Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood

Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.     

Serotonin and neurogenesis in the hippocampal dentate gyrus of adult mammals

It is well documented that in mammals new neurons are generated in the dentate gyrus (DG) and integrated into hippocampal circuits throughout their life. However, functions of these newly generated cells are still hotly debated. One of the important factors that may influence the rate of DG neurogenesis is serotonin. Apart from being a neurotransmitter and neuromodulator it plays many other roles in the central nervous system, including the role of a trophic factor influencing functional state of neurons. In this review I discuss the changing views on adult hippocampal neurogenesis then briefly describe the anatomy and function of the hippocampus, focusing on its serotonergic innervation and receptors. Further, the possible role of serotonin and the newly generated DG neurons in hippocampus-dependent memory is discussed. Finally mechanisms by which serotonin and its receptors influence neurogenesis in the adult DG are summarized and hypotheses linking the decreased rate of DG neurogenesis with mechanisms of depression are discussed.     

Monoaminergic regulation of Sonic hedgehog signaling cascade expression in the adult rat hippocampus

Monoamines are implicated in the modulation of adult hippocampal neurogenesis in depression models and following chronic antidepressant treatment. Given the key role of Sonic hedgehog (Shh) in adult neurogenesis, we examined whether monoaminergic perturbations regulate the expression of Shh or its co-receptors Smoothened (Smo) and Patched (Ptc). Combined depletion of both serotonin and norepinephrine with para-chlorophenylalanine (PCPA) resulted in a significant decrease in Smo and Ptc mRNA within the dentate gyrus subfield of the hippocampus. However, selective depletion of serotonin, using the serotonergic neurotoxin 5,7-dihyrdroxytryptamine (5,7-DHT), or norepinephrine, using the noradrenergic neurotoxin DSP-4, did not alter expression of Shh and its co-receptors, Smo and Ptc. Acute treatment with the monoamine releasing agent, para-chloroamphetamine (PCA) significantly upregulated Smo mRNA within the dentate gyrus. However, acute or chronic treatment with pharmacological antidepressants that modulate monoaminergic neurotransmission did not regulate Shh cascade expression. These results indicate that robust changes in monoamine levels can regulate the expression of the Shh signaling cascade in the adult rodent brain.     

Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus

Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse 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.     

Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain

Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.     

The hormone therapy,Premarin, impairs hippocampus-dependent spatial learning and memory and reduces activation of new granule neurons in response to memory in female rats

Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer's disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 μg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin-treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons.     

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.     

Valproic acid reduces spatial working memory and cell proliferation in the hippocampus

Valproic acid (VPA) is widely used clinically, as an anticonvulsant and mood stabilizer but is, however, also known to block cell proliferation through its ability to inhibit histone deacetylase enzymes. There have been a number of reports of cognitive impairments in patients taking VPA. In this investigation we examined the relationship between cognition and changes in cell proliferation within the hippocampus, a brain region where continued formation of new neurons is associated with learning and memory. Treatment of rats by i.p. injection of VPA, reduced cell proliferation in the sub granular zone of the dentate gyrus within the hippocampus. This was linked to a significant impairment in their ability to perform a hippocampus-dependent spatial memory test (novel object location). In addition, drug treatment caused a significant reduction in brain-derived neurotrophic factor (BDNF) and Notch 1 but not doublecortin levels within the hippocampus. These results support the idea that VPA may cause cognitive impairment and provide a possible mechanism for this by reducing neurogenesis within the hippocampus.     

Impact of N-tau on adult hippocampal neurogenesis,anxiety, and memory

Different pathological tau species are involved in memory loss in Alzheimer's disease, the most common cause of dementia among older people. However, little is known about how tau pathology directly affects adult hippocampal neurogenesis, a unique form of structural plasticity implicated in hippocampus-dependent spatial learning and mood-related behavior. To this aim, we generated a transgenic mouse model conditionally expressing a pathological tau fragment (26–230 aa of the longest human tau isoform, or N-tau) in nestin-positive stem/progenitor cells. We found that N-tau reduced the proliferation of progenitor cells in the adult dentate gyrus, reduced cell survival and increased cell death by a caspase-3–independent mechanism, and recruited microglia. Although the number of terminally differentiated neurons was reduced, these showed an increased dendritic arborization and spine density. This resulted in an increase of anxiety-related behavior and an impairment of episodic-like memory, whereas less complex forms of spatial learning remained unaltered. Understanding how pathological tau species directly affect neurogenesis is important for developing potential therapeutic strategies to direct neurogenic instructive cues for hippocampal function repair.     

