Peripherally injected lipopolysaccharide induces apoptosis in the subventricular zone of young adult mice

Because the subventricular zone (SVZ) constantly supplies newly generated neurons to the olfactory bulb (OB) along the rostral migratory stream (RMS) in adult brain, SVZ-RMS-OB axis has been thought to work as a unit. We previously reported that peripherally injected lipopolysaccharide (LPS) induces apoptosis in the OB in young adult mice. Therefore, this study was undertaken to examine whether peripherally injected LPS induces apoptotic cell death also in the SVZ. Two mouse strains were used: C3H/HeN and Toll-like receptor 4-mutated C3H/HeJ, and wild-type C57BL/6 and TNFR1^−/−-2^−/−, in which the genes tumor necrosis factor receptor (TNFR)1 and TNFR2 are knocked out. Immunohistochemical study and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay done on the SVZ-RMS pathway of young adult male mice showed that peripherally injected LPS switches on the apoptotic signal by cleaving pro-caspase-3, thus possibly increasing the number of cells dying from apoptosis in these areas in adult mice. Activation of the tumor necrosis factor (TNF)-α-TNFR system played a critical role in fully inducing apoptosis in this pathway. We suggest that TNF-α was probably released not from microglia but from astrocytes in the SVZ and RMS.     

喙端迁移流的发生及其细胞凋亡

目的 研究生后不同日龄小鼠喙端迁移流（RMS）的发育,神经干细胞增殖和凋亡的规律。方法 利用Caspase-8免疫荧光标记法和5’-溴脱氧尿嘧啶核苷（BrdU）法,对小鼠RMS内的神经干细胞增殖和凋亡进行研究（n =92）。结果 生后早期小鼠脑内,尤其是室管下区（SVZ）和RMS,存在大量的增殖细胞。随着小鼠年龄的增加,脑内干细胞逐渐减少,到成年,大脑皮质几乎见不到增殖的神经干细胞,但在SVZ和RMS仍可以看到许多增殖的神经干细胞。在RMS,神经干细胞增殖的同时伴随着细胞凋亡,干细胞的增殖与凋亡存在着正相关关系。结论 RMS的神经干细胞增殖与凋亡有重要的生理意义,通过细胞凋亡,RMS可以调节神经干细胞向嗅球迁移的数量,也可以调节干细胞向颗粒细胞分化。     

Effects of short-duration electromagnetic radiation on early postnatal neurogenesis in rats: Fos and NADPH-d histochemical studies

The immediate effects of whole body electromagnetic radiation (EMR) were used to study postnatal neurogenesis in the subventricular zone (SVZ) and rostral migratory stream (RMS) of Wistar rats of both sexes. Newborn postnatal day 7 (P7) and young adult rats (P28) were exposed to pulsed electromagnetic fields (EMF) at a frequency of 2.45 GHz and mean power density of 2.8 mW/cm² for 2 h. Post-irradiation changes were studied using immunohistochemical localization of Fos and NADPH-d. We found that short-duration exposure induces increased Fos immunoreactivity selectively in cells of the SVZ of P7 and P28 rats. There were no Fos positive cells visible within the RMS of irradiated rats. These findings indicate that some differences exist in prerequisites of proliferating cells between the SVZ and RMS regardless of the age of the rats. Short-duration exposure also caused praecox maturation of NADPH-d positive cells within the RMS of P7 rats. The NADPH-d positive cells appeared several days earlier than in age-matched controls, and their number and morphology showed characteristics of adult rats. On the other hand, in the young adult P28 rats, EMR induced morphological signs typical of early postnatal age. These findings indicate that EMR causes age-related changes in the production of nitric oxide (NO), which may lead to different courses of the proliferation cascade in newborn and young adult neurogenesis.     

Activator of G protein signaling type 3 mRNA is widely distributed in the rat brain and is particularly abundant in the subventricular zone-olfactory bulb system of neural precursor cell proliferation, migration and differentiation

Activator of G protein signaling 3 (AGS3) is a guanine nucleotide dissociation inhibitor (GDI) to heterotrimeric G proteins of the Galphai/o class. Previous studies have described the tissue distribution and expression changes of AGS3 in brain extracts; however the precise localization of AGS3 in intact tissue has not yet been determined. The aim of the present study is therefore to map in detail the expression of AGS3 mRNA in the rat brain by using in situ hybridization (ISH) histochemistry with a (33)P-labeled riboprobe. Hybridized sections were analyzed at the regional level after exposure to autoradiography films and at the cellular level after coating with a photographic emulsion. Our results confirm a broad distribution for AGS3 which is expressed throughout the brain. Although most regions show a low level of expression, our results reveal a high abundance of AGS3 mRNA in the cerebellum as well as in regions important for neural precursor cell proliferation (subventricular zone of the anterior lateral ventricle), migration (rostral migratory stream) and differentiation (olfactory bulb). In particular, the high abundance of AGS3 in the subventricular zone-olfactory bulb system further documents the potential role of AGS3 in neural precursor cell division, migration and/or differentiation.     

