The function of BMP4 during neurogenesis in the adult hippocampus in Alzheimer's disease

Alzheimer's disease (AD) is an age-related, progressive and irreversible neurodegenerative disease that results in the loss of selected neurons throughout the basal forebrain, amygdala, hippocampus, and cortical area as well as progressive deficits of cognition and memory. The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is one of the regions where adult neurogenesis occurs in mammals, including humans and non-human primates. The new granule cells, which are the primary excitatory neurons in the DG, contribute to the processes of learning and memory. The changes in neurogenesis observed during the initial stages and progression of AD suggest that the modulation of the new production of neurons at neurogenic sites may exert profound effects on hippocampal function. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin contribute to the modulation of neurogenesis in the adult hippocampus, thereby affecting hippocampal function. This review focuses on the role of BMP4 and Noggin in the control of the stem and precursor cells in the adult hippocampus during AD and their potential as a possible therapeutic strategy for AD sufferers. It is helpful to extend the understanding of the control of stem cells in the normal and diseased hippocampus.     

Inhibitor of vascular endothelial growth factor receptor tyrosine kinase attenuates cellular proliferation and differentiation to mature neurons in the hippocampal dentate gyrus after transient forebrain ischemia in the adult rat

Neurogenesis in the adult hippocampal dentate gyrus is promoted by transient forebrain ischemia. The mechanism responsible for this ischemia-induced neurogenesis, however, remains to be determined. It has been suggested that there may be a close relationship between neurogenesis and the expression of vascular endothelial growth factor, an angiogenic factor. The purpose of the present study was to examine the relationship between vascular endothelial growth factor and cell proliferation in the dentate gyrus after transient forebrain ischemia. The mRNA expression of vascular endothelial growth factor was increased in the dentate gyrus on day 1 after ischemia. Immunohistochemical analysis on day 9 after ischemia, when a significant increase in cell proliferation was seen, showed that the cerebral vessel space in the subgranular zone of the dentate gyrus had not been affected by the ischemia. Neither were the vascular densities on days 1 and 3 after ischemia altered compared with those of non-operated naïve control rats. Furthermore, the distance from the center of the proliferative cells to the nearest cerebral vessel of ischemic rats was comparable to that of the sham-operated rats. We demonstrated that transient forebrain ischemia-induced cell proliferation and differentiation to mature neurons in the hippocampal dentate gyrus was attenuated by the i.c.v. administration of a vascular endothelial growth factor receptor tyrosine kinase inhibitor. These results suggest that vascular endothelial growth factor receptor at the early period of reperfusion may contribute to neurogenesis rather than to angiogenesis in the hippocampal dentate gyrus.     

Reproductive experience alters hippocampal neurogenesis during the postpartum period in the dam

Pregnancy and the postpartum period are a time of maximal neural and behavioral plasticity. Recent work has shown that hippocampus-dependent learning and memory performance and hippocampus morphology are affected by motherhood and reproductive experience (number of times pregnant and given birth). Adult neurogenesis in the dentate gyrus of the hippocampus is influenced by steroid hormones such as estradiol and corticosterone, which fluctuate during pregnancy and the postpartum period. Thus, it is possible that hippocampal neurogenesis may be affected by motherhood and reproductive experience. The present study aimed to investigate the role of reproductive experience on hippocampal neurogenesis via cell proliferation and cell survival and to determine whether differences were due to the effect of pregnancy and/or pup-exposure alone. Four groups of female Sprague-Dawley rats were used; multiparous, primiparous, nulliparous, and nulliparous rats exposed to pups. All rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg) approximately 24 h after birth/pup-exposure with age-matched controls. Rats were perfused either 24 h (Expt. 1: Cell proliferation) or 21 days (Expt. 2: Cell survival) after BrdU injection. Results show there is a significant decrease in cell proliferation in the dentate gyrus of primiparous and multiparous rats during the early postpartum period, and a decrease in cell survival in the dentate gyrus during the postpartum in primiparous rats, regardless of pup-exposure, compared with all other groups. In addition, brief pup exposure to nulliparous rats significantly increased cell proliferation and cell death in the dentate gyrus, while 22 days of pup exposure to nulliparous rats (sensitized rats) resulted in increased cell survival and cell death in the dentate gyrus. Collectively these results indicate that reproductive experience significantly affects hippocampal neurogenesis and that these effects are not due to the effect of pregnancy or pup-exposure alone.     

