The age-dependent change in Olfactory periglomerular neuronal populations is not affected by interrupting subventricular neuroblast migration in adult rats

The olfactory bulb (OB) is rich in the number and variety of neurotransmitter and neuropeptide containing cells, in particular in the glomerular layer. Several reports suggest that numbers of some periglomerular phenotypes could change depending on age. However, it is unclear whether the different classes of periglomerular interneurons are modified or are maintained stable throughout life. Thus, our first objective was to obtain the absolute number of cells belonging to the different periglomerular phenotypes at adulthood. On the other hand, the olfactory bulb is continously supplied with newly generated periglomerular neurons produced by stem cells located in the subventricular zone (SVZ) and rostral migratory stream. Previously, we demonstrated that the implantation of a physical barrier completely prevents SVZ neuroblast migration towards the OB. Then, another objective of this study was to evaluate whether stopping the continuous supply of SVZ neuroblasts modified the different periglomerular populations throughout time. In summary, we estimated the total number of TH-IR, CalB-IR, CalR-IR and GAD-IR cells in the OB glomerular layer at several time points in control and barrier implanted adult rats. In addition, we estimated the volume of glomerular, granular and complete OB. Our main finding was that the number of the four main periglomerular populations is age-dependent, even after impairment of subventricular neuroblast migration. Furthermore, we established that these changes do not correlate with changes in the volume of glomerular layer.     

Sustained increase in adult neurogenesis in the rat hippocampal dentate gyrus after transient brain ischemia

It is known that the number of newly generated neurons is increased in the young and adult rodent subventricular zone (SVZ) and dentate gyrus (DG) after transient brain ischemia. However, it remains unclear whether increase in neurogenesis in the adult DG induced by ischemic stroke is transient or sustained. We here reported that from 2 weeks to 6 months after transient middle cerebral artery occlusion (MCAO), there were more doublecortin positive (DCX+) cells in the ipsilateral compared to the sham-control and contralateral DG of the adult rat. After the S-phase marker 5-bromo-2'-deoxyuridine (BrdU) was injected 2 days after MCAO to label newly generated cells, a large number of BrdU-labeled neuroblasts differentiated into mature granular neurons. These BrdU-labeled neurons survived for at least 6 months. When BrdU was injected 6 weeks after injury, there were still more newly generated neuroblasts differentiated into mature neurons in the ipsilateral DG. Altogether, our data indicate that transient brain ischemia initiates a prolonged increase in neurogenesis and promotes the normal development of the newly generated neurons in the adult DG.     

Deprivation of sensory inputs to the olfactory bulb up-regulates cell death and proliferation in the subventricular zone of adult mice

The main olfactory bulb (MOB) is the first relay on the olfactory sensory pathway and the target of the neural progenitor cells generated in the subventricular zone (SVZ) lining the lateral ventricles and which migrate along the rostral extension of the SVZ, also called the rostral migratory stream (RMS). Within the MOB, the neuroblasts differentiate into granular and periglomerular interneurons. A reduction in the number of granule cells during sensory deprivation suggests that neurogenesis may be influenced by afferent activity. Here, we show that unilateral sensory deafferentation of the MOB by axotomy of the olfactory receptor neurons increases apoptotic cell death in the SVZ and along the rostro-caudal extent of the RMS. The vast majority of dying cells in the RMS are migrating neuroblasts as indicated by double Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling/PSA-NCAM labeling. Counting bromodeoxyuridine-labeled cells in animals killed immediately or 4 days after tracer administration showed a bilateral increase in proliferation in the SVZ and RMS which was balanced by cell death on the operated side. These data suggest that olfactory inputs are required for the survival of newborn neural progenitors. The greatest enhancement in proliferation occurred in the extension of the RMS located in the MOB, revealing a population of local precursors mitotically stimulated following axotomy. Together, these findings indicate that olfactory inputs may strongly modulate the balance between neurogenesis and apoptosis in the SVZ and RMS and provide a model for further investigation of the underlying molecular mechanisms of this activity-dependent neuronal plasticity.     

