Neurogenesis In Hippocampal Dentate Gyrus Research Articles

Akebia saponin D acts via the PPAR-gamma pathway to reprogramme a pro-neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress.

Using drugs to modulate microglial function may be an effective way to treat disorders, such as depression, that involve impaired neurogenesis. Akebia saponin D (ASD) can cross the blood-brain barrier and exert anti-inflammatory and neuroprotective effects, so we wondered whether it might influence adult hippocampal neurogenesis to treat depression. We exposed C57BL/6 mice to chronic mild stress (CMS) as a model of depression and then gave them ASD intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. The potential role of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) or BDNF-TrkB pathway in the pro-neurogenesis and anti-depressant of ASD was identified using there inhibitors GW9662 and K252a, respectively. The neurogenic effects of ASD-treated microglia were evaluated using conditioned culture methods. We found that CMS upregulated pro-inflammatory factors and inhibited hippocampal neurogenesis in dentate gyrus of mice, while inducing depressive-like behaviors. Dramatically, ASD (40 mg/kg) treatment reprogrammed an arginase (Arg)-1+ microglial phenotype in dentate gyrus, which increased brain-derived neurotrophic factor (BDNF) expression and restored the hippocampal neurogenesis, and partially ameliorated the depressive-like behaviors of the CMS-exposed mice. K252a or neurogenesis inhibitor blocked the pro-neurogenic, anti-depressant effects of ASD. Furthermore, ASD activated PPAR-γ in dentate gyrus of CMS mice as well as in primary microglial cultures treated with lipopolysaccharide. Blocking the PPAR-γ using GW9962 suppressed the ASD-reprogrammed Arg-1+ microglia and BDNF expression in dentate gyrus of CMS mice. Such blockade abolished the promoted effects of ASD-treated microglia on NSPC proliferation, survival, and neurogenesis. The pro-neurogenic and anti-depressant effects of ASD were blocked by GW9962. These results suggested that ASD acts via the PPAR-γ pathway to induce a pro-neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neurogenesis.

Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function.

Intrauterine growth restriction (IUGR) complicates up to 10% of human pregnancies and is the second leading cause of perinatal morbidity and mortality after prematurity. The most common etiology of IUGR in developed countries is uteroplacental insufficiency (UPI). For survivors of IUGR pregnancies, long-term studies consistently show a fivefold increased risk for impaired cognition including learning and memory deficits. Among these, only a few human studies have highlighted sex differences with males and females having differing susceptibilities to different impairments. Moreover, it is well established from brain magnetic resonance imaging that IUGR affects both white and gray matter. The hippocampus, composed of the dentate gyrus (DG) and cornu ammonis (CA) subregions, is an important gray matter structure critical to learning and memory, and is particularly vulnerable to the chronic hypoxic-ischemic effects of UPI. Decreased hippocampal volume is a strong predictor for learning and memory deficits. Decreased neuron number and attenuated dendritic and axonal morphologies in both the DG and CA are additionally seen in animal models. What is largely unexplored is the prenatal changes that predispose an IUGR offspring to postnatal learning and memory deficits. This lack of knowledge will continue to hinder the design of future therapy to improve learning and memory. In this review, we will first present the clinical susceptibilities and human epidemiology data regarding the neurological sequelae after IUGR. We will follow with data generated using our laboratory's mouse model of IUGR, that mimics the human IUGR phenotype, to dissect at the cellular and molecular alterations in embryonic hippocampal DG neurogenesis. We will lastly present a newer topic of postnatal neuron development, namely the critical period of synaptic plasticity that is crucial in achieving an excitatory/inhibitory balance in the developing brain. To our knowledge, these findings are the first to describe the prenatal changes that lead to an alteration in postnatal hippocampal excitatory/inhibitory imbalance, a mechanism that is now recognized to be a cause of neurocognitive/neuropsychiatric disorders in at-risk individuals. Studies are ongoing in our laboratory to elucidate additional mechanisms that underlie IUGR-induced learning and memory impairment and to design therapy aimed at ameliorating such impairment.

