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Objectives The present study aimed to investigate the effects of acute hypoxia exposure following prenatal stress on the novelty-seeking behavior and hippocampus of adolescent rats. Methods The offspring were divided into prenatal stress (PS) and non-stress (NS) groups. Both groups were exposed to hypoxia on postnatal day 10 (P10) while control groups were undisturbed. Novel object recognition task was performed in each group. Next, brains were collected to examine hippocampus via immunohistochemical and biochemical studies on postnatal day 35 (P35). Results PS decreased novelty discrimination and synaptophysin (SYN) expressions in both CA1 and CA3 of the hypoxia group prominently (p < 0.05). Nestin-expressing cells were reduced while vascular endothelial growth factor (VEGF) expression was enhanced in the subgranular zone (SGZ) of PS-hypoxia group (p < 0.05). VEGF enhancement triggered angiogenesis in the CA1 and CA3 significantly (p < 0.05). PS also increased thiobarbituric acid reactive substances (TBARS) levels in the hypoxia group as a result of oxidative stress (p < 0.05). Conclusion These findings demonstrated that PS exacerbates neurodevelopmental deficits in the hippocampus of acute hypoxia-induced offspring in adolescence., Ege University [18-SBE-004/2018], Ege University, Grant/Award Number: 18-SBE-004/2018

Evidence on adult mammalian neurogenesis and scarce studies with human brains led to the idea that adult human neurogenesis occurs in the subgranular zone (SGZ) of the dentate gyrus and in the subventricular zone (SVZ). However, findings published from 2018 rekindled controversies on adult human SGZ neurogenesis. We systematically reviewed studies published during the first decade of characterization of adult human neurogenesis (1994–2004) – when the two-neurogenic-niche concept in humans was consolidated – and compared with further studies. The synthesis of both periods is that adult human neurogenesis occurs in an intensity ranging from practically zero to a level comparable to adult mammalian neurogenesis in general, which is the prevailing conclusion. Nonetheless, Bernier and colleagues showed in 2000 intriguing indications of adult human neurogenesis in a broad area including the limbic system. Likewise, we later showed evidence that limbic and hypothalamic structures surrounding the circumventricular organs form a continuous zone expressing neurogenesis markers encompassing the SGZ and SVZ. The conclusion is that publications from 2018 on adult human neurogenesis did not bring novel findings on location of neurogenic niches. Rather, we expect that the search of neurogenesis beyond the canonical adult mammalian neurogenic niches will confirm our indications that adult human neurogenesis is orchestrated in a broad brain area. We predict that this approach may, for example, clarify that human hippocampal neurogenesis occurs mostly in the CA1-subiculum zone and that the previously identified human rostral migratory stream arising from the SVZ is indeed the column of the fornix expressing neurogenesis markers.

We sought to determine whether radiation to the colorectum had an impact on parameters of hippocampal neurogenesis and, if so, whether it could be modulated by a fiber-rich diet. Male C57BL/6J mice were fed a diet containing bioprocessed oat bran or a fiber-free diet, starting two weeks before colorectal irradiation with 4 fractions of 8 Gray or sham-irradiation. Diets were then continued for 1, 6 or 18 weeks, whereafter parameters of hippocampal neurogenesis were analyzed and correlated to serum cytokine levels. No statistically significant changes in neuronal markers or cell proliferation were found at one week post-irradiation. Six weeks post-irradiation there was a decreased cell proliferation in the subgranular zone that appeared slightly more pronounced in irradiated animals on a fiber-free diet and increased numbers of immature neurons per mm2 dentate gyrus in the irradiated mice, with a statistically significant increase in mice on a fiber-rich diet. Microglial abundancy was similar between all groups. 18 weeks post-irradiation, a fiber-free diet had reduced the number of immature neurons, whereas irradiation resulted in an increase. Despite this, the population of mature neurons was stable. Analysis of serum cytokines revealed a negative correlation between MIP1-α and the number of immature neurons one week after irradiation, regardless of diet. Our findings show that pelvic radiotherapy has the potential to cause a long-lasting impact on hippocampal neurogenesis, and dietary interventions may modulate this impact. More in-depth studies on the relationship between irradiation-induced intestinal injury and brain health are warranted. (Less)

Human MYCN is an oncogene amplified in neuroblastoma and many other tumors. Both human MYCN and mouse Mycn genes are important in embryonic brain development, but their functions in adult healthy nerve system are completely unknown. Here, with Mycn-eGFP mice and quantitative RT-PCR, we found that Mycn was expressed in specific brain regions of young adult mice, including subventricular zone (SVZ), subgranular zone (SGZ), olfactory bulb (OB), subcallosal zone (SCZ), and corpus callosum (CC). With immunohistochemistry (IHC), we found that many Mycn-expressing cells expressed neuroblast marker doublecortin (DCX) and proliferation marker Ki67. With Dcx-creER and Mki67-creER mouse lines, we fate mapped Dcx-expressing neuroblasts and Mki67-expressing proliferation cells, along with deleting Mycn from these cells in adult mice. We found that knocking out Mycn from adult neuroblasts or proliferating cells significantly reduced cells in proliferation in SVZ, SGZ, OB, SCZ, and CC. We also demonstrated that the Mycn-deficient neuroblasts in SGZ matured quicker than wild-type neuroblasts, and that Mycn-deficient proliferating cells were more likely to survive in SVZ, SGZ, OB, SCZ, and CC compared to wild type. Thus, our results demonstrate that, in addition to causing tumors in the nervous system, oncogene Mycn has a crucial function in neurogenesis and oligodendrogenesis in adult healthy brain.

This article belongs to the Special Issue Frontiers in Neurogenesis—Series II Neural stem cells (NSCs) are self-renewing, multipotent cells which give rise to all components of the central nervous system (CNS) during embryogenesis, but also activate in response to injury and disease and maintain a certain level of neurogenic activity throughout adulthood. This activity takes place in specialized regions of the brain, the neurovascular niches, whose main role is to control the behaviour of the CNS. In adult mammals, two main 'canonical' niches have been described: The subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. This review discusses our current understanding of the neural stem cells and their canonical niches, as well as their structure, behaviours, and role in neural disease. This research was funded by the Ministerio de Ciencia, Innovación y Universidades, Instituto de Salud Carlos III grants PI18/00462 to M.V.G.-G. and PT20/00044 to M.D., was co-financed by the European Regional Development Fund, "A way of making Europe" initiative. This work was partially supported by Comunidad de Madrid (S2017/BMD-3867 RENIM-CM) and co-financed by the European Structural and Investment Fund. This study was also supported by the Plan Estatal de I+D+I 2013-2016, with funding from the European Regional Development Fund (ERDF), "A way to build Europe" initiative. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (SEV-2015-0505)