Neurogenesis in the striatum of the quinolinic acid lesion model of Huntington's disease

The presence of ongoing neurogenesis in the adult mammalian brain raises the exciting possibility that endogenous progenitor cells may be able to generate new neurons to replace cells lost through brain injury or neurodegenerative disease. We have recently demonstrated increased cell proliferation and the generation of new neurons in the Huntington's disease human brain. In order to better understand the potential role of endogenous neuronal replacement in neurodegenerative disorders and extend our initial observations in the human Huntington's disease brain, we examined the effect of striatal cell loss on neurogenesis in the subventricular zone (SVZ) of the adult rodent forebrain using the quinolinic acid (QA) lesion rat model of Huntington's disease. Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunocytochemistry for cell type-specific markers. BrdU labeling demonstrated increased cell proliferation in the SVZ ipsilateral to the QA-lesioned striatum, resulting in expansion of the SVZ in the lesioned hemisphere. Quantification revealed that QA lesion-induced striatal cell loss produced a significant increase in the area of BrdU-immunoreactivity in the SVZ ipsilateral to the lesioned hemisphere between 1 and 14 days post-lesion compared with sham-lesioned animals, with the greatest increase observed at 7 days post-lesion. These changes were associated with an increase in cells in the anterior SVZ ipsilateral to the lesioned striatum expressing the antigenic marker for SVZ neuroblasts, doublecortin (Dcx). Importantly, we observed Dcx-positive cells extending from the SVZ into the QA-lesioned striatum where a subpopulation of newly generated cells expressed markers for immature and mature neurons. This study demonstrates that loss of GABAergic medium spiny projection neurons following QA striatal lesioning of the adult rat brain increases SVZ neurogenesis, leading to the putative migration of neuroblasts to damaged areas of the striatum and the formation of new neurons.     

The cellular composition and morphological organization of the rostral migratory stream in the adult human brain

The rostral migratory stream (RMS) is the major pathway by which progenitor cells migrate from the subventricular zone (SVZ) to the olfactory bulb (OB) in rodents, rabbits and primates. However, the existence of an RMS within the adult human brain has been elusive. Immunohistochemical studies utilising cell-type specific markers for early progenitor cells (CD133), proliferating cells (PCNA), astrocytes and type B cells (GFAP) and migrating neuroblasts (PSA-NCAM), reveal that the adult human RMS is organized into layers containing glial cells, proliferating cells and neuroblasts. In addition, the RMS is arranged around a remnant of the ventricular cavity that extends from the SVZ to the OB as seen by immunohistological staining analysis and electron microscopy, showing the presence of basal bodies and a typical 9 + 2 arrangement of tubulin in tufts of cilia from all levels of the RMS. Overall, these findings suggest that a pathway of migratory progenitor cells similar to that seen in other mammals is present within the adult human brain and that this pathway could provide for neurogenesis in the human forebrain. These findings contribute to the scientific understanding of adult neurogenesis and establish the detailed cytoarchitecture of this novel neurogenic niche in the human brain.     

Expression of drebrin E in migrating neuroblasts in adult rat brain: coincidence between drebrin E disappearance from cell body and cessation of migration

Migrating neuroblasts in the adult brain form the rostral migratory stream (RMS) from the lateral ventricle to the olfactory bulb (OB) and then differentiate in the OB. In this study, we immunohistochemically analyzed drebrin expression in the RMS of the adult rat brain. Although drebrin is concentrated in dendritic spines of mature neurons, drebrin-immunopositive (DIP) cell bodies were observed in the RMS. The polysialated form of a neural cell adhesion molecule (PSA-NCAM) was detected in DIP cells. K(i)-67, a marker of proliferating cells, was also detected in a subset of DIP cells; however, neither glial fibrillary acidic protein, nestin nor vimentin was detected in DIP cells. These results indicate that DIP cells in the RMS are migrating neuroblasts. An image subtraction method, based on using anti-pan-drebrin and anti-drebrin A antibodies, demonstrated that DIP migrating neuroblasts are immunopositive for drebrin E but not for drebrin A (E+A-). Furthermore, olfactory bulbectomy increased the number of cells with drebrin E+A- signals in the RMS, indicating that these cells migrate along the RMS. Drebrin E+A- cells were also found in the subgranular layer of the dentate gyrus and in the piriform cortex. Thus, detection of drebrin E+A- signals is useful for identifying migrating neuroblasts in the adult brain. In the OB, drebrin E+A- signals were observed in the cell bodies of migrating neuroblasts in the core region; however, only fibrous and punctate drebrin E+A- signals were observed in postmigratory neuroblasts at the outer layers. These data demonstrate that the disappearance of drebrin E+A- signals from the cell body coincides with the cessation of neuronal migration. The disappearance of drebrin E from the cell body may be a molecular switch for the cessation of migration in newly generated neuroblasts.     