Effect of gabapentin on neurogenesis in hippocampal dentate gyrus of adult rats with co-disease of chronic pain and depression.

Chronic pain lasts for more than 3 months and is often associated with negative emotions such as depression and anxiety. Long-term chronic pain stress can lead to plastic changes in hippocampal structure and function. In addition to its analgesic effect, gabapentin also has certain cerebral protective effects. This study aims to observe the effect of gabapentin on neurogenesis in hippocampal dentate gyrus (DG) of the adult rats with co-disease of chronic pain and depression. The adult rats were randomly divided into 4 groups: A sham operation (Sham) group, a comorbidity model+normal saline (CCI+Veh) group (1 mL saline), a comorbidity model+low-dose gabapentin (CCI+LG) group (diluting gabapentin with normal saline to 1 mL at the dose of 30 mg/kg), and a comorbidity model+high-dose gabapentin (CCI+HG) group (diluting gabapentin with normal saline to 1 mL at the dose of 100 mg/kg) (8 rats per group). The comorbidity model was established by sciatic nerve encirclement. On the 30th day after operation, normal saline, low-dose gabapentin, and high-dose gabapentin were given intraperitoneally, respetively, for 7 consecutive days. The paw withdrawal mechanical threshold (PWMT) of the right hindlimb was measured before the operation and on the 7th, 14th, 21th, 28th, and 40th day after the operation. The time of immobility and sugar water preference rate were measured by forced swimming test and sugar water preference test, respectively, on the 28th and 40th day after the operation. The number of doublecortin (DCX) positive neurons and the expression of brain-derived neurotrophic factor (BDNF) in hippocampal dentate gyrus were observed by immunohistochemical staining, and the morphological changes of the hippocampal neurons were observed by Golgi staining. Compared with the Sham group, the PWMT of the CCI comorbidity model rats reached the lowest level on the 7th day after the operation and lasted until the 28th day after the operation, and remained at a low level on the 40th day after the operation (all P<0.05). Compared with the CCI+Veh group, the PWMT in the CCI+LG group and the CCI+HG group was increased on the 40th day after the operation (all P<0.05). Compared with the Sham group, the time of immobility in the CCI comorbidity model rats was increased significantly (all P<0.01) and the sugar water preference rate was decreased significantly (all P<0.01) on the 28th day after the operation. Compared with the CCI+Veh group, the time of immobility in the CCI+HG group was shortened (P<0.05) and the sugar water preference rate was significantly increased (P<0.01) on the 40th day after the operation. Compared with the CCI+Veh group, the number of DCX positive cells in hippocampal DG of the CCI+LG group and the CCI+HG group was increased, and that in the CCI+HG group was increased more significantly (P<0.05). Compared with the Sham group, the expression of BDNF in hippocampal DG was decreased in the CCI+Veh group (P<0.05). Compared with the CCI+Veh group, the expression of BDNF in hippocampal DG and the length of dendritic spines of the hippocampal neurons were increased in the CCI+HG group (all P<0.05). Gabapentin can relieve chronic pain and depression-like behavior in rats with chronic pain and depression, and promote neurogenesis of hippocampal dentate gyrus neurons.

Mild Traumatic Brain Injury Induces Transient, Sequential Increases in Proliferation, Neuroblasts/Immature Neurons, and Cell Survival: A Time Course Study in the Male Mouse Dentate Gyrus.