Antisense Noggin oligodeoxynucleotide administration decreases cell proliferation in the dentate gyrus of adult rats

The dentate gyrus of the hippocampus is one of few regions in the adult mammalian brain characterized by ongoing neurogenesis. It has been demonstrated that Noggin antagonizes bone morphogenetic protein-4 (BMP4) to create a niche for subventricular zone neurogenesis. We previously demonstrated that Noggin and BMP4 showed strong expression in the proliferative subgranular layer of the dentate gyrus in adult rats. To examine the action of Noggin on cell proliferation in the dentate gyrus of adult rats, we administered antisense oligodeoxynucleotide (ASODN) to Noggin by continuous infusion into the lateral ventricle of rats. Antisense-infused rats displayed significant reduction in number of bromodeoxyuridine (BrdU) labeled cells in the dentate gyrus. This indicated that endogenous Noggin activity is important for naturally occurring cell proliferation in the dentate gyrus, and perhaps neurogenesis, and is one of the many factors involved in its regulation.     

The aging hippocampus: a multi-level analysis in the rat

In the current experiment we conducted a multi-level analysis of age-related characteristics in the hippocampus of young adult (3 months), middle-aged (12 months), and old (24 months) Fisher 344xBrown Norway hybrid (FBNF1) rats. We examined the relationships between aging, hippocampus, and memory using a combination of behavioral, non-invasive magnetic resonance imaging and spectroscopy, and postmortem neuroanatomical measures in the same rats. Aging was associated with functional deficits on hippocampus-dependent memory tasks, accompanied by structural alterations observed both in vivo (magnetic resonance imaging-hippocampal volume) and postmortem (dentate gyrus neuronal density and neurogenesis). Neuronal metabolic integrity, assessed by levels of N-acetylaspartate with magnetic resonance spectroscopy, was however, preserved. Further, our results suggest that neurogenesis (doublecortin) seems to be related to both performance deficits on hippocampus-dependent tasks and hippocampal volume reduction. The observed pattern of age-related alterations closely resembles that previously reported in humans and suggests FBNF1 rats to be a useful model of normal human aging.     

Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats

During adulthood, neuronal precursor cells persist in two discrete regions, the subventricular zone[19]and the hippocampal subgranular zone,[11]as recently demonstrated in primates.[10]To date, a few factors such as adrenal steroids[9]and trophic factors[13]are known to regulate adult neurogenesis. Since neuronal activity may also influence cellular development and plasticity in brain, we investigated the effects of serotonin depletion on cell proliferation occurring in these regions. Indeed, in addition to its role as a neurotransmitter, 5-hydroxytryptamine (serotonin) is considered as a developmental regulatory signal.14, 22Prenatal depletion in 5-hydroxytryptamine delays the onset of neurogenesis in 5-hydroxytryptamine target regions[14]and 5-hydroxytryptamine promotes the differentiation of cortical and hippocampal neurons.15, 23Although in the adult brain, a few studies have suggested that 5-hydroxytryptamine may play a role in neuronal plasticity by maintaining the synaptic connections in the cortex and hippocampus,3, 6, 16no information is actually available concerning the influence of 5-hydroxytryptamine on adult neurogenesis. If further work confirms that new neurons can be produced in the adult human brain as is the case for a variety of species, it is particularly relevant to determine the influence of 5-hydroxytryptamine on neurogenesis in the hippocampal formation, a part of the brain largely implicated in learning and memory processes. Indeed, lack of 5-hydroxytryptamine in the hippocampus has been associated with cognitive disorders, such as depression,[1]schizophrenia and Alzheimer's disease.[7]In the present study, we demonstrated that both inhibition of 5-hydroxytryptamine synthesis and selective lesions of 5-hydroxytryptamine neurons are associated with decreases in the number of newly generated cells in the dentate gyrus, as well as in the subventricular zone.     

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.     

Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning

Hippocampus-mediated learning enhances neurogenesis in the adult dentate gyrus (DG), and this process has been suggested to be involved in memory formation. The hippocampus receives abundant cholinergic innervation and acetylcholine (ACh) plays an important role in learning and Alzheimer's disease (AD) pathophysiology. Here, we show that a selective neurotoxic lesion of forebrain cholinergic input with 192 IgG-saporin reduces DG neurogenesis with a concurrent impairment in spatial memory. Conversely, systemic administration of the cholinergic agonist physostigmine increases DG neurogenesis. We find that changes of forebrain ACh levels primarily influence the proliferation and/or the short-term survival rather than the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggest that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.     