模拟失重后大鼠海马齿状回神经发生的实验研究

观察模拟失重对大鼠海马齿状回神经发生的影响,为进一步阐明模拟失重对成年大鼠海马齿状回神经发生影响的规律及其相关生物学机制提供基本的实验依据。采用尾部悬吊法建立大鼠模拟失重模型,通过5-溴-2’-脱氧尿苷(5-bromo-2’-de-oxyuridine,BrdU)标记分裂细胞、微管相关蛋白(doublecortin,DCX)标记神经干细胞、神经元核蛋白(NeuN)标记神经元及胶质原纤维酸性蛋白(GFAP)标记神经胶质细胞的单、双重免疫组织化学染色方法比较尾部悬吊后7、14、28d模拟失重组大鼠与相应时间对照组大鼠之间海马齿状回神经前体细胞增殖、迁移和分化的情况。结果显示:模拟失重后7、14d尾部悬吊法模拟失重大鼠齿状回的BrdU免疫阳性细胞数目较相应对照组明显减少(P<0.01),而模拟失重后28d时两组大鼠齿状回BrdU免疫阳性细胞数目无显著差异(P>0.05)。本研究结果提示,模拟失重可抑制海马齿状回神经发生的水平。     

Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats

Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg), and then 24 h later were given subcutaneous injections of either estradiol benzoate (33 mug/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.     

Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats

Adult neurogenesis in the dentate gyrus of the hippocampus is altered with stress exposure and has been implicated in depression. High levels of corticosterone (CORT) suppress neurogenesis in the dentate gyrus of male rats. However both acute and chronic stress do not consistently reduce adult hippocampal neurogenesis in female rats. Therefore, this study was conducted to investigate the effect of different doses of corticosterone on hippocampal neurogenesis in male and female rats. Rats received 21 days of s.c. injections of either oil, 10 or 40 mg/kg CORT. Subjects were perfused 24 h after the last CORT injection and brains were analyzed for cell proliferation (Ki67-labeling) or immature neurons (doublecortin-labeling). Results show that in both males and females high CORT, but not low CORT, reduced both cell proliferation and the density of immature neurons in the dentate gyrus. Furthermore, high CORT males had reduced density in immature neurons in both the ventral and dorsal regions while high CORT females only showed the reduced density of immature neurons in the ventral hippocampus. The high dose of CORT disrupted the estrous cycle of females. Further, the low dose of CORT significantly reduced weight gain and increased basal CORT levels in males but not females, suggesting a greater vulnerability in males with the lower dose of CORT. Thus we find subtle sex differences in the response to chronic CORT on both body weight and on neurogenesis in the dorsal dentate gyrus that may play a role in understanding different vulnerabilities to stress-related neuropsychiatric disorders between the sexes.     

营养不良可增加幼鼠齿状回颗粒下层的细胞增殖和神经生发(英文)

为了观察营养不良对幼鼠海马齿状回 (DG)和脑室下层 (SVZ)的细胞增殖和神经发生的影响 ,采用 5 -溴 -2 -脱氧尿苷(Brd U)标记结合免疫组织化学方法对脑切片分别进行 Brd U、Tu J1(β tubulin,β微管蛋白 )及 GFAP(胶质纤维酸性蛋白 )反应或双重反应。结果表明 ,营养不良幼鼠齿状回的细胞增殖和神经生发明显高于营养良好的幼鼠而脑室下层的细胞增殖数量在两者却无明显差异。在齿状回 ,新生的细胞中大约有 5 0 %为新生的神经元 ,10～ 2 0 %为神经胶质细胞。本文结果提示 ,幼鼠海马齿状回的细胞增殖和神经生发可能因营养不良而增加 ,这些新生的细胞可能对日后某些海马依赖性行为产生一定的影响     

Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis.