Mild traumatic brain injuries (mTBIs) are prevalent worldwide. mTBIs can impair hippocampal-based functions such as memory and cause network hyperexcitability of the dentate gyrus (DG), a key entry point to hippocampal circuitry. One candidate for mediating mTBI-induced hippocampal cognitive and physiological dysfunction is injury-induced changes in the process of DG neurogenesis. There are conflicting results on how TBI impacts the process of DG neurogenesis; this is not surprising given that both the neurogenesis process and the post-injury period are dynamic, and that the quantification of neurogenesis varies widely in the literature. Even within the minority of TBI studies focusing specifically on mild injuries, there is disagreement about if and how mTBI changes the process of DG neurogenesis. Here we utilized a clinically relevant rodent model of mTBI (lateral fluid percussion injury, LFPI), gold-standard markers and quantification of the neurogenesis process, and three time points post-injury to generate a comprehensive picture of how mTBI affects adult hippocampal DG neurogenesis. Male C57BL/6J mice (6-8 weeks old) received either sham surgery or mTBI via LFPI. Proliferating cells, neuroblasts/immature neurons, and surviving cells were quantified via stereology in DG subregions (subgranular zone [SGZ], outer granule cell layer [oGCL], molecular layer, and hilus) at short-term (3 days post-injury, dpi), intermediate (7 dpi), and long-term (31 dpi) time points. The data show this model of mTBI induces transient, sequential increases in ipsilateral SGZ/GCL proliferating cells, neuroblasts/immature neurons, and surviving cells which is suggestive of mTBI-induced neurogenesis. In contrast to these ipsilateral hemisphere findings, measures in the contralateral hemisphere were not increased in key neurogenic DG subregions after LFPI. Our work in this mTBI model is in line with most literature on other and more severe models of TBI in showing TBI stimulates the process of DG neurogenesis. However, as our DG data in mTBI provide temporal, subregional, and neurogenesis-stage resolution, these data are important to consider in regard to the functional importance of TBI-induction of the neurogenesis process and future work assessing the potential of replacing and/or repairing DG neurons in the brain after TBI.

Astragaloside IV improves neurobehavior and promotes hippocampal neurogenesis in MCAO rats though BDNF-TrkB signaling pathway

Astragaloside IV (AST) as the main active ingredient of Astragalus membranaceus. Clinical and laboratory-based studies have demonstrated the effects of AST on cerebral protection and angiogenesis after ischemia stroke. In addition, several reports investigated the effect of AST on proliferation of neural stem cells. The current study was aimed to evaluate the influence of AST on neurogenesis in hippocampal dentate gyrus (DG) of MCAO rats and to explore the possible mechanisms. In this study, the neurobehavioral tests (Ludmila Belayev 12-point scoring, Screen test, fore limb placing test) had been employed to investigate the effect of AST treatment against functional deficit of MCAO rats. The immunofluorescence staining, western-blot and qRT-PCR was performed to evaluate the effects of AST on proliferation, differentiation and maturity of neural stemr cells in hippocampus. Moreover, we investigated the possible mechanism of the AST treatment in promoting neurogenesis after ischemic stroke. The findings indicated that AST treatment ameliorated the neurobehavior of MCAO rats. The results indicated that AST treatment possessed the potential to improve proprioceptive sense and motor function of MCAO rats. AST treatment sustained neuronal viability and stimulates sensorimotor integration functional recovery in MCAO rats. The results suggested that AST improved neurobehavior deficit after ischemic stroke. Furthermore, AST promoted neurogenesis through upregulating the expressing of BNDF/TrkB signaling pathway. Therefore AST might be a promising therapeutic agent for ischemic stroke.

Promoting neurogenesis in hippocampal dentate gyrus of chronic unpredictable stress-induced depressive-like rats with paeoniflorin.

Hippocampal neurogenesis plays an important role in the onset and treatment of depressive disorders. Previous studies suggest that paeoniflorin could be used as an antidepressant for treating rats subjected to chronic unpredictable stress. In this study, the effects of paeoniflorin on neurogenesis in the hippocampus dentate gyrus and potential mechanism of action are further investigated in chronic unpredictable stress-induced rat. Results suggest that paeoniflorin markedly increased both sucrose consumption and the number of 5-bromo-2-deoxyuridine-positive cells in the dentate gyrus of chronic unpredictable stress-induced rats, and the ratio of co-expressed 5-bromo-2-deoxyuridine and glial fibrillary acidic protein-positive cells, but exerted no significant effect on the ratio of co-expressed 5-bromo-2-deoxyuridine and neuronal nuclei-positive cells. Compared with the vehicle group, a significant increase was detected in the number of brain-derived neurotrophic factor-positive cells and the expression of brain-derived neurotrophic factor mRNA in the hippocampus of the paeoniflorin-treated group. According to the results, paeoniflorin promoted neural stem cell proliferation, their differentiation into astrocytes, and neurogenesis in the hippocampal dentate gyrus of chronic unpredictable stress-induced rats. Apart from enhancing the protein expression and gene transcription of brain-derived neurotrophic factor, it also activated the expression of tropomyosin receptor kinase B (a high-affinity receptor of brain-derived neurotrophic factor). This suggests that paeoniflorin might promote neurogenesis in the hippocampus dentate gyrus of chronic unpredictable stress-induced rats and act as an antidepressant by regulating the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway.