Neurogenesis occurs during the embryological development of the brain. However, it is universally accepted that in all adult mammalian brains, there are two sites of high-density cell division: the subventricular zone of the lateral ventricles (SVZ) and the subgranular zone (SGZ) of the dentate gyrus of the hippocampal formation. Doxorubicin (DOX) is an anthracycline agent which results in cognitive deterioration and memory impairment, whereas memantine (MEM) is an NMDA receptor antagonist which is approved for the treatment of Alzheimer’s dementia. Many studies have revealed MEM’s positive impact on memory and demonstrated that it stimulates neuronal division in the hippocampus. This study aimed to assess the effect of MEM on spatial memory and neural proliferation in the hippocampus in adult male rats treated with DOX. For this purpose, forty male Sprague-Dawley rats were divided into four groups of ten rats each according to the agent: control, MEM (2.5 mg/kg), DOX (2 mg/kg), and DOX with MEM. The rats were given seven intraperitoneal injections every other day. We tracked the rat’s weights to assess the weight-reducing effects of the drugs. In order to test spatial memory, the rats were subjected to the novel location recognition (NLR) task 30 minutes after the last injection. Additionally, Ki67 immunohistochemistry was performed to examine hippocampal proliferation. The results showed a significant reduction in discrimination index (DI) in the DOX-treated group compared to MEM- (p < 0.001) and MEM with DOX-treated groups (p < 0.001). There was a significant increase in Ki67-positive cells in the MEM-treated group compared to the saline-treated group. Treatment with DOX impaired hippocampal proliferation compared to treatment with MEM or saline. The co-administration of MEM with DOX ameliorated the decline in hippocampal proliferation compared to treatment with DOX alone. There was a significant weight reduction in the DOX group in comparison to the control group, but MEM attenuated DOX-induced weight loss. Rats treated with DOX displayed a drop in memory, hippocampal proliferation, and weight compared to the MEM-treated group, whereas the co-administration of MEM with DOX protected memory, hippocampal proliferation, and doxorubicin-induced weight loss.

Adult neurogenesis is the production of new nerve cells in the adult brain. Neurogenesis is a clear example of the neuroplasticity phenomenon which can be observed in most of mammalian species, including human beings. This phenomenon occurs, at least, in two regions of the brain: the subgranular zone of the dentate gyrus in hippocampus and the ventricular zone of lateral ventricles. Numerous studies have investigated the relationship between sex steroid hormones and neurogenesis of adult brain; of which, mostly concentrated on the role of estradiol. It has been shown that estrogen plays a significant role in this process through both classic and non-classic mechanisms, including a variety of different growth factors. Therefore, the objective of this review is to investigate the role of female sex steroids with an emphasis on estradiol and also its potential implications for regulating the neurogenesis in the adult brain.

Neurogenesis was believed to end after the period of embryonic development. However, the possibility of obtaining an expressive number of cells with functional neuronal characteristics implied a great advance in experimental research. New techniques have emerged to demonstrate that the birth of new neurons continues to occur in the adult brain. Two main rich sources of these cells are the subventricular zone (SVZ) and the subgranular zone of the hippocampal dentate gyrus (SGZ) where adult neural stem cells (aNSCs) have the ability to proliferate and differentiate into mature cell lines. The cultivation of neurospheres is a method to isolate, maintain and expand neural stem cells (NSCs) and has been used extensively by several research groups to analyze the biological properties of NSCs and their potential use in injured brains from animal models. Throughout this review, we highlight the areas where this type of cell culture has been applied and the advantages and limitations of using this model in experimental studies for the neurological clinical scenario.

Objective The purpose of the present study is to investigate whether angiopoietin-like 4 (ANGPTL4) can promote angiogenesis and neurogenesis following stroke, as well as to explore the potential underlying mechanisms. Methods ANGPTL4 (40 μg/kg) or a vehicle was administered via tail vein beginning 5 min prior to electrocoagulation-induced stroke in male C57/B6 J mice. Infarct volume was measured via Nissl staining at day 3 post-stroke. Angiogenesis, neurogenesis and activation of microglia were evaluated by immunofluorescence co-labelling bromodeoxyuridine (BrdU) with von Willebrand factor (vWF), doublecortin (DCX), neuronal nuclei (NeuN) and Iba1 at day 7 post-stroke. The levels of p-AKT, T-AKT, VEGF, MPO, Fas and FasL in the ipsilesional brain were detected by Western blot analysis at day 1 post-stroke. Results Compared with the Vehicle group, ANGPTL4 reduced infarct volume significantly at day 3 post-stroke. ANGPTL4 significantly increased the number of BrdU+, BrdU+/vWF+and BrdU+/DCX+ cells in the peri-infarct zone, subventricular zone and subgranular zone and inhibited BrdU+/Iba1+ cells in the peri-infarct zone at day 7 post-stroke. The level of p-AKT and the ratio of phospho-AKT to total-AKT in the ipsilesional brain were significantly elevated, the levels of MPO, Fas and FasL were significantly declined; however, there was no significant difference at day 1 post-stroke between the VEGF and total-AKT levels in both groups. Conclusions ANGPTL4 enhances angiogenesis and neurogenesis post-stroke by upregulating the phosphorylation of AKT, reduces neuronal death and inhibits inflammatory response, which resultes from the inhibition of FasL/Fas expression and its downstream pathway.

The dentate gyrus (DG) is a unique brain structure in that neurons can be generated postnatally and integrated within existing circuitry throughout life. The maturation process of these newly generated neurons (granule cells) is modulated by nicotinic acetylcholine receptors (nAChRs) through a variety of mechanisms such as neural stem pool proliferation, cell survival, signal modulation, and dendritic integration. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, predominantly the α7 subtype, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined histological and behavioral effects of knocking out α7 nAChRs in GABAergic neurons. Deletion of α7 nAChRs resulted in a reduction of radial glia-like cells within the subgranular zone of the DG and a concomitant trend towards decreased immature neurons, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition and spatial learning. Overall, these findings suggest α7 nAChRs expressed in GABAergic neurons play an important role in regulating the adult neural stem cell pool and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

Background In the brain of adult mammals, neural stem cells persist in the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus, which are specialized niches with proliferative capacity. Most neural stem cells are in a quiescent state, but in response to extrinsic stimuli, they can exit from quiescence and become reactivated to produce new neurons, so neural stem cells are considered to be a potential source for cell replacement therapy of many nervous system diseases. We characterized the expression of Ndel1 during the differentiation of neural stem cells induced by hippocampus exosomes, and assessed the effect of Ndel1 on neural stem cells differentiation. Methods Hippocampal exosomes were isolated and extracted, and co-cultured exosomes with neural stem cells. Western blot, flow cytometry, and immunofluorescence analyses were used to analyze expression of neuronal markers. Further, utilizing high-throughput RNA sequencing technology, we found that nudE neurodevelopment protein 1-like 1 was significantly upregulated in exosomes derived from denervated hippocampus, and then characterized its mechanism and function during neural stem cells differentiation by qRT-PCR, western blot, flow cytometry, and immunofluorescence analyses. Results Our results revealed that exosomes of denervated hippocampus promoted the differentiation of neural stem cells into neuron. Hence, we identified that nudE neurodevelopment protein 1-like 1 was significantly upregulated and highly expressed in the nervous system. In addition, we found that miR-107-3p may regulate neural stem cell differentiation by targeting Ndel1. Conclusions Our results revealed that deafferentation of the hippocampal exosomes co-cultured with neural stem cells could promote them to differentiate into neurons. Hence, we found that miR-107-3p may regulate neural stem cells differentiation by targeting Ndel1. Importantly, Ndel1 enhanced spatial learning and hippocampal neurogenesis in rats after fimbria fornix transection in vivo. These findings set the stage for a better understanding of neurogenesis, a process that 1 day may inspire new treatments for central nervous system diseases.

Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short-term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long-lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36-44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain-derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety-like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba-1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro-BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long-lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal-dependent learning and memory in adolescence.

Neurogenesis process in the chronic phase of ischemic stroke has become the focus of research on stroke treatment recently, mainly through the activation of related pathways to increase the differentiation of neural stem cells (NSCs) in the brain sub-ventricular zone (SVZ) and subgranular zone (SGZ) of hippocampal dentate gyrus (DG) areas into neurons, promoting neurogenesis. While there is still debate about the longevity of active adult neurogenesis in humans, the SVZ and SGZ have the capacity to upregulate neurogenesis in response to cerebral ischemia, which opens discussion about potential treatment strategies to harness this neuronal regenerative response. Wnt signaling pathway is one of the most important approaches potentially targeting on neurogenesis after cerebral ischemia, appropriate activation of which in NSCs may help to improve the sequelae of cerebral ischemia. Various therapeutic approaches are explored on preclinical stage to target endogenous neurogenesis induced by Wnt signaling after stroke onset. This article describes the composition of Wnt signaling pathway and the process of neurogenesis after cerebral ischemia, and emphatically introduces the recent studies on the mechanisms of this pathway for post-stroke neurogenesis and the therapeutic possibility of activating the pathway to improve neurogenesis after stroke.

Summary The primary cilium is the non-motile cilium present in most mammalian cell types and functions as an antenna for cells to sense signals. Ablating primary cilia in postnatal newborn neurons of the dentate gyrus (DG) results in both reduced dendritic arborization and synaptic strength, leading to hippocampal-dependent learning and memory deficits. Fragile X syndrome (FXS) is a common form of inheritance for intellectual disabilities with a high risk for autism spectrum disorders, and Fmr1 KO mice, a mouse model for FXS, demonstrate deficits in newborn neuron differentiation, dendritic morphology, and memory formation in the DG. Here, we found that the number of primary cilia in Fmr1 KO mice is reduced, specifically in the DG of the hippocampus. Moreover, this cilia loss was observed postnatally mainly in newborn neurons generated from the DG, implicating that these primary ciliary deficits may possibly contribute to the pathophysiology of FXS., Graphical Abstract, Highlights • Primary cilia are significantly reduced in the DG of Fmr1 KO mice • Fmr1 KO mice show age-dependent primary cilia deficits • Neuronal ciliogenesis defects are shown in the DG of Fmr1 KO mice • Primary cilia deficits are observed in newborn neurons from SGZ, but not from DNe, In this article, Lee and colleagues show that Fmr1 KO mice, a mouse model for fragile X syndrome, have primary cilia deficits in the dentate gyrus (DG) found specifically in newborn neurons originating from the subgranular zone (SGZ) of the DG, but not in other hippocampal brain regions or from neurons originating from the dentate neuroepithelium (DNe).

Summary Active neural stem cells (aNSCs) and quiescent neural stem cells (qNSCs) are two distinct subpopulations found in the adult hippocampal dentate gyrus (DG). However, to date, no cell surface marker has been established to identify and profile qNSCs in the adult hippocampus. Here, we identified expression of vascular cell adhesion molecule 1 (VCAM1) on the cell surface of NSCs, through which we identified a previously unrecognized subpopulation of NSCs in the adult mouse DG. Interestingly, most VCAM1-expressing NSCs were largely quiescent. By injecting virus into Ai14 reporter mice to conduct lineage tracing in the adult DG, we confirmed that VCAM1-expressing cells were multipotent and capable of generating neurons and astrocytes. Furthermore, depletion of Vcam1 during the embryonic or adult stage impaired spatial learning and memory in mice, accompanied by a reduced number of radial glial-like cells and proliferating NSCs in the subgranular zone of Vcam1 knockout mice., Graphical Abstract, Highlights • VCAM1 expresses on the cell surface of qNSCs in adult hippocampus • VCAM1+ cells were multipotent and capable of generating neurons and astrocytes • Loss of VCAM1+ cells impaired spatial learning and memory in mice., In this article, Hu and colleagues show that VCAM1 expresses on the cell surface of qNSCs in adult hippocampus. These VCAM1-expressing NSCs were multipotent and capable of generating neurons and astrocytes. Loss of VCAM1-expressing NSCs during the embryonic or adult stage impaired spatial memory in mice, which indicates that VCAM1+ NSCs in the SGZ were critical for spatial learning and memory.

The subgranular zone of the dentate gyrus is a subregion of the hippocampus that has two uniquely defining features; it is one of the most active sites of adult neurogenesis as well as the location where the highest concentrations of synaptic zinc are found, the mossy fiber terminals. Therefore, we sought to investigate the idea that vesicular zinc plays a role as a modulator of hippocampal adult neurogenesis. Here, we used ZnT3 −/− mice, which are depleted of synaptic‐vesicle zinc, to test the effect of targeted deletion of this transporter on adult neurogenesis. We found that this manipulation reduced progenitor cell turnover as well as led to a marked defect in the maturation of newborn cells that survive in the DG toward a neuronal phenotype. We also investigated the effects of zinc (ZnCl2), n‐acetyl cysteine (NAC), and ZnCl2 plus 2NAC (ZN) supplement on adult hippocampal neurogenesis. Compared with ZnCl2 or NAC, administration of ZN resulted in an increase in proliferation of progenitor cells and neuroblast. ZN also rescued the ZnT3 loss‐associated reduction of neurogenesis via elevation of insulin‐like growth factor‐1 and ERK/CREB activation. Together, these findings reveal that ZnT3 plays a highly important role in maintaining adult hippocampal neurogenesis and supplementation by ZN has a beneficial effect on hippocampal neurogenesis, as well as providing a therapeutic target for enhanced neuroprotection and repair after injury as demonstrated by its ability to prevent aging‐dependent cognitive decline in ZnT3 −/− mice. Therefore, the present study suggests that ZnT3 and vesicular zinc are essential for adult hippocampal neurogenesis., This study utilized ZnT3 −/− mice with a genetic loss‐of‐function approach to investigate the consequences of vesicular zinc depletion in adult hippocampal neurogenesis. We found that ZnT3 −/− mice displayed reduced hippocampal neurogenesis under physiological conditions even at 3 months of age. We also found that administration of ZnCl2 plus 2NAC (ZN) not only reversed the ZnT3 loss‐associated reduction of neurogenesis, but also improved aging‐dependent cognitive decline in ZnT3 −/− mice.