成年大鼠脑室下区吻侧迁移流的细胞形态学研究

为了探讨成年大鼠脑室下区吻侧迁移流(RMS)神经干细胞的分布及特点,我们利用Nissl染色,BrdU、GFAP、PSA-NCAM和nestin免疫组织化学染色,nestin与GFAP免疫荧光双标记染色等方法观察了正常成年SD大鼠RMS的组织化学和免疫组织化学特征;同时观察了正常RMS的超微结构特征。结果观察到:(1)在光镜下,Nissl染色切片的RMS由深染和浅染细胞组成,其中深染细胞为PSA-NCAM、BrdU及nestin免疫反应阳性,浅染细胞为GFAP及nestin免疫反应阳性;(2)电镜下,RMS存在数量不等、由同一种类型的细胞聚集形成的细胞团,以及星型胶质细胞和少量少突胶质细胞,细胞团中可看到正在分裂的细胞。结果提示:(1)除少突胶质细胞外,RMS主要由两种类型细胞组成,即成神经细胞和星型胶质细胞;(2)成神经细胞存在于RMS全长并保持分裂特性,属神经元前体细胞;(3)目前还没有充分的证据证实RMS中存在干细胞。     

Selective upregulation of 3-phosphoglycerate dehydrogenase (Phgdh) expression in adult subventricular zone neurogenic niche

In the adult rodent brain, constitutive neurogenesis occurs in two restricted regions, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus, where multipotent neural stem/progenitor cells generate new neurons. Using Western blotting and immunohistochemistry for established markers, we demonstrated that the expression of 3-phosphoglycerate dehydrogenase (Phgdh), an enzyme involved in de novo synthesis of l-serine, was upregulated in the SVZ. The expression was selective to cells having morphological features and expressing markers of astrocyte-like primary neural stem cells (type B cells) and their progeny, actively proliferating progenitors (type C cells). By contrast, Phgdh protein expression was virtually absent in committed neuronal precursors (type A cells) derived from type C cells. High levels of Phgdh were also expressed by glial tube cells located in the rostral migratory stream (RMS). Interestingly, ensheathment of type A cells by these Phgdh-expressing cells was persistent in the SVZ and RMS, suggesting that l-serine mediates trophic support for type A cells via these glial cells. In vitro neurosphere assays confirmed that growth-factor-responsive, transient amplifying neural progenitors in the SVZ, but not differentiated neurons, expressed Phgdh. In the aged brain, a decline in Phgdh expression was evident in type B and C cells of the SVZ. These observations support the notion that availability of l-serine within neural stem/progenitor cells may be a critical factor for neurogenesis in developing and adult brain.     

Adult neurogenesis and the olfactory system

Though initially described in the early 1960s, it is only within the past decade that the concept of continuing adult neurogenesis has gained widespread acceptance. Neuroblasts from the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) into the olfactory bulb, where they differentiate into interneurons. Neuroblasts from the subgranular zone (SGZ) of the hippocampal formation show relatively little migratory behavior, and differentiate into dentate gyrus granule cells. In sharp contrast to embryonic and perinatal development, these newly differentiated neurons must integrate into a fully functional circuit, without disrupting ongoing performance. Here, after a brief historical overview and introduction to olfactory circuitry, we review recent advances in the biology of neural stem cells, mechanisms of migration in the RMS and olfactory bulb, differentiation and survival of new neurons, and finally mechanisms of synaptic integration. Our primary focus is on the olfactory system, but we also contrast the events occurring there with those in the hippocampal formation. Although both SVZ and SGZ neurogenesis are involved in some types of learning, their full functional significance remains unclear. Since both systems offer models of integration of new neuroblasts, there is immense interest in using neural stem cells to replace neurons lost in injury or disease. Though many questions remain unanswered, new insights appear daily about adult neurogenesis, regulatory mechanisms, and the fates of the progeny. We discuss here some of the central features of these advances, as well as speculate on future research directions.     