Cell migration in the normal and pathological postnatal mammalian brain

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 (DG) of the hippocampus 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, proteins 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 toward 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.     

Presenilin mouse and zebrafish models for dementia: focus on neurogenesis

Autosomal dominant mutations in the presenilin gene PSEN cause familial Alzheimer's disease (AD), a neurological disorder pathologically characterized by intraneuronal accumulation and extracellular deposition of amyloid-β in plaques and intraneuronal, hyperphosphorylated tau aggregation in neurofibrillary tangles. Presenilins (PS/PSENs) are part of the proteolytic γ-secretase complex, which cleaves substrate proteins within the membrane. Cleavage of the amyloid precursor protein (APP) by γ-secretase releases amyloid-β peptides. Besides its role in the processing of APP and other transmembrane proteins, presenilin plays an important role in neural progenitor cell maintenance and neurogenesis. In this review, we discuss the role of presenilin in relation to neurogenesis and neurodegeneration and review the currently available presenilin animal models. In addition to established mouse models, zebrafish are emerging as an attractive vertebrate model organism to study the role of presenilin during the development of the nervous system and in neurodegenerative disorders involving presenilin. Zebrafish is a suitable model organism for large-scale drug screening, making this a valuable model to identify novel therapeutic targets for AD.     

Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice,animal model for autism

Autism spectrum disorders are characterized by impaired social and communication skills and seem to result from altered neural development. We sought to determine whether the anatomy of the meninges and extracellular matrix (ECM) is altered in an animal model of autism, the BTBR T+ tf/J mouse. This mouse displays white matter tract anatomical defects and exhibits several symptoms of autism. Immunofluorescence cytochemistry for laminin, a major ECM marker, was performed on series of coronal sections of the adult BTBR T+ tf/J brain and the anatomy was analyzed in comparison to B6 wild type mice. Laminin immunoreactivity visualized meninges, blood vessels and the subventricular zone (SVZ) stem cell-associated ECM structures, which I have named fractones. All BTBR T+ tf/J mice observed showed the same forebrain defects. The lateral ventricle volume was severely reduced, the falx cerebri elongated, the arteries enlarged and the choroid plexus atrophied. Compared to B6 mice, fractone numbers in BTBR T+ tf/J mice were reduced by a factor three in the SVZ of the anterior portion of the lateral ventricle. This represents the primary neurogenic zone during adulthood. Fractones were reduced by a factor 1.5 in posterior portions of the lateral ventricle. Moreover, fractone size was reduced throughout the lateral ventricle SVZ. These results show hitherto unsuspected alterations in connective tissue/vasculature and associated ECM in the adult BTBR T+ tf/J mouse. The drastic changes of the connective tissue and ECM in the neurogenic zone of the lateral ventricle may contribute to incorrect neurogenesis during developmental and adult stages.     

Quadriplegia recovery after hemi-section and transplant model of spinal cord at the level of C5 and C6

Reduced olfactory bulb (OB) volume and olfactory sensitivity have been observed in depressed patients, the exact mechanisms underlying, however, are still unknown. Our previous study found that decreased neurogenesis and pre-synaptic dysfunction in the OB of a rat model of depression may be responsible for the phenomena. Nevertheless, whether the apoptosis would also play a certain role in this process is not clear. In this study, we investigated the apoptosis in the OB of a chronic unpredictable mild stress (CUMS) rat model of depression using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Simultaneously, the pro-apoptosis protein bax and anti-apoptosis protein bcl-2 were detected by Western blot. The results showed that the number of TUNEL-positive cells increased dramatically in the glomerular layer of the OB of the CUMS rats, accompanied with up-regulated expression of bax protein and down-regulated expression of bcl-2 protein. The findings indicate that increased apoptosis may be attributed to explain at some level for the reduced OB volume and olfactory dysfunction in depressed patients. Moreover, the mitochondria-dependent death pathway might be involved in apoptosis in the OB of the CUMS rats.     

Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation

Cognitive health of an organism is considered to be maintained by the capacity of hippocampal precursors to proliferate and differentiate. Environmental stressors including irradiation have been shown to inhibit neurogenesis and are associated with the onset of cognitive impairments. Over the last two decades, much evidence has been gathered showing that enhanced free radical levels and an impaired antioxidant pool are important factors underlying the pathophysiological mechanisms in a variety of neurocognitive and neurodegenerative ailments. Since oxidative stress is reported to be implicated in impaired neurogenesis, it is likely that antioxidants such as melatonin and its metabolites could restore or minimize cellular death in the hippocampal dentate gyrus. The present review summarizes the recent studies documenting the protective role of melatonin against radiation-induced impairment of neurogenesis and cognitive functions.     