Urodeles and some fishes possess a remarkable capacity to regenerate their limbs/fins, a property that correlates with their additional ability to regenerate large areas of the brain and/or produce a variety of new neurons during adulthood. In contrast, neurogenesis in adult mammals is apparently restricted to two main regions, the subventricular zone of lateral ventricles and the subgranular zone of the hippocampus. There, astrocyte-like neural stem cells (NSCs) reside and derive into new neurons. Although it is becoming apparent that other brain regions carry out neurogenesis, in many cases, its functional significance is controversial, particularly, because very few putative NSCs capable of deriving into new neurons have been found. Hence, is renewal of certain neurons a requirement for a healthy brain? Are there specific physiological conditions that stimulate neurogenesis in a particular region? Does the complexity of the brain demand reduced neurogenesis? In this study, we review the production of new neurons in the vertebrate adult brain in the context of a possible functional relevance. In addition, we consider the intrinsic properties of potential cellular sources of new neurons, as well as the contribution of the milieu surrounding them to estimate the reparative capacity of the brain upon injury or a neurodegenerative condition. The conclusion of this review should bring into debate the potential and convenience of promoting neuronal regeneration in the adult human brain.

The hippocampus is characterized by the presence of life-long neurogenesis. To elucidate the molecular mechanism regulating hippocampal neurogenesis, we studied the functions of the chemorepellent Draxin in neuronal proliferation and differentiation in the postnatal dentate gyrus. The present in vivo cell labeling and fate tracking analyses revealed enhanced differentiation of hippocampal neural stem and progenitor cells (hNSPCs) in the subgranular zone (SGZ) of Draxin-deficient mice. We observed a reduction in the number of BrdU-pulse labeled or Ki-67 immunopositive SGZ cells in the mutant mice. However, Draxin deficiency did not affect cell cycle duration of SGZ cells. In situ hybridization analysis indicated that the receptor component of the canonical Wnt pathway, Lrp6, is expressed in SGZ cells, including Nestin and Sox2 double-positive hNSPCs. Taken together with the previous finding that Draxin interacts physically with Lrp6, we postulate that Draxin plays a pivotal role in the regulation of Wnt-driven hNSPC differentiation to modulate the rate of neuronal differentiation in the progenitor population.

Midazolam, a widely used anesthetic, inhibits proliferation of neural stem cells (NSCs) and induces neuroapoptosis in neonates. Dexmedetomidine, an effective auxiliary medicine in clinical anesthesia, protects the developing brain against volatile anesthetic-induced neuroapoptosis. Whether dexmedetomidine protects against neurogenesis damage induced by midazolam remains unknown. This study aims to clarify the protective effect of dexmedetomidine on midazolam-induced neurogenesis damage and explore its potential mechanism. Postnatal 7-day-old Sprague-Dawley (SD) rats and cultured NSCs were treated with either normal saline, midazolam, or dexmedetomidine combined with midazolam. The rats were sacrificed at 1, 3, and 7 days after treatment. Cell proliferation was assessed by 5-bromodeoxyurdine (BrdU) incorporation. Cell viability was determined using MTT assay. Cell differentiation and apoptosis were detected by immunofluorescent staining and terminal dUTP nick-end labeling (TUNEL), respectively. The protein levels of p-JNK, p-P38, and cleaved caspase-3 were quantified using Western blotting. Midazolam decreased cell proliferation and increased cell apoptosis in the subventricular zone (SVZ), the subgranular zone (SGZ) of the hippocampus, and cultured NSCs. Moreover, midazolam decreased cell viability and increased the expression of p-JNK and p-P38 in cultured NSCs. Co-treatment with dexmedetomidine attenuated midazolam-induced changes in cell proliferation, viability, apoptosis, and protein expression of p-JNK and p-P38 in cultured NSCs. Midazolam and dexmedetomidine did not affect the differentiation of the cultured NSCs. These results indicate that dexmedetomidine alleviated midazolam-induced neurogenesis damage via JNK and P38 MAPK pathways.

Microtubule severing regulates cytoskeletal rearrangement underlying various cellular functions. Katanin, a heterodimer, consisting of catalytic (p60) and regulatory (p80) subunits severs dynamic microtubules to modulate several stages of cell division. The role of p60 katanin in the mammalian brain with respect to embryonic and adult neurogenesis is poorly understood. Here, we generated a Katna1 knockout mouse and found that consistent with a critical role of katanin in mitosis, constitutive homozygous Katna1 depletion is lethal. Katanin p60 haploinsufficiency induced an accumulation of neuronal progenitors in the subventricular zone during corticogenesis, and impaired their proliferation in the adult hippocampus dentate gyrus (DG) subgranular zone. This did not compromise DG plasticity or spatial and contextual learning and memory tasks employed in our study, consistent with the interpretation that adult neurogenesis may be associated with selective forms of hippocampal-dependent cognitive processes. Our data identify a critical role for the microtubule-severing protein katanin p60 in regulating neuronal progenitor proliferation in vivo during embryonic development and adult neurogenesis.

Stroke consists of an abrupt reduction of cerebral blood flow resulting in hypoxia that triggers an excitotoxicity, oxidative stress, and neuroinflammation. After the ischemic process, neural precursor cells present in the subventricular zone of the lateral ventricle and subgranular zone of the dentate gyrus proliferate and migrate towards the lesion, contributing to the brain repair. The neurogenesis is induced by signal transduction pathways, growth factors, attractive factors for neuroblasts, transcription factors, pro and anti-inflammatory mediators and specific neurotransmissions. However, this endogenous neurogenesis occurs slowly and does not allow a complete restoration of brain function. Despite that, understanding the mechanisms of neurogenesis could improve the therapeutic strategies for brain repair. This review presents the current knowledge about brain repair process after stroke and the perspectives regarding the development of promising therapies that aim to improve neurogenesis and its potential to form new neural networks.