The dentate gyrus of the hippocampus is one of few regions in the adult mammalian brain characterized by ongoing neurogenesis. Significantly, recent studies indicate that the rate of neurogenesis in the hippocampus declines with age, perhaps contributing to age-related cognitive changes. Although a variety of factors may influence the addition of new neurons in the adult dentate gyrus, the mechanisms responsible for the age-related reduction remain to be established. Insulin-like growth factor-I (IGF-I) is one promising candidate to regulate neurogenesis in the adult and aging brain since it influences neuronal production during development and since, like the rate of neurogenesis, it decreases with age. In the current study, we used bromodeoxyuridine labeling and multilabel immunofluorescence to assess age-related changes in neuronal production in the dentate gyrus of adult Brown Norway x Fischer 344 rats. In addition, we investigated the relationship between changes in neurogenesis and the age-dependent reduction in IGF-I by evaluating the effect of i.c.v. infusion of IGF-I on neurogenesis in the senescent dentate gyrus. The analyses revealed an age-dependent reduction in the number of newly generated cells in the adult dentate subgranular proliferative zone and, in addition, a 60% reduction in the differentiation of newborn cells into neurons. Restoration of IGF-I levels in senescent rats significantly restored neurogenesis through an approximately three-fold increase in neuronal production.The results of this study suggest that IGF-I may be an important regulator of neurogenesis in the adult and aging hippocampus and that an age-related decline in IGF-I-dependent neurogenesis could contribute to age-related cognitive changes.     

Neurogenesis in the adult dentate gyrus after cortical infarcts: effects of infarct location, N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment

Stimulation of cell proliferation and neurogenesis in the adult dentate gyrus has been observed after focal and global brain ischemia but only little is known about the underlying mechanisms. We here analyzed neurogenesis in the dentate gyrus after small cortical infarcts leaving the hippocampal formation and subcortical regions intact. Using the photothrombosis model in adult rats, focal ischemic infarcts were induced in different cortical areas (sensorimotor forelimb and hindlimb cortex) and proliferating cells were labeled at days 3-14 after infarct induction with bromodeoxyuridine. At 2, 4, and 10 weeks after ischemia, immunocytochemistry was performed with immature neuronal (doublecortin), mature neuronal (neuronal nuclei antigen) and glial (calcium-binding protein beta S100beta) markers. When compared with sham-operated controls, animals with infarcts in the forelimb as well as hindlimb cortex revealed an increase in survival of newborn progenitor cells at four and 10 weeks after the insult with predominance at the ipsilateral side. Triple immunofluorescence and confocal laser scanning microscopy revealed an increase in neurogenesis in all groups that was more pronounced 10 weeks after the infarct. Application of the N-methyl-D-aspartate (NMDA)-receptor antagonist MK-801 during lesion induction significantly enhanced neurogenesis in the dentate gyrus. An even stronger increase in newborn neurons was observed after anti-inflammatory treatment with indomethacine during the first 16 days of the experiment. The present study demonstrates that small cortical infarcts leaving subcortical structures intact increase neurogenesis in the dentate gyrus and that these processes can be stimulated by N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment.     

