Neurogenesis, the formation of new neurons, can be observed in the adult brain of many mammalian species, including humans. Despite significant progress in our understanding of adult neurogenesis, we are still missing data about the extent and location of production of neural precursors in the adult mammalian brain. We used 5-ethynyl-2''-deoxyuridine (EdU) to map the location of proliferating cells throughout the entire adult mouse brain and found that neurogenesis occurs at two locations in the mouse brain. The larger one we define as the main proliferative zone (MPZ), and the smaller one corresponds to the subgranular zone of the hippocampus. The MPZ can be divided into three parts. The caudate migratory stream (CMS) occupies the middle part of the MPZ. The cable of proliferating cells emanating from the most anterior part of the CMS toward the olfactory bulbs forms the rostral migratory stream. The thin layer of proliferating cells extending posteriorly from the CMS forms the midlayer. We have not found any additional aggregations of proliferating cells in the adult mouse brain that could suggest the existence of other major neurogenic zones in the adult mouse brain.     

成年海马中神经发生及影响因素

动物成年后在其中枢神经系统内仍有神经发生。成年神经发生的主要区域是海马齿状回的颗粒下层和脑室下区的侧脑室外侧壁。目前认为成年后的海马神经发生参与记忆的形成,尤其对癫痫和神经退行性疾病的缓解和治疗具有重要意义。成年海马的神经发生受多种生理、病理因素的调控。我们就近年来成年海马神经发生的影响因素及其可能机制进行综述。     

Adult Neurogenesis in Drosophila

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Adult Neurogenesis in Humans

Adult neurogenesis appears very well conserved among mammals. It was, however, not until recently that quantitative data on the extent of this process became available in humans, largely because of methodological challenges to study this process in man. There is substantial hippocampal neurogenesis in adult humans, but humans appear unique among mammals in that there is no detectable olfactory bulb neurogenesis but continuous addition of new neurons in the striatum.There has been an enormous expansion in the knowledge regarding adult neurogenesis in experimental animals over the last two decades. A strong motivation in this research field has been that similar processes are likely to operate in humans, and that alterations in adult neurogenesis could underlie neurological or psychiatric diseases. Moreover, many have hoped that the potential of resident neural stem cells could be harnessed to promote the generation of new neurons for cell replacement in neurological diseases. A seminal study by Eriksson, Gage and colleagues (Eriksson et al. 1998), in which they were able to show the presence of 5-bromo-2-deoxyuridine (BrdU) in hippocampal neurons of cancer patients who had received the label for diagnostic purposes, established the presence of adult-born neurons in the human hippocampus. This study was exceptionally important in that it provided strong evidence for the presence of adult neurogenesis in humans. However, it did not enable any quantitative estimates, and a lingering question has been whether adult neurogenesis decreased with primate evolution, and whether the extent of this process in humans is sufficient to have any functional impact (Rakic 1985; Kempermann 2012).     

成年哺乳动物神经发生的研究进展

神经干细胞是一类具有自我更新能力和多向分化潜能的干细胞。在特定条件下,神经干细胞可分化为神经元、少突胶质细胞和星形胶质细胞从而参与神经功能的修复过程,该过程称为神经发生。一直以来,人们认为神经发生主要发生在哺乳动物胚胎时期,而成体是不存在神经发生的。然而近年的研究表明,成体神经发生在哺乳动物中枢神经系统中是终生存在的,且通过多种信号通路来调控。现就成年哺乳动物神经发生的研究进展展开论述。     