Age-dependent regional changes in the rostral migratory stream

Throughout life the subventricular zone (SVZ) is a source of new olfactory bulb (OB) interneurons. From the SVZ, neuroblasts migrate tangentially through the rostral migratory stream (RMS), a restricted route approximately 5 mm long in mice, reaching the OB within 10–14 days. Within the OB, neuroblasts migrate radially to the granule and glomerular layers where they differentiate into granule and periglomerular (PG) cells and integrate into existing synaptic circuits. SVZ neurogenesis decreases with age, and might be a factor in age-related olfactory deficits. However, the effect of aging on the RMS and on the differentiation of interneuron subpopulations remains poorly understood. Here, we examine RMS cytoarchitecture, neuroblast proliferation and clearance from the RMS, and PG cell subpopulations at 6, 12, 18, and 23 months of age. We find that aging affects the area occupied by newly generated cells within the RMS and regional proliferation, and the clearance of neuroblasts from the RMS and PG cell subpopulations and distribution remain stable.     

Subependymal zone: immunohistochemically distinct compartment in the adult mammalian forebrain

The subependymal zone (SEZ) lining lateral walls of the lateral cerebral ventricles represents the site of active neurogenesis in the brain of adult mammals. Peroxidase immunohistochemistry performed in paraffin-embedded sections reveals that structural organization of the SEZ differs from other regions in the brain. The SEZ is devoid of synapses that are abundant in the adjacent striatal neuropil. Therefore immunostaining of synaptophysin detects sharp borders of the SEZ. Using immunophenotypization, we identified cell types constituting the SEZ in the intact rat forebrain. The presence of neural progenitor/stem cells was confirmed by finding of nestin-immunopositive cells. Detection of the astroglial marker GFAP confirmed that astrocytes represented major supporting elements responsible for creating a unique microenvironment of the SEZ. One type of the astroglia participated in covering surfaces of the blood vessels and boundaries of the SEZ. The second astroglial cell type formed branched elongated tubes that enwrapped other SEZ cell types with their cytoplasmic extensions. The interior of astrocytic channels was occupied with small densely aggregated NCAM-immunoreactive neuroblasts. Bipolar morphology indicated that these cells probably underwent migration. Immunodetection of other neuronal markers like beta-III tubulin, MAP-2 and Pan neurofilaments identified positive cells in the neighbouring brain parenchyma but not in the SEZ. The rostral migratory stream (RMS) linked with the anterior SEZ had a similar structural arrangement. It contained a large amount of nestin+ and vimentin+ cells. The RMS consisted of GFAP+ astrocytic tubes ensheathing NCAM+ neuroblasts. On the contrary to the SEZ, the RMS neuroblasts expressed beta-III tubulin. However, markers of postmitotic neurons MAP-2, Pan neurofilaments and synaptophysin were not expressed in the RMS. Our study describes a complex histological structure of the rat SEZ, identifies its individual cell types and demonstrates a usefulness of immunohistochemical detection of cell-specific markers in a study of microenvironment forming neurogenic zones in the mammalian brain.     

Differential neurogenesis and gliogenesis by local and migrating neural stem cells in the olfactory bulb