BMP4参与海人酸损伤后成年大鼠海马齿状回颗粒细胞增殖及胶质增生

目的探讨海人酸（KA）侧脑室注射致大鼠海马损伤后骨形成蛋白-4（BMP4）的表达变化及其与颗粒细胞增殖和胶质细胞增生的关系。方法将成年大鼠分为对照组与实验组。侧脑室注射KA7d后,用尼氏染色检测海马神经元丢失,用免疫组织化学与原位杂交的方法检测海马齿状回BMP4mRNA阳性细胞与BrdU标记细胞、GFAP阳性细胞数的变化。结果正常成年大鼠BMP4mRNA阳性细胞主要分布于海马齿状回的门区、颗粒下层、CA3、CAI区。BrdU标记细胞主要分布在齿状回颗粒下层。GFAP阳性细胞主要分布在齿状回、CA3区。在KA侧脑室注射致海马损伤后7d,海马CA3、CA4区神经元丢失明显,BMP4mRNA阳性细胞与BrdU、GFAP阳性细胞均明显增加。结论KA侧脑室注射致海马损伤后,成年大鼠海马齿状回颗粒细胞增殖增强和胶质增生可能与BMP4表达增加有关。     

Effect of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis in adult rat hippocampus and spatial learning

The dentate gyrus of the hippocampal formation produces new neurons throughout adulthood in mammalian species. Several experimental statuses and factors regulating to neurogenesis have been identified in the adult dentate gyrus. For example, exposure to an enriched environment enhances neurogenesis in the dentate gyrus and improves hippocampus-dependent spatial learning. Furthermore, serotonin is known to influence adult neurogenesis, and learning and memory. However, the effects of long-lasting depletion of serotonin over the developing period on neurogenesis have not been investigated. Thus, we examined the influence of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis and spatial memory performance. As reported previously, environmental enrichment significantly increased new neurons in the dentate gyrus. However, there was no improvement of the spatial learning test in adult rats in standard and in environmental enrichment housings. Intracisternal administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine, on postnatal day 3 apparently reduced serotonin content in the adult hippocampus without regeneration. This experimental depletion of serotonin in the hippocampus of rats housed in an enriched environment had no effect on spatial memory performance, but produced significant decreases in the number of bromodeoxyuridine-labeled new cells in the dentate gyrus. These findings indicate that newly generated cells stimulated by environmental enrichment are not critical for improvements in hippocampus-dependent learning. Furthermore, numbers of bromodeoxyuridine-labeled cells in the dentate gyrus of 5,7-dihydroxytryptamine-injected rats did not differ between 1 day and 4 weeks after bromodeoxyuridine injection. These data suggest that survival of newly generated dentate gyrus cells remains relatively constant under long-lasting serotonin depletion.     

Novel effects of Nelumbo nucifera rhizome extract on memory and neurogenesis in the dentate gyrus of the rat hippocampus

Memory enhancement is a matter of concern in general, and in particular to people suffering from cognitive dysfunction. In this study, we investigated the effect of Nelumbo nucifera rhizome extract on learning and memory function. A step-through passive avoidance test was performed with Wistar rats. In addition, immunohistochemistry was used to investigate cell proliferation and differentiation in the dentate gyrus of the hippocampus. The methanol extract of N. nucifera rhizome (MNR) resulted in significant improvements of memory functions and neurogenesis in the dentate gyrus. In the passive avoidance test, the retention time of MNR-treated rats was significantly longer than that of controls. Immunohistochemical analyses using BrdU, Ki-67, and DCX showed significantly increased cell proliferation and cell differentiation in the dentate gyrus. These results suggest that N. nucifera rhizome extract may improve learning and memory with enhancing neurogenesis in the DG of the hippocampus.     

Early life experience alters response of adult neurogenesis to stress

Maternal deprivation produces persistent abnormalities in behavioral and neuroendocrine functions associated with the hippocampus, a brain region that shows considerable structural change in response to experience throughout life. Here we show that adverse experience early in life affects the regulation of adult neurogenesis in the hippocampus. More specifically, a decrease in cell proliferation and immature neuron production are observed in the dentate gyrus of adult rats that are maternally separated as pups. Although maternally separated rats show normal basal levels of corticosterone, the suppression of cell proliferation in these rats can be reversed by lowering corticosterone below the control value. In addition, normal stress-induced suppression of cell proliferation and neurogenesis, despite normal activation of the hypothalamic pituitary adrenal (HPA) axis, is not observed in maternally separated rats. Our results suggest that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood.     