Epilepsy and Adult Neurogenesis

Seizure activity in the hippocampal region strongly affects stem cell-associated plasticity in the adult dentate gyrus. Here, we describe how seizures in rodent models of mesial temporal lobe epilepsy (mTLE) affect multiple steps in the developmental course from the dividing neural stem cell to the migrating and integrating newborn neuron. Furthermore, we discuss recent evidence indicating either that seizure-induced aberrant neurogenesis may contribute to the epileptic disease process or that altered neurogenesis after seizures may represent an attempt of the injured brain to repair itself. Last, we describe how dysfunction of adult neurogenesis caused by chronic seizures may play an important role in the cognitive comorbidities associated with mTLE.The epilepsies are a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures. Some epilepsies result from inherited mutations in single or multiple genes, termed idiopathic or primary epilepsies, whereas symptomatic or secondary epilepsies develop as a consequence of acquired brain abnormalities, such as from tumor, trauma, stroke, infection, or developmental malformation. Of acquired epilepsies, mesial temporal lobe epilepsy (mTLE) is a particularly common and often intractable form. In addition to pharmacoresistant seizures, the syndrome of mTLE almost always involves impairments in cognitive function (Helmstaedter 2002; Elger et al. 2004; von Lehe et al. 2006) that may progress even with adequate seizure control (Blume 2006).Seizure activity in mTLE subjects typically arises from the hippocampus or other mesial temporal lobe structures. Simple and complex partial seizures, the most common seizure types in this epilepsy syndrome, often become medically refractory and may respond only to surgical resection of the epileptogenic tissue. Patients usually also have secondarily generalized tonic–clonic seizures, although these are often controlled by anticonvulsants. Hippocampi in pharmacoresistant mTLE usually show substantial structural abnormalities that include pyramidal cell loss, astrogliosis, dentate granule cell axonal reorganization (mossy fiber sprouting), and dispersion of the granule cell layer (GCL) (Blumcke et al. 1999, 2012).Humans with mTLE often have a history of an early “precipitating” insult, such as a prolonged or complicated febrile seizure, followed by a latent period and then the development of epilepsy in later childhood or adolescence. These historical findings have led to the development of what are currently the most common animal models, the status epilepticus (SE) models, used to study epileptogenic mechanisms in mTLE. In these models, a prolonged seizure induced by chemoconvulsant (typically kainic acid or pilocarpine) treatment or electrical stimulation leads to an initial brain injury, followed, after a latent period of days to weeks, by spontaneous recurrent seizures. These models recapitulate much of the pathology of human mTLE (reviewed in Buckmaster 2004). Experimental paradigms are necessary to investigate mechanisms underlying mTLE, as surgical specimens from mTLE cases are collected at late stages of the disease and, thus, are unlikely to reveal early features critical for the disease process. Studies of experimental mTLE indicate that excess neural activity in the course of seizures not only damages existing, mature structures of the hippocampal formation but also dramatically affects endogenous neural stem cells (NSCs) within the adult rodent dentate gyrus (Bengzon et al. 1997; Parent et al. 1997; Scott et al. 1998). In the following, we will discuss the consequences of seizure activity on proliferation of NSCs, maturation and integration of newborn neurons, and the functional relevance of seizure-induced neurogenesis.     

Neurogenesis in the Adult Avian Song-Control System

New neurons are added throughout the forebrain of adult birds. The song-control system is a model to investigate the addition of new long-projection neurons to a cortical circuit that regulates song, a learned sensorimotor behavior. Neuroblasts destined for the song nucleus HVC arise in the walls of the lateral ventricle, and wander through the pallium to reach HVC. The survival of new HVC neurons is supported by gonadally secreted testosterone and its downstream effectors including neurotrophins, vascularization, and electrical activity of postsynaptic neurons in nucleus RA (robust nucleus of the arcopallium). In seasonal species, the HVC→RA circuit degenerates in nonbreeding birds, and is reconstructed by the incorporation of new projection neurons in breeding birds. There is a functional linkage between the death of mature HVC neurons and the birth of new neurons. Various hypotheses for the function of adult neurogenesis in the song system can be proposed, but this remains an open question.Song behavior in oscine birds is regulated by a network of pallial and striatal nuclei. The song-control system shows extensive plasticity in adults, including ongoing neurogenesis in several nuclei (Brenowitz 2008). The addition of new neurons to the adult brain of higher vertebrates was first suggested by the pioneering studies of Altman and Das (1965) and Kaplan and Hinds (1977). They reported that labeled cells were present in the dentate gyrus (DG) of rats following the injection of ³H-thymidine. Their claims, however, met with skepticism and the neuronal identity of the new cells that they observed was called into question (Gross 2000). In an influential study, Rakic (1985) injected adult rhesus monkeys with ³H-thymidine and reported that, “all neurons of the rhesus monkey brain are generated during prenatal and early postnatal life.” The study of neuronal addition to the adult brain, was subsequently dropped for ∼20 years in the face of the dogma that neurogenesis was largely completed by birth (Gross 2000). This prevailing view only started to be overturned when Nottebohm and colleagues published a series of studies showing that new cells are added to the cortical-like song nucleus HVC (Fig. 1) of adult canaries (Serinus canarius) (Goldman and Nottebohm 1983). These new cells have neuronal morphology, some of these cells fire action potentials in response to sound (Paton and Nottebohm 1984), receive synaptic input (Burd and Nottebohm 1985), may synapse on neurons in the efferent robust nucleus of the arcopallium (RA) (Alvarez-Buylla et al. 1990), and express neuron-specific proteins (Barami et al. 1995). Together, these studies in songbirds showed that new neurons are born and incorporated into functional circuits in the brains of adults of higher vertebrates (Nottebohm 2004). This research on adult neurogenesis in songbirds stimulated investigators to re-examine this topic in mammals. It soon became clear that new neurons are added throughout life to the DG and olfactory bulb of mammals including humans (Cameron and Gould 1994; Gould et al. 1997, 1999a; Lim et al. 1997; Eriksson et al. 1998). Because of these initial confirmatory reports, there has been explosive growth in study of the mechanisms and functions of adult neurogenesis in the mammalian DG and olfactory bulb.Open in a separate windowFigure 1.A schematic of the neurogenic regions in the avian brain overlaid on the avian song circuits. Neurogenic regions are shown in red. Note the proximity of HVC (and hippocampus [HC]) to the ventricular zone (VZ). A schematic version of the motor pathway for song production is shown in blue. A schematic of the ascending auditory pathway is shown in green. The dotted line indicates an indirect route through many nuclei of the ascending auditory pathway leading to field L in the telencephalon. The anterior forebrain circuit for song learning and plasticity is shown in yellow. NCM, Caudomedial nidopallium; RA, arcopallium; LMAN, lateral magnocellular nucleus of the anterior neostriatum; OB, olfactory bulb; DLM, dorsolateral medial; PAm, parambigualis; RAm, retroambigualisBirds continue to be a productive model for the study of neurogenesis in the adult brain, as discussed below. In this article, we will focus on neurogenesis in the song-control system as this is the most intensively studied model in birds. (For a review of neurogenesis in the avian hippocampus [HC], see Barnea and Pravosudov 2011.) We will discuss the mechanisms of neurogenesis in the song system, intrinsic and extrinsic factors that influence neuronal addition, a linkage between cell death and neurogenesis, seasonal plasticity, and consider potential functions of adult neurogenesis.     

