Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo

Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po₂ values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po₂ levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.     

Radical pairs may explain reactive oxygen species-mediated effects of hypomagnetic field on neurogenesis

Exposures to a hypomagnetic field can affect biological processes. Recently, it has been observed that hypomagnetic field exposure can adversely affect adult hippocampal neurogenesis and hippocampus-dependent cognition in mice. In the same study, the role of reactive oxygen species (ROS) in hypomagnetic field effects has been demonstrated. However, the mechanistic reasons behind this effect are not clear. This study proposes a radical pair mechanism based on a flavin-superoxide radical pair to explain the modulation of ROS production and the attenuation of adult hippocampal neurogenesis in a hypomagnetic field. The results of our calculations favor a singlet-born radical pair over a triplet-born radical pair. Our model predicts hypomagnetic field effects on the triplet/singlet yield of comparable strength as the effects observed in experimental studies on adult hippocampal neurogenesis. Our predictions are in qualitative agreement with experimental results on superoxide concentration and other observed ROS effects. We also predict the effects of applied magnetic fields and oxygen isotopic substitution on adult hippocampal neurogenesis.     

Inflammation mediates varying effects in neurogenesis: relevance to the pathogenesis of brain injury and neurodegenerative disorders

Brain inflammation is a complex cellular and molecular response to stress, injury or infection of the CNS in attempt to defend against insults, clear dead and damaged neurons and return the CNS to a normal state. Inflammation in the CNS is driven by the activation of resident microglia, astrocytes and infiltrating peripheral macrophages, which release a plethora of anti- and pro-inflammatory cytokines, chemokines, neurotransmitters and reactive oxygen species. This inflammatory state inadvertently causes further bystander damage to neurons and produces both detrimental and favorable conditions for neurogenesis. Inflammatory factors have varying effects on neural progenitor cell proliferation, migration, differentiation, survival and incorporation of newly born neurons into the CNS circuitry. The unique profile of inflammatory factors, which depends on the severity of inflammation, can have varying consequences on neurogenesis. Inflammatory factors released during mild acute inflammation usually stimulate neurogenesis; where as the factors released by uncontrolled inflammation create an environment that is detrimental to neurogenesis. This review will provide a summary of current progress in this emerging field and examine the potential mechanisms through which inflammation affects neurogenesis during neurological complications.     

Exosomes from human urine‐derived stem cells enhanced neurogenesis via miR‐26a/HDAC6 axis after ischaemic stroke

Endogenous neurogenesis holds promise for brain repair and long‐term functional recovery after ischaemic stroke. However, the effects of exosomes from human urine‐derived stem cells (USC‐Exos) in neurogenesis remain unclear. This study aimed to investigate whether USC‐Exos enhanced neurogenesis and promoted functional recovery in brain ischaemia. By using an experimental stroke rat model, we found that intravenous injection of USC‐Exos enhanced neurogenesis and alleviated neurological deficits in post‐ischaemic stroke rats. We used neural stem cells (NSCs) subjected to oxygen‐glucose deprivation/reoxygenation (OGD/R) as an in vitro model of ischaemic stroke. The in vitro results suggested that USC‐Exos promoted both proliferation and neuronal differentiation of NSCs after OGD/R. Notably, a further mechanism study revealed that the pro‐neurogenesis effects of USC‐Exos may be partially attributed to histone deacetylase 6 (HDAC6) inhibition via the transfer of exosomal microRNA‐26a (miR‐26a). Taken together, this study indicates that USC‐Exos can be used as a novel promising strategy for brain ischaemia, which highlights the application of USC‐Exos.     

Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat

Previously we have demonstrated that a Rhodiola crenulata extract (RCE), containing a potent antioxidant salidroside, promotes neurogenesis in the hippocampus of depressive rats. The current study was designed to further investigate the protective effect of the RCE on neurogenesis in a rat model of Alzheimer's disease (AD) induced by an intracerebroventricular injection of streptozotocin (STZ), and to determine whether this neuroprotective effect is induced by the antioxidative activity of salidroside. Our results showed that pretreatment with the RCE significantly improved the impaired neurogenesis and simultaneously reduced the oxidative stress in the hippocampus of AD rats. In vitro studies revealed that (1) exposure of neural stem cells (NSCs) from the hippocampus to STZ strikingly increased intracellular reactive oxygen species (ROS) levels, induced cell death and perturbed cell proliferation and differentiation, (2) hydrogen peroxide induced similar cellular activities as STZ, (3) pre-incubation of STZ-treated NSCs with catalase, an antioxidant, suppressed all these cellular activities induced by STZ, and (4) likewise, pre-incubation of STZ-treated NSCs with salidroside, also an antioxidant, suppressed all these activities as catalase: reduction of ROS levels and NSC death with simultaneous increases in proliferation and differentiation. Our findings indicated that the RCE improved the impaired hippocampal neurogenesis in the rat model of AD through protecting NSCs by its main ingredient salidroside which scavenged intracellular ROS.     

Redox balance- and radiation-mediated alteration in hippocampal neurogenesis

Changes in the intracellular and extracellular redox balance have been correlated with cell fate decisions in terms of proliferation versus differentiation, entering versus existing cell cycle and survival versus cell death. Adult hippocampal neurogenesis has been correlated with neuronal plasticity of learning and memory; however, the process is exquisitely sensitive to changes in redox balance. Cranial irradiation is an effective modality in treating brain tumours but often leads to deficits in hippocampus-related learning and memory, which is most likely due to sustained elevation of oxygen free radical production and suppression of hippocampal neurogenesis. The subcellular redox environment affecting hippocampal neurogenesis is largely unknown. Using mutant mice deficient in each one of the three superoxide dismutase (SOD, EC 1.15.1.1) isoforms, we have begun to determine the consequences of SOD deficiency in hippocampal neurogenesis and the related functions of learning and memory under normal condition and following cranial irradiation.     

Effects of low molecular weight fungal compounds on inflammatory gene transcription and expression in mouse alveolar macrophages

1,2-Diacetylbenzene (DAB) is a neurotoxic minor metabolite of 1,2-diethylbenzene or naphthalene reaction product with OH radical. DAB causes central and peripheral neuropathies that lead to motor neuronal deficits. However, the potent effects and molecular mechanisms of DAB on neural progenitor cells and hippocampus are unknown. In the current study, we report the DAB damage at lower doses (less than 50 μM) to neural progenitor cell (NPC) invitro and hippocampal neurogenesis invivo. DAB significantly suppressed NPC proliferation with increased reactive oxygen species (ROS) production in a dose-dependent manner. The suppression of NPC proliferation was effectively blunted by the action of an antioxidant, N-acetyl cysteine. Six-week-old male C57BL/6 mice were treated with 1 or 5 mg/kg DAB for 2 weeks. DAB significantly suppressed NPC proliferation in the dentate gyrus of the hippocampus, indicating impaired hippocampal neurogenesis. Increased ROS production and the formation of oxidative stress-associated dinitrophenyl adducts were detected in the hippocampal homogenates of DAB-treated mice. DAB activated Mac-1-positive immune cells which are involved in inflammatory process in the hippocampus. Taken together, these results confirm that oxidative stress by DAB might be cause of adverse effects in NPC proliferation and hippocampal neurogenesis.     

Redox balance- and radiation-mediated alteration in hippocampal neurogenesis

Abstract

Changes in the intracellular and extracellular redox balance have been correlated with cell fate decisions in terms of proliferation versus differentiation, entering versus existing cell cycle and survival versus cell death. Adult hippocampal neurogenesis has been correlated with neuronal plasticity of learning and memory; however, the process is exquisitely sensitive to changes in redox balance. Cranial irradiation is an effective modality in treating brain tumours but often leads to deficits in hippocampus-related learning and memory, which is most likely due to sustained elevation of oxygen free radical production and suppression of hippocampal neurogenesis. The subcellular redox environment affecting hippocampal neurogenesis is largely unknown. Using mutant mice deficient in each one of the three superoxide dismutase (SOD, EC 1.15.1.1) isoforms, we have begun to determine the consequences of SOD deficiency in hippocampal neurogenesis and the related functions of learning and memory under normal condition and following cranial irradiation.     