Neural precursor proliferation and newborn cell survival in the adult rat dentate gyrus are affected by vitamin E deficiency

The adult hippocampal neurogenesis is affected by vitamin E deficiency. In the present investigation we examined if neural precursor proliferation, newborn cell survival or both are altered by vitamin E deficiency. 5-Bromo-2'-deoxyuridine (BrdU) was employed as a marker of proliferating cells. BrdU-labelled cells were revealed 1 and 30 days after BrdU administration in order to evaluate proliferation and newborn cell survival, respectively. Cell proliferation decreased in controls from juvenile to adult age, and the decrease was lesser in vitamin E deficiency. Thus we found a higher number of proliferating cells in vitamin E-deficient rats than in age-matched controls at 5 months of age. Comparing the number of BrdU-positive cells between 1 and 30 days after the last BrdU injection revealed a remarkable decrease in all groups; this is the greatest in vitamin E-deficient rats and the lowest in control rats. Consistently cell death in the dentate gyrus, assessed by TUNEL technique, was found to decrease from 1 to 5 months of age, but at 5 months it was significantly higher in vitamin E-deficient rats than in age-matched controls. These data show that vitamin E deficiency enhances neural precursor proliferation and cell death during adult neurogenesis.     

Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation

Neuronal nitric oxide synthase, the major nitric oxide synthase isoform in the mammalian brain, is implicated in some developmental processes, including neuronal survival, precursor proliferation and differentiation. However, reports about the role of neuronal nitric oxide synthase in neurogenesis in the adult dentate gyrus are conflicting. Here we show that 5-bromodeoxyuridine-labeled dividing progenitor cells in the dentate gyrus were significantly increased in mice receiving 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, and in null mutant mice lacking neuronal nitric oxide synthase gene (nNOS-/-) 6 h and 4 weeks after 5-bromodeoxyuridine incorporation. The increase in 5-bromodeoxyuridine positive cells in 7-nitroindazole-treated mice was accompanied by activation of cyclic AMP response element binding protein phosphorylation in the dentate gyrus. Pretreatment with N-methyl-D-aspartate receptor antagonist MK-801 fully abolished the effects of 7-nitroindazole on neurogenesis and cyclic AMP response element binding protein phosphorylation. Furthermore, neuronal nitric oxide synthase inhibition significantly enhanced the survival of newborn cells and the number of 5-bromodeoxyuridine positive/NeuN positive cells in the dentate gyrus. These results indicate that neuronal nitric oxide synthase-derived nitric oxide suppresses neurogenesis in the adult dentate gyrus, in which N-methyl-D-aspartate receptor functions and cyclic AMP response element binding protein phosphorylation may be involved.     

Estrogen receptor alpha and beta mRNA expressions by proliferating and differentiating cells in the adult rat dentate gyrus and subventricular zone

Numerous factors modulate neurogenesis in the adult dentate gyrus and subventricular zone, but it is often not clear if the modulation is mediated by direct effects on the proliferating and differentiating cells or secondary to effects on other cells. Also, while some factors selectively affect neurogenesis in one of the neurogenetic zones, it is not clear how selectivity is achieved. Estrogen is a hormonal modulator of neurogenesis. To address the issues of direct versus indirect control and regional specificity we investigated the colocalization of immunoreactivity for a proliferating cell marker, Ki-67, and a marker for migrating and differentiating cells with a neuronal phenotype, doublecortin, with the expressions of mRNA for estrogen receptors alpha and beta. We found an extensive colocalization of estrogen receptor alpha with both markers in the dentate gyrus and only with Ki-67 in the subventricular zone. An extensive colocalization of estrogen receptor beta with both markers was found in the dentate gyrus, but only a few Ki-67-immunoreactive and no doublecortin-immunoreactive cells of the subventricular zone expressed estrogen receptor beta mRNA. Estrogen receptor alpha and beta mRNAs were not expressed in other telencephalic Ki-67-immunoreactive cells or in constitutively doublecortin-immunoreactive cells of the piriform cortex. The extensive colocalization of immunoreactive markers for cell proliferation and differentiation with mRNAs for estrogen receptor alpha and estrogen receptor beta points to the direct modulation of dentate cell proliferation, differentiation and survival by estrogen, while direct effects of estrogen in the subventricular zone appear restricted to estrogen receptor alpha-mediated effects operating at the time of cell proliferation.     