Astragaloside IV Promotes Adult Neurogenesis in Hippocampal Dentate Gyrus of Mouse through CXCL1/CXCR2 Signaling.

Astragaloside IV (ASI) has been reported to promote neural stem cells proliferation in vitro and CXCR2 expression on neutrophils. The present study was aimed to investigate the influence of ASI on adult neurogenesis in hippocampal dentate gyrus (DGs) of mouse and to discuss the possible underlying mechanisms. Total number of proliferative cells (BrdU+), pre-mature neurons (DCX+), early proliferative cells (BrdU+/DCX+), proliferative radial gila-like cells (BrdU+/GFAP+) and newly generated neurons (BrdU+/NeuN+) after ASI or vehicle administration for two weeks were counted, respectively. The results showed that BrdU+ cells and DCX+ cells were significantly increased in DGs of mice administered with ASI. The numbers of BrdU+/DCX+, BrdU+/GFAP+ cells and BrdU+/NeuN+ cells were also elevated in the ASI group. Correspondingly, ASI increased the protein expression of hippocampal DCX, GFAP and NeuN. Further study disclosed that ASI remarkably up-regulated the mRNA and protein expressions of CXCL1 as well as that of CXCR2 in the hippocampus. The promotive effect of ASI on DCX, GFAP and NeuN protein expression was abolished by SB225002, the inhibitor of CXCR2. Our results indicated that ASI modulated the homeostasis of the CXCL1/CXCR2 signaling pathway, which might be responsible for the increased neurogenesis within the hippocampal DGs of mice.

Effects of sevoflurane on hippocampal neurogenesis in dentate gyrus of mice of different ages

Objective To evaluate the effects of sevoflurane on hippocampal neurogenesis in dentate gyrus (DG) of mice of different ages. Methods Ninety-six SPF healthy male C57BL/6 mice, aged 2 weeks, 6 weeks, 9 months and 20 months (24 mice for each age, 12 mice for each group), were divided into 2 groups (n=48 each) using a random number table method: control group (group C) and sevoflurane group (group S). Group S inhaled 3.0% sevoflurane for 2 h once a day for 3 consecutive days, while group C inhaled the mixture of air and O2.Six mice of each age were selected, and 5′-bromo-2′-deoxyuridine (BrdU) 50 mg/kg was intraperitoneally injected immediately before and after inhalation once a day for 3 consecutive days in two groups.Mice were sacrificed at 24 h after the last inhalation (T1), brains were removed and hippocampi isolated for determination of the number of nestin and doublecortin (DCX) positive cells in DG by immunohistochemistry.Mice were sacrificed at 4 weeks after the last inhalation (T2), brains were removed and hippocampi isolated for determination of the number of neuronal nuclei antigen (NeuN)/BrdU and glial fibrillary acid protein (GFAP)/BrdU positive cells by immunofluorescence. Results Compared with group C, the number of nestin and DCX positive cells was significantly reduced at T1, and the number of NeuN/BrdU and GFAP/BrdU positive cells was reduced at T2 in mice of 2 weeks and 20 months old (P 0.05). Conclusion Three percent sevoflurane can inhibit hippocampal neurogenesis in DG of immature and old mice and exerts no influence on hippocampal neurogenesis in DG of juvenile and adult mice. Key words: Anesthetic, inhalation; Age; Neurogenesis; Hippocampus

Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB

Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB.