BACKGROUND Multiple ethanol binge drinking-like exposures during adolescence in rat induce neuroinflammation, neurogenesis loss and cognitive deficits at adulthood. Interestingly, the very first ethanol binge drinking-like exposures during adolescence also induce cognitive and synaptic plasticity impairments in the hippocampus at short term while the cellular mechanisms of these effects remain unclear. Here, we sought to determine which of the cellular effects of ethanol might play a role in cognitive and synaptic plasticity disturbances observed in adolescent male rat after only two binge-like ethanol exposures. METHODS Using immunochemistry, we determined neurogenesis, neuronal loss, astrogliosis, neuroinflammation and synaptogenesis in the hippocampus of adolescent rat 48h after two binge-like ethanol exposures (3 g/kg, i.p, 9 hours apart). Flow cytometry was used to analyze activated microglia and to identify the TLR4 expressing cell types. RESULTS Increased DCX immunoreactivity was detected in the subgranular zone (SGZ) of the dentate gyrus (DG) together with astrogliosis in the SGZ and a lower number of mature neurons in the DG and in CA3, suggesting compensatory neurogenesis. Synaptic density decreased in the stratum oriens of CA1 revealing structural plasticity. There was no change in microglial TLR4 expression nor in the number of activated microglia, suggesting a lack of neuroinflammatory processes although neuronal TLR4 was decreased in CA1 and DG. CONCLUSIONS Our findings demonstrate that the cognitive deficits associated with hippocampal synaptic plasticity alterations that we previously characterized 48h after the very first binge-like exposures are associated with hippocampal structural plasticity, astrogliosis and decreased neuronal TLR4 expression, but not with microglia reactivity.

Cadmium (Cd) is a toxic heavy metal and a significant public health concern. Epidemiological studies suggest that Cd is a potential neurotoxicant, and its exposure is associated with cognitive deficits in children, adults, and seniors. Our previous study has found that adulthood-only Cd exposure can impair cognition in mice. However, few studies have addressed the effects of Cd exposure during adolescence on cognitive behavior in animals later in life. In the present study, we exposed 4-week-old male C57BL/6 mice to 3 mg/L Cd via drinking water for 28 weeks and assessed their hippocampus-dependent learning and memory. Cd did not affect anxiety or locomotor activity in the open field test. However, Cd exposure impaired short-term spatial memory and contextual fear memory in mice. A separate cohort of 4-week-old mice was similarly exposed to Cd for 13 weeks to investigate the potential mechanism of Cd neurotoxicity on cognition. We observed that Cd-treated mice had fewer adult-born cells, adult-born neurons, and a reduced proportion of adult-born cells that differentiated into mature neurons in the subgranular zone of the dentate gyrus. These results suggest that Cd exposure from adolescence to adulthood is sufficient to cause cognitive deficits and impair key processes of hippocampal neurogenesis in mice.

The subgranular zone of the dentate gyrus provides a local microenvironment (niche) for neural stem cells. In the adult brain, it has been established that the vascular compartment of such niches has a significant role in regulating adult hippocampal neurogenesis. More recently, evidence showed that neurovascular coupling, the relationship between blood flow and neuronal activity, also regulates hippocampal neurogenesis. Here, we review the most recent articles on addressing the intricate relationship between neurovasculature and adult hippocampal neurogenesis and a novel pathway where functional hyperemia enhances hippocampal neurogenesis. In the end, we have further reviewed recent research showing that impaired neurovascular coupling may cause declined neurogenesis and contribute to brain damage in neurodegenerative diseases.

Background The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental agonists and dietary tryptophan metabolites for the immune response and cell cycle regulation. Emerging evidence suggests that AHR activation after acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown. Methods We adopted conditional knockout of AHR from nestin-expressing neural stem/progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist 6,2′,4′-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined at 2 and 7 days after MCAO. Results The AHR signaling pathway was significantly upregulated after stroke. Both TMF-treated WT and AHRcKO mice showed significantly decreased infarct volume, improved sensorimotor, and nonspatial working memory functions compared with their respective controls. AHR immunoreactivities were increased predominantly in activated microglia and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis. Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone. At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-treated and AHRcKO mice demonstrated downregulated IL-1β, IL-6, IFN-γ, CXCL1, and S100β, and concomitantly upregulated Neurogenin 2 and Neurogenin 1. Conclusion Neural cell-specific AHR activation following acute ischemic stroke increased astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving neurogenesis.

The brain has long been considered a site of "immune privilege"; however, recent evidence indicates the presence of brain-immune interactions in physiological and pathological conditions. Neurogenesis, a process of generating functionally integrated neurons, occurs in the adult brain of mammals. The adult neurogenesis predominantly takes place in the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ). Several studies have shown that an immune reaction or alteration could affect adult neurogenesis activity, suggesting a link between the immune system and adult neurogenesis. Helminth infection is one of the activators of Th2 immune response. However, the influence of this type of immune reaction on adult neurogenesis is not well studied. In this study, we evaluated adult neurogenesis in mice infected with the helminth Nippostrongylus brasiliensis (Nb). Immunohistochemically, the number of both doublecortin-positive cells and doublecortin/5-bromodeoxyuridine (BrdU)-double-positive cells was decreased in the SGZ of Nb-infected mice by day 9 after infection. However, the total number of BrdU-positive newborn cells in the SGZ did not change. In no significant alterations were detected in the SVZ of infected mice. In addition, using reverse transcription-quantitative polymerase chain reaction, we observed no significant changes in the expression levels of neurotropic factors important for neurogenesis in the hippocampus. In conclusion, our results indicate that adult neurogenesis in SGZ, but not in SVZ, is inhibited by Nb infection. Th2 immune response might have a suppressive effect on hippocampal neurogenesis.

Exposure to commonly used anesthetics is associated with widespread neuroapoptosis in neonatal animals. Vulnerability of developing hippocampal dentate gyrus granule cells to anesthetic neurotoxicity peaks approximately 2 weeks after cell birth, as measured by bromodeoxyuridine birth dating, regardless of the age of the animal. The present study examined whether the vulnerable window can be further characterized by utilizing a transgenic approach. Proopiomelanocortin enhanced green fluorescent protein (POMC-EGFP) mice (postnatal day 21) were exposed to 3% sevoflurane for 6 h. Following exposure, cleaved caspase 3, expression of EGFP and differential maturational markers were quantified and compared with unanesthetized littermates. Electrophysiological properties of EGFP+ and EGFP− cells in the subgranular zone and the inner half of the granule cell layer were recorded by whole-cell patch-clamp. We found that sevoflurane significantly increased apoptosis of POMC-EGFP+ granule cells that accounted for approximate 1/3 of all apoptotic cells in dentate gyrus. Apoptotic EGFP− granule cells more frequently expressed the immature neuronal marker calretinin (75.4% vs 45.0%, P