The rostral migratory stream (RMS) is a unique forebrain structure that provides a long-distance migratory route for the neural stem cells of the periventricular region towards the olfactory bulb (OB). The purpose of the study presented here is to examine the extent of neurogenesis and gliogenesis by the neural stem cells of different origins (periventricular vs. intrabulbar) in the OB. After the RMS had been subjected to injury, the rats received intraperitoneal injections of 5-bromodeoxyuridine (BrdU) and were further reared for 2 weeks. Neuronal and glial differentiations of the BrdU(+) cells in the olfactory bulbar granule cell (OB-GCL) and the olfactory glomerular (OB-GL) layers were examined immunohistochemically using antibodies against neuronal (NeuN, neuronal nuclei) and glial (GFAP, glial fibrillary acidic protein) markers in the OBs with injured and uninjured (control) RMS. In the completely RMS-lesioned OB, where migration of the periventricular neural stem cells was inhibited, a small number of BrdU(+) NeuN(+) cells were found in both the OB-GCL and OB-GL. The BrdU(+) NeuN(+) cells accounted for a much higher percentage of the BrdU(+) cells on the control side (OB-GCL, 36.7%; OB-GL, 8.8%) than on the completely RMS-lesioned side (OB-GCL, 3.7%; OB-GL, 0.6%). The percentage of the BrdU(+) GFAP(+) cells relative to the BrdU(+) cells did not show any major difference between the control and completely RMS-lesioned sides. This study revealed differences in neurogenesis and gliogenesis between the local and migrating neural stem cells in the OB of the adult rodent.     

Brain inflammation and adult neurogenesis: the dual role of microglia

In the adult mammalian brain, neurogenesis from neural stem/progenitor cells continues in two regions: the subgranular zone in the dentate gyrus and the subventricular zone lining the lateral ventricles. The generated neuroblasts migrate to their appropriate location and differentiate to mature granule cells and olfactory bulb interneurons, respectively. Following injury such as stroke, neuroblasts generated in the subventricular zone migrate also into areas which are not normally neurogenic, e.g. striatum and cerebral cortex. In the initial studies in rodents, brain inflammation and microglia activation were found to be detrimental for the survival of the new hippocampal neurons early after they had been born. The role of inflammation for adult neurogenesis has, however, turned out to be much more complex. Recent experimental evidence indicates that microglia under certain circumstances can be beneficial and support the different steps in neurogenesis, progenitor proliferation, survival, migration, and differentiation. Here we summarize the current knowledge on the role of inflammation and in particular of microglia in adult neurogenesis in the intact and injured mammalian brain. We conclude that microglia activation, as an indicator of inflammation, is not pro- or antineurogenic per se but the net outcome is dependent on the balance between secreted molecules with pro- and antiinflammatory action.     

Chemoattractive activity of sonic hedgehog in the adult subventricular zone modulates the number of neural precursors reaching the olfactory bulb

The adult subventricular zone (SVZ) supports neural stem cell self-renewal and differentiation and continually gives rise to new neurons throughout adult life. The mechanisms orienting the migration of neuroblasts from the SVZ to the olfactory bulb (OB) via the rostral migratory stream (RMS) have been extensively studied, but factors controlling neuroblast exit from the SVZ remain poorly explored. The morphogen Sonic Hedgehog (Shh) displays proliferative and survival activities toward neural stem cells and is an axonal chemoattractant implicated in guidance of commissural axons during development. We identify here the presence of Shh protein in SVZ extracts and in the cerebrospinal fluid of adult mice, and we demonstrate that migrating neuroblasts in the SVZ and RMS express the Shh receptor Patched. We show that Shh displays a chemoattractive activity in vitro on SVZ-derived neuronal progenitors, an effect blocked by Cur61414, a Smoothened antagonist. Interestingly, Shh-expressing cells grafted above the RMS of adult mice exert a chemoattractive activity on migrating neuroblasts in vivo, thus inducing their accumulation and deviation from their normal migratory pathway. Furthermore, the adenoviral transfer of Shh into the lateral ventricle or the blocking of Shh present in the SVZ of adult mice using its physiological antagonist Hedgehog interacting protein or neutralizing Shh antibodies provides in vivo evidence that Shh can retain SVZ-derived neuroblasts. The ability to modulate the number of neuroblasts leaving the SVZ and reaching the OB through the chemoattractive activity of Shh suggests a novel degree of plasticity in cell migration of this adult stem cell niche.     