Draxin regulates hippocampal neurogenesis in the postnatal dentate gyrus by inhibiting DCC-induced apoptosis

Hippocampal neurogenesis in the dentate gyrus (DG) is controlled by diffusible molecules that modulate neurogenic processes, including cell proliferation, differentiation and survival. To elucidate the mechanisms underlying hippocampal neurogenesis, we investigated the function of draxin, originally identified as a neural chemorepellent, in the regulation of neuronal survival in the DG. Draxin was expressed in Tbr2 (+) late progenitors and NeuroD1 (+) neuroblasts in the dentate granule cell lineage, whereas expression of its receptor DCC (deleted in colorectal cancer) was mainly detectable in neuroblasts. Our phenotypic analysis revealed that draxin deficiency led to enhanced apoptosis of DCC-expressing neuroblasts in the neurogenic areas. Furthermore, in vitro assays using a hippocampal neural stem/progenitor cell (HNSPC) line indicated that draxin inhibited apoptosis in differentiating HNSPCs, which express DCC. Taken together, we postulate that draxin plays a pivotal role in postnatal DG neurogenesis as a dependence receptor ligand for DCC to maintain and promote survival of neuroblasts.

Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

Persistent Decreases in Adult Subventricular and Hippocampal Neurogenesis Following Adolescent Intermittent Ethanol Exposure.

Neurogenesis in hippocampal dentate gyrus (DG) and subventricular zone (SVZ) matures during adolescence to adult levels. Binge drinking is prevalent in adolescent humans, and could alter brain neurogenesis and maturation in a manner that persists into adulthood. To determine the impact of adolescent binge drinking on adult neurogenesis, Wistar rats received adolescent intermittent ethanol (AIE) exposure (5.0 g/kg/day, i.g., 2 days on/2 days off from postnatal day, P25–P54) and sacrificed on P57 or P95. Neural progenitor cell proliferation, differentiation, survival and maturation using immunohistochemistry was determined in the DG and SVZ. We found that AIE exposure decreased neurogenesis in both brain regions in adulthood (P95). In the DG at P57, AIE exposure resulted in a significant reduction of SOX2+, Tbr2+, Prox1+ and parvalbumin (PV)+IR expression, and at P95 decreased DCX+ and PV+IR expression. AIE exposure also reduced the expression of two cell proliferation markers (Ki67+ and BrdU+IR with 300 mg/kg, 2 h) at P95. The immune signaling molecule β-2 microglobulin+ and the cell death marker activated caspase-3+IR were significantly increased in the DG by AIE exposure. In the SVZ, AIE exposure decreased SOX2+, Mash1+, DCX+ and Dlx2+IR expression at P95, but not at P57. Thus, in adulthood both brain regions have reduced neurogenesis following AIE exposure. To assess progenitor cell survival and maturation, rats were treated with BrdU (150 mg/kg/day, 14 days) to label proliferating cells and were sacrificed weeks later on P95. In the hippocampus DG, AIE exposure increased survival BrdU+ cells which differentiated into Iba1+ microglia. In contrast, SVZ had decreased BrdU+ cells similar to decreased DCX+ neurogenesis. These data indicate that AIE exposure causes a lasting decrease in both adult hippocampal DG and forebrain SVZ neurogenesis with brain regional differences in the AIE response that persist into adulthood.

Neuronal nitric oxide synthase contributes to pentylenetetrazole-kindling-induced hippocampal neurogenesis.

Neuronal nitric oxide synthase (nNOS), the major nitric oxide synthase isoform in the mammalian brain, is implicated in the pathophysiology of several neurological conditions, including epilepsy. Neurogenesis in hippocampal dentate gyrus (DG) persists throughout life in the adult brain. Alterations in this process occur in many neurological diseases, including epilepsy. Few studies, however, have addressed the role of nNOS in hippocampal DG neurogenesis in epileptic brain. The present study, therefore, investigated the role of nNOS in pentylenetetrazole (PTZ)-kindling-induced neurogenesis in hippocampal DG. Our results showed that nNOS expression and enzymatic activity were significantly increased in the hippocampus of PTZ-kindled mice. Meanwhile, these PTZ-kindled mice were characterized by significant enhancement of new born cells proliferation and survival in hippocampal DG, and these survived cells are co-labeled with NeuN and GFAP. Selective inhibition of nNOS by 7-NI, however, suppressed PTZ-kindling-induced hippocampal DG new born cells proliferation and survival, suggesting that nNOS contributes to PTZ-kindling-induced hippocampal neurogenesis.