Macroautophagy/autophagy is generally regarded as a cytoprotective mechanism, and it remains a matter of controversy whether autophagy can cause cell death in mammals. Here, we show that chronic restraint stress suppresses adult hippocampal neurogenesis in mice by inducing autophagic cell death (ACD) of hippocampal neural stem cells (NSCs). We generated NSC-specific, inducible Atg7 conditional knockout mice and found that they had an intact number of NSCs and neurogenesis level under chronic restraint stress and were resilient to stress- or corticosterone-induced cognitive and mood deficits. Corticosterone treatment of adult hippocampal NSC cultures induced ACD via SGK3 (serum/glucocorticoid regulated kinase 3) without signs of apoptosis. Our results demonstrate that ACD is biologically important in a mammalian system in vivo and would be an attractive target for therapeutic intervention for psychological stress-induced disorders. Abbreviations: AAV: adeno-associated virus; ACD: autophagic cell death; ACTB: actin, beta; Atg: autophagy-related; ASCL1/MASH1: achaete-scute family bHLH transcription factor 1; BafA1: bafilomycin A1; BrdU: Bromodeoxyuridine/5-bromo-2ʹ-deoxyuridine; CASP3: caspase 3; cKO: conditional knockout; CLEM: correlative light and electron microscopy; CORT: corticosterone; CRS: chronic restraint stress; DAB: 3,3ʹ–diaminobenzidine; DCX: doublecortin; DG: dentate gyrus; GC: glucocorticoid; GFAP: glial fibrillary acidic protein; HCN: hippocampal neural stem; i.p.: intraperitoneal; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MKI67/Ki67: antigen identified by monoclonal antibody Ki 67; MWM: Morris water maze; Nec-1: necrostatin-1; NES: nestin; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NSC: neural stem cell; PCD: programmed cell death; PFA: paraformaldehyde; PX: Phox homology; PtdIns3P: phosphatidylinositol-3-phosphate; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; SGK: serum/glucocorticoid-regulated kinases; SGZ: subgranular zone; SOX2: SRY (sex determining region Y)-box 2; SQSTM1: sequestosome 1; STS: staurosporine; TAM: tamoxifen; Ulk1: unc-51 like kinase 1; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VIM: vimentin; WT: wild type; ZFYVE1: zinc finger, FYVE domain containing 1; Z-VAD/Z-VAD-FMK: pan-caspase inhibitor

Our recent study has shown that acute fasting produces antidepressant‐like effects in male mice. However, there is little evidence regarding the antidepressant‐like effects of acute fasting in female mice. Moreover, it is not yet clear whether estrogen produces additive effects with acute fasting. Therefore, this study aims to investigate the antidepressant‐like effects of acute fasting plus estrogen treatment. In this study, the acute fasting produced antidepressant‐like effects in female mice and the antidepressant‐like effects of 9 hours fasting with those of β‐estradiol (E2) were additive. Activity of the cyclic adenosine monophosphate (cAMP) response element‐binding protein (CREB)‐brain‐derived neurotrophic factor (BDNF) pathway in the prefrontal cortex (PFC) and hippocampus (HP) was increased, as well as neurogenesis in the subgranular zone of the hippocampus. Serum ghrelin and estrogen were also increased by fasting plus E2. Furthermore, RNA‐seq analysis indicated that fasting and E2 co‐regulate similar gene expression pathways, underlying similar neurological functions. Taken together, these data suggest that E2 produces additive antidepressant‐like effects with fasting by activating the CREB‐BDNF pathway in the PFC and HP. Genome‐wide transcriptome mapping suggests that fasting may be used as an adjunct to estrogen replacement therapy for the treatment of depression associated with reduced estrogen function.

This review focuses on the anti-dementia and antidepressant-like effects of peptides including glucagon-like peptide (GLP)-1, GLP-2, neuromedin U (NmU), and oxytocin, and the intranasal delivery of these peptides to the brain. Intracerebroventricularly administered GLP-1, NmU, and oxytocin improved impairment of learning and memory in mice treated with lipopolysaccharide or β-amyloid protein. GLP-1 also improved impairment of learning and memory in juvenile diabetes model rats. On the other hand, GLP-2 exhibited antidepressant-like effects in mice during the forced-swim test, which were associated with 5-HT1A, α2, β1, and D2 receptors. GLP-2 also exerted antidepressant-like effects in adrenocorticotropic hormone (ACTH)-treated mice through restoration of the hypothalamic-pituitary-adrenal-axis and neurogenesis in the subgranular zone of the dentate gyrus. Because intracerebroventricular administration is invasive and the peptides are unable to penetrate the blood-brain barrier, we introduced our new method of intranasal administration to deliver the peptides to the brain. We prepared a GLP-2 derivative containing cell-penetrating peptides (CPPs) and a penetration accelerating sequence (PAS). Intranasally administered PAS-CPPs-GLP-2 was distributed throughout the brain, and exhibited antidepressant-like effects in both naive and ACTH-treated mice. The derivatives of GLP-1, NmU, and oxytocin with the PAS and CPPs were also distributed throughout the brain after intranasal administration, and improved impairment of learning and memory. We confirmed that our peptide derivatives were effectively delivered into the brain by intranasal administration. As such, these derivatives may be useful for the clinical treatment of psychiatric and neurological diseases.

Adult neurogenesis in mammals is a tightly regulated process where neural stem cells (NSCs), especially in the subgranular zone (SGZ) of the hippocampal dentate gyrus, proliferate and differentiate into new neurons that form new circuits or integrate into old circuits involved in episodic memory, pattern discrimination, and emotional responses. Recent evidence suggests that changes in the hyaluronan (HA)-based extracellular matrix of the SGZ may regulate neurogenesis by controlling NSC proliferation and early steps in neuronal differentiation. These studies raise the intriguing possibility that perturbations in this matrix, including HA accumulation with aging, could impact adult neurogenesis and cognitive functions, and that alterations to this matrix could be beneficial following insults to the central nervous system that impact hippocampal functions.

Neural proliferation in the dentate gyrus (DG) is closely linked with learning and memory, but the transcriptional programming that drives adult proliferation remains incompletely understood. Our lab previously elucidated the critical role of the transcription factor ΔFosB in the dorsal hippocampus (dHPC) in learning and memory, and the FosB gene has been suggested to play a role in neuronal proliferation. However, the subregion-specific and potentially cell-autonomous role of dHPC ΔFosB in neurogenesis-dependent learning has not been studied. Here, we crossed neurotensin receptor-2 (NtsR2) Cre mice, which express Cre within the subgranular zone (SGZ) of dHPC DG, with floxed FosB mice to show that knockout of ΔFosB in hippocampal SGZ neurons reduces antidepressant-induced neurogenesis and impedes hippocampus-dependent learning in the novel object recognition task. Taken together, these data indicate that FosB gene expression in SGZ is necessary for both hippocampal neurogenesis and memory formation.