嗅球切除对成年大鼠侧脑室外侧壁新生细胞增殖和分化的影响

目的 研究嗅球切除后成年大鼠侧脑室外侧壁(SVZ)新生细胞增殖和分化的情况,进一步探讨嗅球对SVZ神经生发活动的影响.方法 建立成年SD雄性大鼠右侧嗅球切除模型,并分别存活4周和12周,利用Nissl染色、多唾液酸神经细胞黏附分子(PSA-NCAM)和BrdU免疫组织化学染色的方法观察了成年SD大鼠嗅球切除后存活不同时间两侧吻侧迁移流(RMS)BrdU阳性细胞数占总细胞百分比的变化以及两侧RMS PSA-NCAM阳性细胞的形态学变化.结果 1.嗅球切除后不同时间点,嗅球切除侧RMS的细胞数增加,BrdU免疫阳性细胞数增加,但BrdU免疫阳性细胞数占总细胞数的百分比随嗅球切除后大鼠存活时间的延长而下降,且以RMS的吻侧部分下降更明显;2.嗅球切除后,在切除侧断端吻侧颗粒层和RMS均出现较对照侧更多的具有较长突起的PSA-NCAM阳性细胞.结论 嗅球切除后仍有新生神经元沿RMS向吻侧迁移,但其增殖率随时间延长下调;嗅球的切除似乎并没有影响成神经细胞的分化.     

Increased neurogenesis in brains of scrapie-infected mice

Persistent neurogenesis occurs in the adult brain throughout the life of all mammals. Recent studies have shown that neurogenesis was increased in adult gerbil and rat brains after ischemia. Neurogenesis has not been examined during neurodegenerative diseases such as scrapie. To investigate the regeneration of neurons after scrapie-infection, we infused 5-bromo-2'-deoxyuridine (BrdU), a DNA replication indicator, into both control and scrapie-infected mice. Mice were sacrificed at 150 days post-infection, i.e., at the start of clinical disease and a time when PrP(Sc) was readily detected in brain by both immunostaining and Western blot. We investigated expression of BrdU in each region of brain and observed cellular localization of BrdU using various cell markers such as neuronal nuclear (NeuN), microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP). Immunohistochemically, BrdU-labeled cells were observed in the striatum, hippocampus, and brain stem of scrapie-infected brains. BrdU-labeled cells were much more prevalent in the hippocampus of scrapie-infected mice compared to hippocampus of control brains. In scrapie mice, there was more staining in hippocampus than in other brain regions. We also found that BrdU-positive cells colocalized with the neuronal markers NeuN and MAP2, whereas BrdU staining was not merged with GFAP, an astrocytic marker. Taken together, our results suggest that scrapie-infection induces region-specific increases in neuron regeneration.     

Control of neuroblast production and migration by converging GABA and glutamate signals in the postnatal forebrain

The production of adult-born neurons is an ongoing process accounting for > 10 000 immature neurons migrating to the olfactory bulb every day. This high turnover rate necessitates profound control mechanisms converging onto neural stem cells and neuroblasts to achieve adequate adult-born neuron production. Here, we elaborate on a novel epigenetic control of adult neurogenesis via highly coordinated, non-synaptic, intercellular signalling. This communication engages the neurotransmitters GABA and glutamate, whose extracellular concentrations depend on neuroblast number and high affinity uptake systems in stem cells. Previous studies show that neuroblasts release GABA providing a negative feedback control of stem cell proliferation. Recent findings show an unexpected mosaic expression of glutamate receptors leading to calcium elevations in migrating neuroblasts. We speculate that stem cells release glutamate that activates glutamate receptors on migrating neuroblasts providing them with migratory and survival cues. In addition, we propose that the timing of neurotransmitter release and their spatial diffusion will determine the convergent coactivation of neuroblasts and stem cells, and provide a steady-state level of neuroblast production. Upon external impact or injury this signalling may adjust to a new steady-state level, thus providing non-synaptic scaling of neuroblast production.     