Simvastatin prevents β-amyloid25–35-impaired neurogenesis in hippocampal dentate gyrus through α7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate

Simvastatin (SV) is reported to improve cognition and slow progression of Alzheimer's disease (AD), however underlying mechanism still remains unclear. In hippocampal dentate gyrus (DG), β-amyloid (Aβ) selectively impairs survival and neurite growth of newborn neurons in the 2nd week after birth. The aim of this study was to examine the effects of SV on the impairment of neurogenesis and the spatial cognitive deficits in Aβ25–35 (3 nmol)-injected (i.c.v.) mice (Aβ25–35-mice). Herein, we reported that the SV-treatment (20 mg/kg) on days 2–14 after BrdU-injection could dose-dependently protect the survival and neurite growth of newborn neurons, which was blocked by the α7nAChR antagonist MLA or the farnesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the α4β2nAChR antagonist DHβE. The SV-treatment in Aβ25–35-mice rescued the decline of Akt phosphorylation and increased the ERK1/2 phosphorylation in hippocampus, which was sensitive to MLA and FOH. The PI3K inhibitor LY294002 could abolish the SV-protected neurogenesis in Aβ25–35-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in Aβ25–35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV-treatment in Aβ25–35-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV-treatment in Aβ25–35-mice via reduction of FPP can protect neurogenesis through α7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function.

Seipin knockout impairs proliferation and differentiation of adult stem/progenitor cells in hippocampal dentate gyrus via reduction of PPARγ

ABSTRACTThe seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.

Regular exercise cures depression-like behavior via VEGF-Flk-1 signaling in chronically stressed mice

In animals, chronic stress leads to the development of depression-like behavior and decreases neurogenesis and blood vessel density in hippocampus, whereas antidepressants increase adult neurogenesis in hippocampus. Regular exercise training also has antidepressant action and increases hippocampal neurogenesis; however, whether exercise-induced antidepressant action is related to hippocampal microvasculature is unclear. To address this issue, we compared depression-like behavior, blood vessel density, and neurogenesis in hippocampal dentate gyrus between stressed and exercised mice with or without administration of inhibitor of vascular endothelial growth factor (VEGF) receptor. Chronic stress led to the development of depression-like behavior, decreased blood vessel density, and neurogenesis in hippocampus. Regular exercise training improved depression-like behavior, the decrease of hippocampal blood vessel density, and neurogenesis in the stress state, whereas the combination of regular exercise and administration of SU1498, VEGF receptor Flk-1 inhibitor, canceled the exercise-induced antidepressant effect. These findings suggested that the improvement of hippocampal blood vessel and adult neurogenesis via VEGF signaling pathway is necessary for exercise-induced antidepressant effect.

The effects of zinc administration on seizure-induced aberrant neurogenesis in hippocampal dentate gyrus

Repeated brief seizures, such as those induced by electroconvulsive therapy (ECT), markedly elevate neurotrophic factor levels in the adult rat brain, but it is not known whether a similar response to seizures occurs in immature animals. To address this question, we evoked brief seizures with electroconvulsive shock (ECS) in rat pups at different stages of postnatal development and examined basic fibroblast growth factor (FGF-2), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) proteins in selected brain regions in which these trophic factors are known to increase in the adult rat following ECS-induced seizures.ECS treatments were administered daily (3 episodes/day) over 7 days to rat pups of three different ages: postnatal day (P)1–7, P7–13, or P14–20. Protein levels were measured 6 h after the last ECS using Western blotting for FGF-2 in rhinal cortex, ELISA for BDNF and NGF in hippocampus, and NGF in frontal cortex.7 days of repeated ECS-induced seizures during P1–7 did not alter protein levels for BDNF, FGF-2, or NGF. The repeated seizures during P7–13 affected only BDNF protein, causing a significant elevation of 40% in hippocampus over sham-treated controls. In P14–20 pups, the repeated seizures resulted in a significant increase in BDNF in hippocampus (162% over controls) and FGF-2 in rhinal cortex (34% over controls), while NGF protein did not show a significant change in either hippocampus or frontal cortex.The results suggest that during the first postnatal week there is a resistance to seizure-induced increase in neurotrophic factors, but by the third postnatal week, both BDNF and FGF-2 are elevated substantially in response to repeated seizures. This time-dependent profile suggests that synthesis of these proteins is initially activity-independent, becoming subject to activity-dependent regulation by 3 weeks of age. This maturation of seizure-evoked changes in trophic factors may be important for understanding the impact of ECT and seizures in childhood.