Neurovascular crosstalk coordinates the central nervous system development

Purpose of the review: The synchronic development of vascular and nervous systems is orchestrated by common molecules that regulate the communication between both systems. The identification of these common guiding cues and the developmental processes regulated by neurovascular communication are slowly emerging. In this review, we describe the molecules modulating the neurovascular development and their impact in processes such as angiogenesis, neurogenesis, neuronal migration, and brain homeostasis. Recent findings: Blood vessels not only are involved in nutrient and oxygen supply of the central nervous system (CNS) but also exert instrumental functions controlling developmental neurogenesis, CNS cytoarchitecture, and neuronal plasticity. Conversely, neurons modulate CNS vascularization and brain endothelial properties such as blood–brain barrier and vascular hyperemia. Summary: The integration of the active role of endothelial cells in the development and maintenance of neuronal function is important to obtain a more holistic view of the CNS complexity and also to understand how the vasculature is involved in neuropathological conditions.     

Oxidative stress and adult neurogenesis-Effects of radiation and superoxide dismutase deficiency

Hippocampus plays an important role in learning and memory and in spatial navigation. Production of new neurons that are functionally integrated into the hippocampal neuronal network is important for the maintenance of functional plasticity. In adults, production of new neurons in the hippocampus takes place in the subgranular zone (SGZ) of dentate gyrus. Neural progenitor/stem cells go through processes of proliferation, differentiation, migration, and maturation. This process is exquisitely sensitive to oxidative stress, and perturbation in the redox balance in the neurogenic microenvironment can lead to reduced neurogenesis. Cranial irradiation is an effective treatment for primary and secondary brain tumors. However, even low doses of irradiation can lead to persistent elevation of oxidative stress and sustained suppression of hippocampal neurogenesis. Superoxide dismutases (SODs) are major antioxidant enzymes for the removal of superoxide radicals in different subcellular compartments. To identify the subcellular location where reactive oxygen species (ROS) are continuously generated after cranial irradiation, different SOD deficient mice have been used to determine the effects of irradiation on hippocampal neurogenesis. The study results suggest that, regardless of the subcellular location, SOD deficiency leads to a significant reduction in the production of new neurons in the SGZ of hippocampal dentate gyrus. In exchange, the generation of new glial cells was significantly increased. The SOD deficient condition, however, altered the tissue response to irradiation, and SOD deficient mice were able to maintain a similar level of neurogenesis after irradiation while wild type mice showed a significant reduction in the production of new neurons.     

Aging neural progenitor cells have decreased mitochondrial content and lower oxidative metabolism

Although neurogenesis occurs in discrete areas of the adult mammalian brain, neural progenitor cells (NPCs) produce fewer new neurons with age. To characterize the molecular changes that occur during aging, we performed a proteomic comparison between primary-cultured NPCs from the young adult and aged mouse forebrain. This analysis yielded changes in proteins necessary for cellular metabolism. Mitochondrial quantity and oxygen consumption rates decrease with aging, although mitochondrial DNA in aged NPCs does not have increased mutation rates. In addition, aged cells are resistant to the mitochondrial inhibitor rotenone and proliferate in response to lowered oxygen conditions. These results demonstrate that aging NPCs display an altered metabolic phenotype, characterized by a coordinated shift in protein expression, subcellular structure, and metabolic physiology.     

Optically derived metabolic and hemodynamic parameters predict hippocampal neurogenesis in the BTBR mouse model of autism