Time-of-Day-Dependent Enhancement of Adult Neurogenesis in the Hippocampus

Background

Adult neurogenesis occurs in specific regions of the mammalian brain such as the dentate gyrus of the hippocampus. In the neurogenic region, neural progenitor cells continuously divide and give birth to new neurons. Although biological properties of neurons and glia in the hippocampus have been demonstrated to fluctuate depending on specific times of the day, it is unclear if neural progenitors and neurogenesis in the adult brain are temporally controlled within the day.

Methodology/Principal Findings

Here we demonstrate that in the dentate gyrus of the adult mouse hippocampus, the number of M-phase cells shows a day/night variation throughout the day, with a significant increase during the nighttime. The M-phase cell number is constant throughout the day in the subventricular zone of the forebrain, another site of adult neurogenesis, indicating the daily rhythm of progenitor mitosis is region-specific. Importantly, the nighttime enhancement of hippocampal progenitor mitosis is accompanied by a nighttime increase of newborn neurons.

Conclusions/Significance

These results indicate that neurogenesis in the adult hippocampus occurs in a time-of-day-dependent fashion, which may dictate daily modifications of dentate gyrus physiology.     

Topographical Atlas of the Gangliosides of the Adult Human Brain

Forty different brain samples, consisting of neocortical, archicortical, and paleocortical areas; telencephalic, diencephalic, and mesencephalic subcortical nuclei; and the cerebellum as well as some of the corresponding white matter bundles were analyzed with respect to total content of ganglioside-sialic acid and the ganglioside pattern. The total content of gangliosides seems to depend mainly on the proportions of gray and white matter. Thus, neocortical areas, which are rich in gray matter, have a four- to fivefold higher ganglioside content (per milligram of protein) than white matter-rich samples such as optic chiasm, capsula interna, or corpus callosum. White matter-rich regions, although very heterogeneous in ganglioside composition, are further characterized by appreciable amounts of the myelin-enriched GM4. In the neocortex a remarkable degree of regional pattern differences was revealed. In the frontal and parietal areas there is a moderate, and in the temporal region a strong preponderance of sialic acid bound to gangliosides of the a-pathway (GD1a, GM1). In contrast, the occipital cortex favors the b-pathway of ganglioside synthesis (GQ1b, GT1b, GD1b). A predominance of "b-gangliosides" was found in all structures that are related to the visual system (optic chiasm, pulvinar-thalamus, superior colliculi, visual cortex) as well as in the cerebellum and the nucleus ruber. All diencephalic nuclei tend to favor slightly "b-gangliosides," while the mesencephalic nuclei are very heterogeneous in their ganglioside composition. A preponderance of "a-gangliosides" was found in the periamygdalar cortex, putamen, inferior colliculi, substantia nigra, frontal white matter, internal capsule, globus pallidus, basal nucleus of Meynert, and corpus callosum as well as in the frontal, parietal, and temporal cortices. An exceptional predominance of GM1 and GD1a was revealed for the hippocampal archicortex and the amygdala, suggesting a possible functional correlation to glutaminergic synaptic transmission.     

Expansion of Multipotent Stem Cells from the Adult Human Brain

The discovery of stem cells in the adult human brain has revealed new possible scenarios for treatment of the sick or injured brain. Both clinical use of and preclinical research on human adult neural stem cells have, however, been seriously hampered by the fact that it has been impossible to passage these cells more than a very few times and with little expansion of cell numbers. Having explored a number of alternative culturing conditions we here present an efficient method for the establishment and propagation of human brain stem cells from whatever brain tissue samples we have tried. We describe virtually unlimited expansion of an authentic stem cell phenotype. Pluripotency proteins Sox2 and Oct4 are expressed without artificial induction. For the first time multipotency of adult human brain-derived stem cells is demonstrated beyond tissue boundaries. We characterize these cells in detail in vitro including microarray and proteomic approaches. Whilst clarification of these cells’ behavior is ongoing, results so far portend well for the future repair of tissues by transplantation of an adult patient’s own-derived stem cells.