Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus

Aging leads to functional changes in the hippocampus, and consequently induces cognitive deficits, such as failure of memory. Neurogenesis in the hippocampal dentate gyrus continues throughout life, but steadily declines from early adulthood. Apoptosis occurs under various pathologic and physiologic conditions, and excessive apoptotic cell death can cause a number of functional disorders in humans. Apoptosis in the hippocampus also disturbs cognitive functions. In this study, we examined the effect of treadmill exercise on memory in relation to neurogensis and apoptosis in the hippocampal dentate gyrus of old-aged rats. The present results showed that loss of memory by aging was associated with a decrease in neurogenesis and an increase in apoptosis in the hippocampal dentate gyrus. Treadmill exercise improved short-term and spatial memories by enhancing neurogenesis and suppressing apoptosis in the hippocampal dentate gyrus of old-aged rats. In the present study, we showed that treadmill exercise is a very useful strategy for preventing failure of memory in the elderly.     

Increased neurogenesis in dentate gyrus of long-lived Ames dwarf mice

Neurogenesis occurs throughout adult life in the dentate gyrus of mammalian hippocampus and has been suggested to play an important role in cognitive function. Multiple trophic factors including IGF-I have been demonstrated to regulate hippocampal neurogenesis. Ames dwarf mice live considerably longer than normal animals and maintain physiological function at youthful levels, including cognitive function, despite a deficiency of circulating GH and IGF-I. Here we show an increase in numbers of newly generated cells [bromodeoxyuridine (BrdU) positive] and newborn neurons (neuronal nuclear antigen and BrdU positive) in the dentate gyrus of adult dwarf mice compared with normal mice using BrdU labeling. Despite the profound suppression of hippocampal GH expression, hippocampal IGF-I protein levels are up-regulated and the corresponding mRNAs are as high in Ames dwarf as in normal mice. Our results suggest that local/hippocampal IGF-I expression may have induced the increase in hippocampal neurogenesis, and increased neurogenesis might contribute to the maintenance of youthful levels of cognitive function during aging in these long-lived animals.     

Imaging correlates of brain function in monkeys and rats isolates a hippocampal subregion differentially vulnerable to aging

The hippocampal formation contains a distinct population of neurons organized into separate anatomical subregions. Each hippocampal subregion expresses a unique molecular profile accounting for their differential vulnerability to mechanisms of memory dysfunction. Nevertheless, it remains unclear which hippocampal subregion is most sensitive to the effects of advancing age. Here we investigate this question by using separate imaging techniques, each assessing different correlates of neuronal function. First, we used MRI to map cerebral blood volume, an established correlate of basal metabolism, in the hippocampal subregions of young and old rhesus monkeys. Second, we used in situ hybridization to map Arc expression in the hippocampal subregions of young and old rats. Arc is an immediate early gene that is activated in a behavior-dependent manner and is correlated with spike activity. Results show that the dentate gyrus is the hippocampal subregion most sensitive to the effects of advancing age, which together with prior studies establishes a cross-species consensus. This pattern isolates the locus of age-related hippocampal dysfunction and differentiates normal aging from Alzheimer's disease.     

Continuation of neurogenesis in the hippocampus of the adult macaque monkey

We present evidence for continuous generation of neurons, oligodendrocytes, and astrocytes in the hippocampal dentate gyrus of adult macaque monkeys, using immunohistochemical double labeling for bromodeoxyuridine and cell-type-specific markers. We estimate that the relative rate of neurogenesis is approximately 10 times less than that reported in the adult rodent dentate gyrus. Nevertheless, the generation of these three cell types in a discreet brain region suggests that a multipotent neural stem cell may be retained in the adult primate hippocampus. This demonstration of adult neurogenesis in nonhuman Old World primates-with their phylogenetic proximity to humans, long life spans, and elaborate cognitive abilities-establishes the macaque as an unexcelled animal model to experimentally investigate issues of neurogenesis in humans and offers new insights into its significance in the adult brain.     

Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus

Although hippocampal neurogenesis has been described in many adult mammals, the functional impact of this process on physiology and behavior remains unclear. In the present study, we used two independent methods to ablate hippocampal neurogenesis and found that each procedure caused a limited behavioral deficit and a loss of synaptic plasticity within the dentate gyrus. Specifically, focal X irradiation of the hippocampus or genetic ablation of glial fibrillary acidic protein-positive neural progenitor cells impaired contextual fear conditioning but not cued conditioning. Hippocampal-dependent spatial learning tasks such as the Morris water maze and Y maze were unaffected. These findings show that adult-born neurons make a distinct contribution to some but not all hippocampal functions. In a parallel set of experiments, we show that long-term potentiation elicited in the dentate gyrus in the absence of GABA blockers requires the presence of new neurons, as it is eliminated by each of our ablation procedures. These data show that new hippocampal neurons can be preferentially recruited over mature granule cells in vitro and may provide a framework for how this small cell population can influence behavior.     

Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice

It is now well established that neurogenesis in the rodent subgranular zone of the hippocampal dentate gyrus continues throughout adulthood. Neuroblasts born in the dentate subgranular zone migrate into the granule cell layer, where they differentiate into neurons known as dentate granule cells. Suppression of neurogenesis by irradiation or genetic ablation has been shown to disrupt synaptic plasticity in the dentate gyrus and impair some forms of hippocampus-dependent learning and memory. Using a recently developed transgenic mouse model for suppressing neurogenesis, we sought to determine the long-term impact of ablating neurogenesis on synaptic plasticity in young-adult mice. Consistent with previous reports, we found that ablation of neurogenesis resulted in significant deficits in dentate gyrus long-term potentiation (LTP) when examined at a time proximal to the ablation. However, the observed deficits in LTP were not permanent. LTP in the dentate gyrus was restored within 6 wk and this recovery occurred in the complete absence of neurogenesis. The recovery in LTP was accompanied by prominent changes within the dentate gyrus, including an increase in the survival rate of newborn cells that were proliferating just before the ablation and a reduction in inhibitory input to the granule cells of the dentate gyrus. These findings suggest that prolonged suppression of neurogenesis in young-adult mice results in wide-ranging compensatory changes in the structure and dynamics of the dentate gyrus that function to restore plasticity.     

Persistent impairment of hippocampal neurogenesis in young adult rats following early postnatal alcohol exposure

Background: Prenatal alcohol exposure can cause damage to the developing fetus with outcomes including growth deficiency, facial dysmorphology, brain damage, and cognitive and behavioral deficits. Smaller brains in children with FASD have been linked both with reduced cell proliferation in the developing CNS and with apoptotic cell loss of postmitotic neurons. Prenatal alcohol exposure in rodents during the period of brain development comparable to that of the first and second trimesters of human pregnancy persistently alters adult neurogenesis. Long‐term effects of alcohol exposure during the third trimester equivalent, which occurs postnatally in the rat, on adult neurogenesis have not been previously reported. The goal of this study was to examine the effect of postnatal binge‐like alcohol exposure on cell proliferation and neurogenesis in hippocampal dentate gyrus during adolescence and young adulthood. Methods: Male Long‐Evans rat pups were assigned to 3 groups: alcohol‐exposed (AE), sham‐intubated (SI) or suckle control (SC). AE pups received ethanol in a milk formula in a binge manner (2 feedings, 2 hours apart, total dose 5.25 g/kg/day) on postnatal days (PD) 4–9. BrdU was injected every other day on PD30–50. Animals were perfused either on PD50 to examine cytogenesis and neurogenesis in hippocampal dentate gyrus at the end of BrdU injections or on PD80 to evaluate new cell survival. Dorsal hippocampal sections were immunostained for BrdU, a marker for proliferating cells, Ki67, endogenous marker of proliferation, and NeuN, a marker for mature neurons. Results: Binge‐like alcohol exposure on PD4–9 significantly reduced the number of mature neurons in adult hippocampal dentate gyrus (DG) both on PD50 and PD80, without altering cumulative cytogenesis on PD50. In addition, the number of new neurons, that were generated between PD30 and 50, was further reduced after 30 days of survival in all 3 groups (SC, SI, and AE). Conclusions: These observations suggest that early postnatal binge alcohol exposure results in long‐term deficits of adult hippocampal neurogenesis, providing a potential basis for the deficits of hippocampus‐dependent behaviors reported for this model.     

Paradoxical influence of hippocampal neurogenesis on working memory

To explore the function of adult hippocampal neurogenesis, we ablated cell proliferation by using two independent and complementary methods: (i) a focal hippocampal irradiation and (ii) an inducible and reversible genetic elimination of neural progenitor cells. Previous studies using these methods found a weakening of contextual fear conditioning but no change in spatial reference memory, suggesting a supportive role for neurogenesis in some, but not all, hippocampal-dependent memory tasks. In the present study, we examined hippocampal-dependent and -independent working memory using different radial maze tasks. Surprisingly, ablating neurogenesis caused an improvement of hippocampal-dependent working memory when repetitive information was presented in a single day. These findings suggest that adult-born cells in the dentate gyrus have different, and in some cases, opposite roles in distinct types of memory.     