In this study, we made use of dual‐wavelength laser speckle imaging (DW‐LSI) to assess cerebral blood flow (CBF) in the BTBR‐genetic mouse model of autism spectrum disorder, as well as control (C57Bl/6J) mice. Since the deficits in social behavior demonstrated by BTBR mice are attributed to changes in neural tissue structure and function, we postulated that these changes can be detected optically using DW‐LSI. BTBR mice demonstrated reductions in both CBF and cerebral oxygen metabolism (CMRO₂), as suggested by studies using conventional neuroimaging technologies to reflect impaired neuronal activation and cognitive function. To validate the monitoring of CBF by DW‐LSI, measurements with laser Doppler flowmetry (LDF) were also performed which confirmed the lowered CBF in the autistic‐like group. Furthermore, we found in vivo cortical CBF measurements to predict the rate of hippocampal neurogenesis, measured ex vivo by the number of neurons expressing doublecortin or the cellular proliferation marker Ki‐67 in the dentate gyrus, with a strong positive correlation between CBF and neurogenesis markers (Pearson, r = 0.78; 0.9, respectively). These novel findings identifying cortical CBF as a predictive parameter of hippocampal neurogenesis highlight the power and flexibility of the DW‐LSI and LDF setups for studying neurogenesis trends under normal and pathological conditions.      

Opposing effects of bone morphogenetic proteins on neuron production and survival in the olfactory receptor neuron lineage

In olfactory epithelium (OE) cultures, bone morphogenetic proteins (BMPs) can strongly inhibit neurogenesis. Here we provide evidence that BMPs also promote, and indeed are required, for OE neurogenesis. Addition of the BMP antagonist noggin inhibited neurogenesis in OE-stromal cell co-cultures. Bmp2, Bmp4 and Bmp7 were expressed by OE stroma, and low concentrations of BMP4 (below the threshold for inhibition of neurogenesis) stimulated neurogenesis; BMP7 did not exhibit a stimulatory effect at any concentration tested. Stromal cell conditioned medium also stimulated neurogenesis; part of this effect was due to the presence within it of a noggin-binding factor or factors. Studies of the pro-neurogenic effect of BMP4 indicated that it did not increase progenitor cell proliferation, but rather promoted survival of newly generated olfactory receptor neurons. These findings indicate that BMPs exert both positive and negative effects on neurogenesis, depending on ligand identity, ligand concentration and the particular cell in the lineage that is responding. In addition, they reveal the presence of a factor or factors, produced by OE stroma, that can synergize with BMP4 to stimulate OE neurogenesis.     

Irradiation induces neural precursor-cell dysfunction

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.     

Wnt/β‐catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid‐induced epilepsy

Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid‐induced rat epilepsy model to investigate whether Wnt/β‐catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β‐catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up‐regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid‐induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β‐catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β‐catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β‐catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy.     

Deletion of Running-Induced Hippocampal Neurogenesis by Irradiation Prevents Development of an Anxious Phenotype in Mice

Recent evidence postulates a role of hippocampal neurogenesis in anxiety behavior. Here we report that elevated levels of neurogenesis elicit increased anxiety in rodents. Mice performing voluntary wheel running displayed both highly elevated levels of neurogenesis and increased anxiety in three different anxiety-like paradigms: the open field, elevated O-maze, and dark-light box. Reducing neurogenesis by focalized irradiation of the hippocampus abolished this exercise-induced increase of anxiety, suggesting a direct implication of hippocampal neurogenesis in this phenotype. On the other hand, irradiated mice explored less frequently the lit compartment of the dark-light box test irrespective of wheel running, suggesting that irradiation per se induced anxiety as well. Thus, our data suggest that intermediate levels of neurogenesis are related to the lowest levels of anxiety. Moreover, using c-Fos immunocytochemistry as cellular activity marker, we observed significantly different induction patterns between runners and sedentary controls when exposed to a strong anxiogenic stimulus. Again, this effect was altered by irradiation. In contrast, the well-known induction of brain-derived neurotrophic factor (BDNF) by voluntary exercise was not disrupted by focal irradiation, indicating that hippocampal BDNF levels were not correlated with anxiety under our experimental conditions. In summary, our data demonstrate to our knowledge for the first time that increased neurogenesis has a causative implication in the induction of anxiety.     

Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains

New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into preexisting circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large vs. small increases in neurogenesis in response to wheel running so that the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. During the first 10 days mice received daily injections of 5-bromo-2'-deoxyuridine (BrdU) to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Furthermore, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline vs. exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise.     

成年海马中神经发生及影响因素

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