Valproic acid (VPA) is widely used in the treatment of epilepsy. However, VPA has been revealed to impair memory of both humans and animals. The adverse effects of VPA are associated with reductions in hippocampal neurogenesis and memory. There are neuroprotective properties exerted by melatonin. Therefore, we investigated the protective effects of melatonin against the reductions of memory and neurogenesis caused by VPA. Male Sprague–Dawley rats received VPA (300 mg/kg) twice a day for 14 days, or melatonin (8 mg/kg/day) for 14 days, or co-treatment with VPA and melatonin for either 14 days (preventive and recovery groups) or 28 days (throughout group). Novel object location and novel object recognition tests were used to assess spatial memory and non-spatial memory, respectively. Proliferation, survival, and immature neurons in the subgranular zone (SGZ) were examined using immunohistochemistry. Rats showed decreases in proliferation, survival, and immature neurons in the SGZ, which were related to impairments in spatial and non-spatial memory. These behavioral changes were prevented by co-administration with melatonin. In addition, the decreasing of the hippocampal neurogenesis was improved to control levels, which had received co-administration with melatonin (preventive, recovery, and throughout). It is noteworthy that rats receiving melatonin alone showed a significant diversity of proliferation, survival and immature neurons compared to the control rats. These findings suggest that melatonin is able to prevent the spatial and non-spatial memory impairments and a reduction in hippocampal neurogenesis simultaneously induced by VPA. Our results provide a feasible way to prevent this loss using melatonin.

The aim of the study was to evaluate the impact of second generation antiepileptic drug levetiracetam (LEV) with arachidonyl-2′-chloroethylamide (ACEA) on proliferating neural precursor cells in mouse brain. Additionally, we established the relationship between treatment with ACEA in combination with LEV and hippocampal neurogenesis in mouse brain. All experiments were performed on male CB57/BL mice injected i.p. with LEV (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) for 10 days. Experiments were provided in two stages: stage 1- an acute response of proliferating neural precursor cells to ACEA and LEV administration (Ki-67 staining), stage 2 – a long term response to ACEA and LEV administration (BrDU, NeuN, GFAP staining). Results indicate that ACEA + PMSF and ACEA + PMSF + LEV significantly increased the total number of Ki-67 positive cells comparing to the control group. PMSF and LEV administered alone and in combination had no significant impact on cell proliferation compared to the control group. Results from neurogenesis study indicated that ACEA + PMSF administered alone and in combination with LEV increased the total number of BrDU cells compared to the control group, although LEV on its own decreased the number of BrDU cells. Moreover, the combination of ACEA + PMSF + LEV significantly increased the total number of newborn neurons compared to the control group. In turn, LEV significantly decreased the process of neurogenesis. Astrocytes were considerably reduced in all treated groups as compare to the control mice. These data provide substantial evidence that LEV administered chronically decreases the proliferation and differentiation of newly born cells while combination of LEV + ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.

Neonatal hypoxic–ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi—sodium butyrate (SB)—would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia–ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor—CREB—in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF–TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia–ischemia.

New neurons are continuously generated in the adult brain. This generation primarily occurs in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. In the SGZ, neural stem cells (NSCs) give rise to glutamatergic granule cells that integrate into the hippocampal circuitry. Reduction of neurogenesis in the hippocampus impairs learning and memory, which suggests that this process is important for adult hippocampal function. Indeed, the neurogenesis is reduced in the progression of aging, which is thought to contribute to age-related cognitive impairment. Although the mechanism of age-dependent decline in neurogenesis remains largely obscure, astrocytes are thought to play a vital role in regulating NSC proliferation and differentiation. Both astrocytes and NSCs secrete nucleotides to the extracellular space and extracellular nucleotides bind to their receptors on the surface of target cells. In this review, the recent knowledge on adult neurogenesis in the hippocampus is summarized briefly, and possible role of extracellular nucleotides in the age-dependent changes of the adult neurogenesis is discussed.

According to the previous research, metformin, a medication utilized for type 2 diabetes management, inhibits neural aging and reduces infarct size by enhancing angiogenesis in a mouse stroke model. What is more, metformin administration also promotes neural precursor cells proliferation, migration, as well as differentiation for newborn mice with hypoxia-ischemia brain injury. However, whether metformin regulates neurogenesis in an adult rat ischemia/reperfusion (I/R) model remains unclear. The current research found that metformin administration reduced neuronal damage in the CA1 area of hippocampus in a rat model of I/R. The number of neuronal nuclei positive neuron was significantly increased and glial fibrillary acidic protein positive astrocyte became obviously declined in the CA1 region in I/R rats treated with metformin. It was further demonstrated that metformin promoted neuroblasts proliferation and neuronal differentiation in the subgranular zone of the dentate gyrus and inhibited the formation of astrocyte. Our study indicates that activation of endogenous neuroblasts using metformin will become a favorable target in therapeutic intervention of cerebral ischemia injury models.

Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H2O2, the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4-/- mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4-/- mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4-/- animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4-/- mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function.

Mounting evidence in the literature suggests that RNA-RNA binding protein aggregations can disturb neuronal homeostasis and lead to symptoms associated with normal aging as well as dementia. The specific ablation of cyclin A2 in adult neurons results in neuronal polyribosome aggregations and learning and memory deficits. Detailed histologic and ultrastructural assays of aged mice revealed that post-mitotic hippocampal pyramidal neurons maintain cyclin A2 expression and that proliferative cells in the dentate subgranular zone express cyclin A2. Cyclin A2 loss early during neural development inhibited hippocampal development through canonical/cell-cycle mechanisms, including prolonged cell cycle timing in embryonic hippocampal progenitor cells. However, in mature neurons, cyclin A2 colocalized with dendritic rRNA. Cyclin A2 ablation in adult hippocampus resulted in decreased synaptic density in the hippocampus as well as in accumulation of rRNA granules in dendrite shafts. We conclude that cyclin A2 functions in a noncanonical/non-cell cycle regulatory role to maintain adult pyramidal neuron ribostasis.

It is established that neural stem cells (NSC) reside in the hippocampal subgranular zone (SGZ) and contribute to neurogenesis throughout life. Although the molecular events that regulate hippocampal neural stem cell differentiation are known, the precise mechanism is undefined. Here, the role of growth arrest specific 7 (Gas7) protein in SGZ neural progenitor cell differentiation was studied. Immunoblotting and immunohistochemistry for Gas7 were performed on 12 weeks old mice hippocampus. The results displayed a strong signal for Gas7 protein in the mice hippocampal tissue and SGZ cells, therefore suggesting that Gas7 might have a role in neural progenitor cell differentiation in SGZ.