Diminished adult neurogenesis in the marmoset brain precedes old age

With aging there is a decline in the number of newly generated neurons in the dentate gyrus of the hippocampus. In rodents and tree shrews, this age-related decrease in neurogenesis is evident long before the animals become aged. No previous studies have investigated whether primates exhibit a similar decline in hippocampal neurogenesis with aging. To investigate this possibility, young to middle aged adult common marmosets (Callithrix jacchus) were injected with BrdU and perfused 3 weeks later. The number of newly generated cells in the subgranular zone/granule cell layer of the dentate gyrus was significantly lower in older animals and decreased linearly with age. A similar age-related decline in new cells was observed in the subventricular zone but not in the hilar region of the dentate gyrus. These data demonstrate that a substantial decrease in neurogenesis occurs before the onset of old age in the adult marmoset brain, suggesting the possibility that similar alterations occur in the human brain.     

Maturation time of new granule cells in the dentate gyrus of adult macaque monkeys exceeds six months

We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis in the dentate gyrus of the hippocampus. In the first group, six adult monkeys (Macaca mulatta) received a single injection of the thymidine analog BrdU (75 mg/kg), which is incorporated into replicating DNA and serves as a marker for new cell birth. Brain tissue was collected 48 h, 2 wk, and 6 wk after BrdU injection to examine the initial stages of neurogenesis. Because mature neurons were not evident at 6 wk, we examined tissue collected over a longer time course in a second study. In this study, eight monkeys (Macaca fascicularis) who were subjects in a separate exercise study received 10 weekly injections of BrdU (75 mg/kg), and brain tissue was collected at 16 and 28 wk from the first injection. Based on the timing of expression of neuronal cell markers (βIII-tubulin, doublecortin, NeuN), the extent of dendritic arborization, and acquisition of mature cell body morphology, we show that granule cell maturation in the dentate gyrus of a nonhuman primate is protracted over a minimum of a 6-mo time period, more than 6 times longer than in rodents. The lengthened time course for new cell maturation in nonhuman primates may be appropriate for preservation of neural plasticity over their longer life span and is relevant to our understanding of antidepressant and other therapies that have been linked to neurogenesis in humans.     

Moderate fetal alcohol exposure impairs the neurogenic response to an enriched environment in adult mice

BACKGROUND: Prenatal ethanol exposure results in a spectrum of cognitive and behavioral deficits and affects an estimated thirteen percent of children born in the United States. The basis of prenatal ethanol-induced impairment of brain function has been widely studied in animal models, where significant changes in the physiological and structural plasticity of hippocampal function have been documented. Here, we explored the possibility that exposure to moderate levels of alcohol in utero might also result in long-lasting impairment of adult hippocampal neurogenesis, a novel form of plasticity that occurs throughout adulthood. METHODS: Female mice were trained to voluntarily consume 10% EtOH throughout pregnancy using the two-bottle choice paradigm, which results in moderate blood alcohol levels of approximately 121 mg/dl, as previously described (Allan et al., 2003). Offspring were exposed to standard or enriched living conditions for 8-12 weeks post-weaning. BrdU was administered at 50 mg/kg for 12 consecutive days. Mice in each housing condition were sacrificed at either 24 hrs or four weeks following the final BrdU injection, and BrdU cells within the dentate gyrus were evaluated using immuno-histochemical methods. RESULTS: Neither fetal alcohol exposure (FAE) nor enriched environment affected the number of proliferating progenitors within the subgranular zone (SGZ) of the dentate gyrus. However, FAE severely impaired the neurogenic response to enriched environment. Control mice housed in enriched environment displayed a two-fold increase in hippocampal neurogenesis, whereas FAE mice responded to enriched environment with neither enhanced progenitor survival nor enhanced neuronal differentiation. CONCLUSIONS: These observations indicate that moderate FAE results in a long-term, persistent defect in neurogenic responses to behavioral challenge.     

Running enhances spatial pattern separation in mice

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.     