The effects of zinc administration on seizure-induced aberrant neurogenesis in hippocampal dentate gyrus

The effects of zinc administration on seizure-induced aberrant neurogenesis in hippocampal dentate gyrus

Cranial irradiation‐induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: attenuation by melatonin pretreatment

Radiation is an important therapeutic tool in the treatment of cancer. The tremendous development in radiotherapeutic techniques and dosimetry has made it possible to augment the patient survival. Therefore, attention has focused on long-range treatment side effects especially in relation to the neurocognitive changes. As cognitive health of an organism is considered to be maintained by the capacity of hippocampal neurogenesis, this study designed to evaluate the delayed effect of cranial irradiation on hippocampal neurogenesis, possible implication of oxidative stress and prophylactic action of melatonin in mice. One month after cranial irradiation (6 Gy, X-ray), changes in the population of immature and proliferating neurons in dentate gyrus were localized through the expression of the microtubule binding protein doublecortin (Dcx) and proliferation marker Ki-67. We found a substantial reduction in the Dcx and Ki-67 positive cells after irradiation. Melatonin pretreatment significantly ameliorated the radiation-induced decline in the Dcx and Ki-67 positive cells. In addition, profound increase in the 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine positive cells were reported in subventricular zone, granular cell layer and hilus after day 30 postirradiation. Immunoreactivity of these oxidative stress markers were significantly inhibited by melatonin pretreatment. To confirm the magnitude of free-radical scavenging potential of melatonin, we measured the in-vitro OH radical scavenging power of melatonin by electron spin resonance. Interestingly, the melatonin was capable of scavenging the OH radicals at very low concentration (IC(50) = 214.46 nm). The findings indicate the possible benefit of melatonin treatment to combat the delayed side effects of cranial radiotherapy.

Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

Donepezil hydrochloride is a potent and selective acetylcholinesterase inhibitor and has been treated for Alzheimer's disease, in which the cholinergic dysfunction is observed. Recently, the degeneration of medial septal cholinergic nuclei in adult rat suppressed the neurogenesis in hippocampal dentate gyrus (DG) was reported. Then, we determined whether donepezil which activated the brain cholinergic system could modulate hippocampal neurogenesis in normal rats. After the injection of 5′-bromo-2′-deoxyuridine (BrdU) to label dividing cells, we orally treated with donepezil (0.5 or 2 mg/kg) once a day for 4 weeks. In the other group, we performed 4-week subcutaneous infusion of scopolamine (0.75 or 3 mg/day), a muscarinic acetylcholine receptor blocker. The doses of donepezil and scopolamine we used in this study were reported to activate and inhibit cholinergic activity in rats, respectively. One day after the completion of drug treatment, the animals were sacrificed, and immunohistochemical analysis was performed. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the vehicle-treated control. Neither drug had any effects on the percentage of BrdU-positive cells that were also positive for a neuronal marker NeuN, nor the number of proliferating cell nuclear antigen-positive cells in the DG. These results indicate that donepezil enhances and scopolamine suppresses the survival of newborn neurons in the DG without affecting the proliferation of neural progenitor cell and the neuronal differentiation. We also found that chronic treatment of donepezil enhanced, and scopolamine suppressed phosphorylation of cAMP response element binding protein (CREB), which was involved in cell survival, in the DG. These results suggest that donepezil activates the central cholinergic transmission and enhances the survival of newborn neurons in the DG via CREB signaling.