Reducing hippocampal cell proliferation in the adult rat does not prevent the acquisition of cocaine-induced conditioned place preference

Neurogenesis is important for developing certain forms of memory. Recently, hippocampal cell proliferation has been implicated in the development of drug addiction, an extreme form of emotional/motivational pathological memory. Aiming to explore the role of hippocampal neural cell proliferation in cocaine-induced conditioned place preference (CPP), we treated rats with whole brain X-irradiation, which substantially decreases the number of progenitor cells in the subventricular zone of the lateral ventricles and subgranular zone of the dentate gyrus. Surprisingly, there was no difference in the expression of cocaine-induced CPP. These results suggest that the existing neural network, rather than potential new neural circuits mediated by adult neurogenesis, is sufficient for the acquisition of cocaine-induced CPP.     

Synergistic effects of dehydroepiandrosterone and fluoxetine on proliferation of progenitor cells in the dentate gyrus of the adult male rat

The 5-HT re-uptake inhibitor (SSRI) fluoxetine and the adrenal hormone dehydroepiandrosterone (DHEA) both increase the proliferation of progenitor cells in the adult hippocampus and also have antidepressant activity. This paper explores the combined ability of fluoxetine and DHEA to affect this process in the dentate gyrus of adult rats. We show that DHEA can render an otherwise ineffective dose of fluoxetine (2.5 mg/kg) able to increase progenitor cell proliferation to the same extent as doses four times higher (10 mg/kg). This synergistic action does not appear to be mediated by alterations in brain-derived neurotrophic factor (BDNF) gene expression; or by TrkB, mineralocorticoid, glucocorticoid, or 5-HT (5HT1A) receptor expression in the dentate gyrus; or by altered levels of plasma corticosterone. In a second experiment, the synergism between DHEA and fluoxetine was replicated. Furthermore, flattening the diurnal rhythm of plasma corticosterone by implanting additional corticosterone pellets s.c. prevented the effect of fluoxetine on progenitor cell division. This was not overcome by simultaneous treatment with DHEA, despite the latter's reported anti-glucocorticoid actions. The cellular mechanism for the potentiating action of DHEA on the pro- proliferative effects of fluoxetine in the adult hippocampus remains to be revealed. Since altered neurogenesis has been linked to the onset or recovery from depression, one consequence of these results is to suggest DHEA as a useful adjunct therapy for depression.     

p75 neurotrophin receptor regulates basal and fluoxetine-stimulated hippocampal neurogenesis

It is widely acknowledged that neurogenesis occurs in the adult hippocampus under normal conditions and that the rate can be regulated by environmental factors, including antidepressant drugs, with concomitant effects on behaviour. Using a quick and sensitive flow cytometry method that can assess changes in the number of bromodeoxyuridine (BrdU)-positive cells in hippocampus, in combination with traditional histological cell counts in the dentate gyrus, we report that mice lacking the p75 neurotrophin receptor gene (p75^NTR−/−) have significantly reduced hippocampal neurogenesis. Chronic treatment with the antidepressant fluoxetine stimulated hippocampal cell proliferation in p75^NTR−/− animals, but it did not result in an increase above basal levels of the number of newly born neurons in the dentate gyrus. These results indicate that p75^NTR acts as a regulator of fluoxetine-stimulated as well as basal adult hippocampal neurogenesis.