Radial glial cell heterogeneity--the source of diverse progeny in the CNS

Here, we discuss the identity, heterogeneity and functions of radial glial cells mostly in the developing central nervous system (CNS). First, we define radial glial cells by morphological, cell biological and molecular criteria as true glial cells, akin to astroglia. We then describe the appearance of radial glial cells during neural development as a precursor intermediate between immature neuroepithelial cells and differentiating progeny. Then we review the diverse progeny arising in different lineages from radial glial cells as observed by clonal analyses and time-lapse imaging. This leads us to discuss the molecular mechanisms involved in the regulation of the lineage heterogeneity of radial glial cells - including their diversity in distinct regions of the CNS. We conclude by considering the possible mechanisms allowing neurogenic radial glial cells to persist into adulthood in various vertebrate classes ranging from fish to birds, while neurogenic glial cells become restricted to few small regions of the adult forebrain in mice and men.     

Radial glial origin of the adult neural stem cells in the subventricular zone

Adult neurogenesis persists within restricted areas of the mammalian brain, giving rise prevalently to neuronal precursors that integrate inside the hippocampus and olfactory bulb. The source of this continuous cell production consists of neural stem cells which have been identified as elements of the astroglial lineage. This counterintuitive finding overlaps with the recent discovery that embryonic radial glia can themselves act as stem cells, capable of producing both neurons and glia during development. Although radial glia was thought to disappear early postnatally at the end of neurogenesis by transformation into parenchymal astrocytes, it has recently been demonstrated that some radial glial cells somehow persist within the adult forebrain subventricular zone, hidden among astrocytes of the glial tubes. This transformation occurs in parallel with overall morphological and molecular changes within the neurogenic site, whose specific steps, mechanisms, and outcomes are not yet fully understood. The modified radial glia appear to be neural progenitor cells belonging to the astroglial lineage (type B cells) assuring both stem cell self-renewal and production of a differentiated progeny in the adult subventricular zone, and also playing regulatory roles in stem cell niche maintenance.     

Ionizing radiation induced long-term alterations in the adult rat rostral migratory stream

Ionizing radiation can induce significant injury to normal brain structures. To assess radiation-induced late effects, adult male Wistar rats received whole-body exposure with fractionated doses of gamma rays (a total dose of 4 Gy) and were investigated thirty, sixty and ninety days later. Immunohistochemistry and confocal microscopy were used to determine the density of neuroblasts derived from the anterior subventricular zone (SVZa) and brain resident microglia distributed along and/or adjacent to subventricular zone–olfactory bulb axis (SVZ–OB axis). Cell counting was performed in four anatomical parts along the well defined pathway, known as the rostral migratory stream (RMS) represented by the SVZa, vertical arm, elbow and horizontal arm of the RMS. Strong overdistribution of neuroblasts was seen in the SVZa thirty and sixty days after irradiation replaced by a steep decline in the following parts of the RMS and the highest decrease ninety days after radiation treatment along the entire SVZ–OB axis. Radiation treatment led to a decline or loss of microglia in almost all counted parts through the entire experiment. Results showed that ultimate decline of the SVZa descendants and loss of microglia suggests a contributory role of reduced neurogenesis in the development of radiation-induced late effects.     

The ADAMs family: coordinators of nervous system development, plasticity and repair

A disintegrin and metalloprotease (ADAM) transmembrane proteins have metalloprotease, integrin-binding, intracellular signaling and cell adhesion activities. In contrast to other metalloproteases, ADAMs are particularly important for cleavage-dependent activation of proteins such as Notch, amyloid precursor protein (APP) and transforming growth factor alpha (TGFalpha), and can bind integrins. Not surprisingly, ADAMs have been shown or suggested to play important roles in the development of the nervous system, where they regulate proliferation, migration, differentiation and survival of various cells, as well as axonal growth and myelination. On the eleventh anniversary of the naming of this family of proteins, the relatively unknown ADAMs are emerging as potential therapeutic targets for neural repair. For example, over-expression of ADAM10, one of the alpha-secretases for APP, can prevent amyloid formation and hippocampal defects in an Alzheimer mouse model. Another example of this potential neural repair role is the finding that ADAM21 is uniquely associated with neurogenesis and growing axons of the adult brain. This comprehensive review will discuss the growing literature about the roles of ADAMs in the developing and adult nervous system, and their potential roles in neurological disorders. Most excitingly, the expanding understanding of their normal roles suggests that they can be manipulated to promote neural repair in the degenerating and injured adult nervous system.