穹窿海马伞损伤对大鼠学习记忆和海马GFAP阳性神经胶质细胞的影响

为探讨穹隆海马伞损伤鼠学习记忆能力与海马胶质纤维酸性蛋白阳性细胞之间的关系 ,切断 SD成年大鼠左侧穹窿海马伞 ,用 Y迷宫和免疫组织化学结合图像分析系统测试大鼠学习记忆能力和海马胶质纤维酸性蛋白阳性细胞的变化状况及它们的相互关系。结果显示 :损伤 2周后 ,损伤组损伤侧海马 CA1 区辐射层和齿状回分子层胶质纤维酸性蛋白阳性细胞的数密度较正常组分别增多 3 0 .2 9%和 3 0 .15 % (都为 P<0 .0 1) ,胞体面积分别增加 16.0 4%和 19.42 % (都为 P<0 .0 1) ,齿状回分子层胶质纤维酸性蛋白阳性细胞体密度增大 19.40 % (P<0 .0 5 )。经相关分析 ,大鼠学习记忆能力与海马 CA1 区胶质纤维酸性蛋白阳性细胞数密度呈负相关 (r=-0 .83 6,P<0 .0 1) ,与齿状回数密度呈负相关 (r=-0 .792 ,P<0 .0 1)。提示海马星形胶质细胞可能参与学习记忆过程     

Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation

Adult neurogenesis in the hippocampus continues throughout life and may play an important role in hippocampus-dependent learning and memory. Previous research has been equivocal, demonstrating that spatial learning may enhance, decrease or not significantly affect the survival of new neurons. A potential cause of these varying results may be differences in when bromodeoxyuridine (BrdU) was administered relative to spatial training. We examined whether the time elapsed between BrdU administration and spatial learning would alter the survival of the labeled cells. We injected rats with BrdU once on day 0 and then trained in the standard place version of the Morris water task on days 1-5, 6-10 or 11-15 after BrdU injection. We found an enhancement of neurogenesis in the hippocampus only when BrdU was administered 6 days prior to the beginning of spatial training. There was no significant change in hippocampal neurogenesis for groups that started training either 1 or 11 days following BrdU administration. This suggests that a critical period exists in the development of new neurons during which time their survival may be altered by activation of the hippocampus. Furthermore, when dividing rats into poor versus good learners based on overall performance using a median split, only poor place learners and not good place learners exhibit increased hippocampal neurogenesis compared with cue learning, collapsed across time of training. These findings provide further evidence of a link between learning and adult neurogenesis.     

Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat

The generation of new neurons in the adult mammalian brain has been documented in numerous recent reports. Studies undertaken so far indicate that adult hippocampal neurogenesis is related in a number of ways to hippocampal function.Here, we report that subjecting adult rats to fractionated brain irradiation blocked the formation of new neurons in the dentate gyrus of the hippocampus. At different time points after the termination of the irradiation procedure, the animals were tested in two tests of short-term memory that differ with respect to their dependence on hippocampal function. Eight and 21 days after irradiation, the animals with blocked neurogenesis performed poorer than controls in a hippocampus-dependent place-recognition task, indicating that the presence of newly generated neurons may be necessary for the normal function of this brain area. The animals were never impaired in a hippocampus-independent object-recognition task. These results are in line with other reports documenting the functional significance of newly generated neurons in this region. As our irradiation procedure models prophylactic cranial irradiation used in the treatment of different cancers, we suggest that blocked neurogenesis contributes to the reported deleterious side effects of this treatment, consisting of memory impairment, dysphoria and lethargy.     

Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis

Alzheimer's disease is a learning and memory disorder pathologically characterized by the deposition of beta-amyloid plaques and loss of neurons and synapses in affected areas of the brain. Mutations in presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD), and are associated with accelerated plaque deposition. However, since the function of PS1 is pleiotropic, we reasoned that the FAD mutations may alter multiple PS1-mediated pathways, and the combination of which may account for the early onset nature of the disease phenotype. Using the PS1M146V knockin mice in which the M146V mutation was incorporated into the endogenous mouse PS1 gene, we report here that the FAD mutation results in impaired hippocampus-dependent associative learning, as measured by a contextual fear conditioning paradigm, at 3 months of age. This is correlated with reduced adult neurogenesis in the dentate gyrus. However, short-term and long-term synaptic plasticity in both area CA1 and dentate gyrus are not affected. Our results suggest that impaired adult neurogenesis may contribute to the memory deficit associated with FAD.     

慢性复合应激增强大鼠海马Doublecortin的表达

目的 探讨慢性复合应激性学习记忆增强大鼠海马齿状回(DG)新生神经元数量变化以及Doublecortin(DCX)在海马组织中表达的变化及其意义.方法 成年雄性大鼠随机分为复合应激组和正常对照组.复合应激组动物每天交替暴露于复合应激原中达6周.实验结束后,所有动物分别进行3d的Morris水迷宫测试,记录其学习和记忆成绩.运用免疫细胞化学方法观察海马DG新生神经元数量的变化,同时运用Western blotting和RT-PCR技术分别检测DCX在海马的表达及其mRNA水平的变化.结果 与对照组相比,复合应激组动物的学习与记忆成绩优于对照组(P＜0.05);其海马DG新生神经元数明显增多(P＜0.05);海马DCX蛋白的表达明显增加(P＜0.05);海马DCX mRNA水平明显上调(P＜0.05).结论 慢性复合应激致大鼠的学习与记忆能力增强,海马DG内DCX阳性细胞数增多,提示新生神经元数量增加是导致大鼠学习记忆能力增强的原因之一.