Traumatic brain injury is an important cause of mortality and morbidity all over the world. After the initial injury there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim not only to counteract these mechanisms but also to replenish the lost cell population in order to achieve a better recovery. The adult mammal brain in not as plastic as the postnatal, but it has at least two neurogenic regions that maintains physiological functions in the brain; the subgranular zone of the dentate gyrus of the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) of the lateral ventricles, that produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs. Brain injuries, as well as neurodegenerative diseases, induce the SVZ to respond by increasing cell proliferation and migration to the injured areas. Here we report that SVZ cells migrate to the injured cortex after traumatic brain injury in mice, and that the physiological RMS migration is not impaired. We also show that Prokineticin 2 (PROK2), a chemokine important for the olfactory bulb neurogenesis by promoting the directional migration of neuroblasts, is induced in the injured cortex. Using PROK2 receptor antagonist and recombinant PROK2 we show for the first time that PROK2 can directionally attract SVZ cells in vitro and in vivo. The data we present here links one more element of the inflammatory process, PROK2 secreted by microglia, to the attempt to regenerate an acutely injured mammalian cortex.AbbreviationsSGZsubgranular zoneSVZsubventricular zoneRMSrostral migratory streamPROK2Prokineticin 2

HIF-1α is a hypoxia-inducible protein that regulates many cellular processes, including neural stem cell maintenance. Previous work demonstrated constitutive stabilization of HIF-1α in neural stem cells (NSCs) of the adult mouse subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Genetic inactivation of NSC-encoded HIF-1α in the adult SVZ results in gradual loss of NSCs, but whether HIF-1α is required for the maintenance of SGZ hippocampal progenitors and adult hippocampal neurogenesis has not been determined. Here we tested the hypothesis that HIF-1α plays an essential role in the maintenance of adult hippocampal neurogenesis using Nestin-CreER(T2)/R26R-YFP/Hif1a(fl/fl) triple transgenic mice, in which HIF-1α was genetically inactivated in nestin(+) hippocampal progenitors and their downstream progeny following tamoxifen exposure. We found that disruption of HIF-1α gene expression resulted in a marked 50% reduction of adult-generated dentate granule cells (DGCs) that was highly correlated with impaired hippocampal function, as assessed using two behavioral assays of pattern discrimination. These behavioral tests included the A-B contextual fear-conditioning task and the trial-unique, delayed nonmatching-to-location (TUNL) touch-screen operant chamber task. Our findings identify HIF-1α as a novel regulator of adult hippocampal neurogenesis under non-pathological conditions, and underscore the importance of neurogenesis for pattern discrimination learning.

Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30did not affect paired-pulse facilitation, IH30suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30increased the number of proliferating Sox2+neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.SIGNIFICANCE STATEMENTIndividuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.

Exposure to sterigmatocystin (STC) raises concerns on developmental neurological disorders. The present study investigated the effects of maternal oral STC exposure on postnatal hippocampal neurogenesis of offspring in rats. Dams were exposed to STC (1.7, 5.0, and 15.0 ppm in diet) from gestational day 6 until day 21 post-delivery (weaning), and offspring were maintained without STC exposure until adulthood on postnatal day (PND) 77, in accordance with OECD chemical testing guideline Test No. 426. On PND 21, 15.0-ppm STC decreased type-3 neural progenitor cell numbers in the subgranular zone (SGZ) due to suppressed proliferation. Increased γ-H2AX-immunoreactive (+) cell numbers in the SGZ and Ercc1 upregulation and Brip1 downregulation in the dentate gyrus suggested induction of DNA double-strand breaks in SGZ cells. Upregulation of Apex1 and Ogg1 and downregulation of antioxidant genes downstream of NRF2-Keap1 signaling suggested induction of oxidative DNA damage. Increased p21WAF1/CIP1+ SGZ cell numbers and suppressed cholinergic signaling through CHRNB2-containing receptors in GABAergic interneurons suggested potential neurogenesis suppression mechanisms. Multiple mechanisms involving N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic signaling and various GABAergic interneuron subpopulations, including CHRNA7-expressing somatostatin+ interneurons activated by BDNF-TrkB signaling, may be involved in ameliorating the neurogenesis. Upregulation of Arc, Ptgs2, and genes encoding NMDA receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors suggested synaptic plasticity facilitation. On PND 77, ARC+ granule cells decreased, and Nos2 was upregulated following 15.0 ppm STC exposure, suggesting oxidative stress-mediated synaptic plasticity suppression. Inverse pattern in gene expression changes in vesicular glutamate transporter isoforms, Slc17a7 and Slc17a6, from weaning might also be responsible for the synaptic plasticity suppression. The no-observed-adverse-effect level of maternal oral STC exposure for offspring neurogenesis was determined to be 5.0 ppm, translating to 0.34-0.85 mg/kg body weight/day.

Neuron-restrictive silencing factor (NRSF) is a zinc-finger transcription factor that regulates expression of a diverse set of genes. However, NRSF function in brain development still remains elusive. In the present study, we generated NRSF-conditional knockout (NRSF-cKO) mice by hGFAP-Cre/loxp system to study the effect of NRSF deficiency on brain development. Results showed that NRSF conditional knockout caused a smaller hippocampus and a thinner granule cell layer (GCL) in mice. Moreover, the reduction and disarrangement of GFAP+ cells in subgranular zone (SGZ) of NRSF-cKO mice was accompanied with the decreased number of premature neurons, neural stem cells (NSCs) and neural progenitor cells (NPCs), as well as compromising the majority of mitotically active cells. The analysis of postnatal development of hippocampus indicated the existence of an abnormality at postnatal day (P) 8, rather than at P1, in NRSF-cKO mice, although the densities of Ki67+ cells with mitotic ability in dentate gyrus were relatively unaffected at P1 and P8. Meanwhile, NRSF deficiency led to abnormal organization of SGZ at P8 during postnatal development. RNA-Seq analysis revealed 79 deregulated genes in hippocampus of NRSF-cKO mice at P8, which were involved in p53 signal transduction, neuron migration and negative regulation of cell proliferation, etc. The deregulation of p53 pathway in NRSF-cKO mice at P1 and P8 was evidenced, of which p21/Cdkn1a was accumulated in a portion of NSCs and NPCs in hippocampus during postnatal development. Together, these results, for the first time, revealed that NRSF could significantly influence the postnatal development of hippocampus, especially the formation of SGZ.

Postnatal and adult neurogenesis in the subventricular zone and subgranular zone of animals such as rodents and non-human primates has been observed with many different technical approaches. Since most techniques used in animals cannot be used in humans, the majority of human neurogenesis studies rely on postmortem immunohistochemistry. This technique is difficult in human tissue, due to poor and variable preservation of antigens and samples. Nevertheless, a survey of the literature reveals that most published studies provide evidence for childhood and adult neurogenesis in the human brain stem cell niches. There are some conflicting results even when assessing the same markers and when using the same antibodies. Focusing on immunohistochemical studies on post-mortem human sections, we discuss the relative robustness of the literature on adult neurogenesis. We also discuss the response of the subventricular and subgranular zones to human disease, showing that the two niches can respond differently and that the stage of disease impacts neurogenesis levels. Thus, we highlight strong evidence for adult human neurogenesis, discuss other work that did not find it, describe obstacles in analysis, and offer other approaches to evaluate the neurogenic potential of the subventricular and subgranular zones of Homo sapiens. This article is categorized under: Neurological Diseases > Stem Cells and Development Reproductive System Diseases > Stem Cells and Development.