Fibroblast growth factor 2 enhances striatal and nigral neurogenesis in the acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

In response to injury, endogenous precursors in the adult brain can proliferate and generate new neurons, which may have the capacity to replace dysfunctional or dead cells. Although injury-induced neurogenesis has been demonstrated in animal models of stroke, Alzheimer's disease (AD) and Huntington's disease (HD), studies of Parkinson's disease (PD) have produced conflicting results. In this study, we investigated the ability of adult mice to generate new neurons in response to the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes selective degeneration of nigrostriatal dopamine neurons. MPTP lesions increased the incorporation of 5-bromo-2′-deoxyuridine-5′-monophosphate (BrdU), as well as the number of cells that co-expressed BrdU and the immature neuronal marker doublecortin (DCX), in two neuroproliferative regions—the subgranular zone of the dentate gyrus (DG) and the rostral subventricular zone (SVZ). BrdU-labeled, DCX-expressing cells were not found in the substantia nigra (SN) of MPTP-treated mice, where neuronal cell bodies are destroyed, but were present in increased numbers in the striatum, where SN neurons lost in PD normally project. Fibroblast growth factor-2 (FGF-2), which enhances neurogenesis in a mouse model of HD, also increased the number of BrdU/DCX-immunopositive cells in the SN of MPTP-treated mice. Thus, MPTP-induced brain injury increases striatal neurogenesis and, in combination with FGF-2 treatment, also stimulates neurogenesis in SN.     

Short term treatment with estradiol decreases the rate of newly generated cells in the subventricular zone and main olfactory bulb of adult female mice

Adult neurogenesis occurs most notably in the subgranular zone (SGZ) of the hippocampal dentate gyrus and in the olfactory bulb (OB) where new neurons are generated from neural progenitors cells produced in the subventricular zone (SVZ) of the forebrain. As it is well known that gonadal steroid hormones, primarily estradiol, modulate neurogenesis in the hippocampus of adult female rodents, we wanted to determine whether estradiol would also affect the proliferation of progenitor cells in the SVZ and by consequence the rate of newly generated cells in the main OB. Thus a first group of adult female C57Bl6/J mice was ovariectomized and received a short term treatment with estradiol (single injection of 1 or 10 μg 17β-estradiol or Silastic capsule of estradiol during 2 days) before receiving a single injection with BrdU to determine whether estradiol would modulate the cell proliferation in the SVZ. A second group of adult ovariectomized female mice was submitted to the same estradiol treatment before receiving four BrdU injections, and was sacrificed 21 days later to determine whether a modulation in cell proliferation actually leads to a modulation in the number of newborn cells in the main OB. We observed a decrease in cell proliferation in the SVZ following either dose of estradiol compared to the controls. Furthermore, 21 days after their generation in the SVZ, the number of BrdU labeled cells was also lower in the main OB, both in the granular and periglomerular cell layers of estradiol-treated animals. These results show that a short term treatment with estradiol actually downregulates cell proliferation leading to a decreased number of newborn cells in the OB.     

Expression of amyloid precursor protein-like molecule in astroglial cells of the subventricular zone and rostral migratory stream of the adult rat forebrain

In adult mammals, new neurons in the subventricular zone (SVZ) of the lateral ventricle (LV) migrate tangentially through the rostral migratory stream (RMS) to the olfactory bulb (OB), where they mature into local interneurons. Using a monoclonal antibody for the beta-amyloid precursor protein (APP) (mAb 22C11), which is specific for the amino-terminal region of the secreted form of APP and recognizes all APP isoforms and APP-related proteins, immunoreactivity was detected in specific subpopulations of cells in the SVZ and RMS of the adult rat forebrain. In the SVZ, APP-like immunoreactivity was detected in the ependymal cells lining the LV and some of the subependymal cells. The latter were regarded as astrocytes, because they were positive for the glial markers, S-100 protein (S-100) and glial fibrillary acidic protein (GFAP). APP-like immunoreactive astrocytes exhibited strong labelling of the perinuclear cytoplasm and often possessed a long, fine process similar to that found with radial glia. The process extended to an APP-like immunoreactive meshwork in the RMS that consisted of cytoplasmic processes of astrocytes forming 'glial tubes'. Double-immunofluorescent labelling with a highly polysialylated neural cell adhesion molecule (PSA-NCAM) confirmed that the APP-like immunoreactive astrocytes in the SVZ and meshwork in the RMS made close contact with PSA-NCAM-immunopositive neuroblasts, suggesting an interaction between APP-containing cells and neuroblasts. This region of the adult brain is a useful in vivo model to investigate the role of APP in neurogenesis.