Hippocampal neurogenesis in adult Old World primates

The production of new hippocampal neurons in adulthood has been well documented in rodents. Recent studies have extended these findings to other mammalian species, such as tree shrews and marmoset monkeys. However, hippocampal neurogenesis has not been demonstrated in adult Old World primates. To investigate this possibility, we injected 11 adult Old World monkeys of different ages (5-23 years) with the thymidine analog bromodeoxyuridine and examined the fate of the labeled cells at different survival times by using neuronal and glial markers. In the young-adult and middle-aged monkeys, we found a substantial number of cells that incorporated bromodeoxyuridine and exhibited morphological and biochemical characteristics of immature and mature neurons. New cells located in the dentate gyrus expressed a marker of immature granule neurons, Turned On After Division 64 kDa protein, as well as markers of mature granule neurons including neuron specific enolase, neuronal nuclei, and the calcium-binding protein calbindin. Fewer new cells expressed the astroglial marker glial fibrillary acidic protein. Evidence of neurogenesis was observed in the oldest monkeys (23 years) as well, but it appeared to be less robust. These results indicate that the adult brains of Old World monkeys produce new hippocampal neurons. Adult macaque monkeys may provide a useful primate model for studying the functional significance of adult neurogenesis.     

Running enhances neurogenesis, learning, and long-term potentiation in mice

Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is important for memory function. Consequently, spatial learning and long-term potentiation (LTP) were tested in groups of mice housed either with a running wheel (runners) or under standard conditions (controls). Mice were injected with bromodeoxyuridine to label dividing cells and trained in the Morris water maze. LTP was studied in the dentate gyrus and area CA1 in hippocampal slices from these mice. Running improved water maze performance, increased bromodeoxyuridine-positive cell numbers, and selectively enhanced dentate gyrus LTP. Our results indicate that physical activity can regulate hippocampal neurogenesis, synaptic plasticity, and learning.     

Melatonin synergizes with citalopram to induce antidepressant‐like behavior and to promote hippocampal neurogenesis in adult mice

Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive‐like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14–33%) and citalopram (<17–30%). Additionally, the MLTCITAL combination also decreased immobility (<22–35%) in comparison with control mice, reflecting an antidepressant‐like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of ‐associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant‐like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.     

离子型谷氨酸受体拮抗剂对大鼠脑缺血再灌注后海马齿状回5-溴脱氧尿核苷表达的影响

目的　观察选择性离子型谷氨酸受体 (iGluRs)拮抗剂对大鼠全脑缺血再灌注损伤后齿状回神经发生的调控作用 ,探讨谷氨酸 离子型谷氨酸受体通路在神经发生中的作用。方法　采用 5 溴脱氧尿核苷 (BrdU)标记分裂细胞 ,比较大鼠全脑缺血再灌注损伤后 7d和 14d时各iGluRs拮抗剂处理组与相应对照组之间海马齿状回神经前体细胞的增殖速度。结果　腹腔注射N 甲基 D 天门冬氨酸 (NMDA)受体阻滞剂 5 甲基二氢二苯丙环庚烯亚胺后显著抑制了大鼠全脑缺血后 7d和 14d时齿状回神经发生水平的升高 ,BrdU免疫阳性细胞数较缺血再灌注 +生理盐水组各时间点明显减少 ;而α 氨基羟甲基恶唑丙酸和 (或 )红藻氨酸受体阻滞剂二硝基喹喔啉对全脑缺血后不同时间点齿状回神经发生的增强基本没有影响。结论　全脑缺血再灌注损伤后NMDA受体通路的激活可能促进了齿状回神经发生。     

Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat

Abstract:  It was previously shown that pinealectomy causes delayed loss of pyramidal neurons in rat hippocampal layers CA1/3 and that this is reversed by melatonin supplementation. Here, we used immunohistologic detection of doublecortin, a protein expressed in newborn neurons, to determine if melatonin supplementation promotes neurogenesis after pinealectomy. It was found that melatonin supplementation significantly increased the number of doublecortin immunoreactive neurons in the dentate gyrus over the postsurgical intervals of 2, 4, 6, 8, 10 and 17 months. The increase was most evident at 6 months postsurgery and thereafter, and was apparent despite a severe decline in doublecortin-labeled cells over the 17 month postsurgical interval in all groups of rats. Doublecortin immunoreactive cells were not observed in the pyramidal layer itself. These results indicate that melatonin promotes neurogenesis in the dentate gyrus of pinealectomized rats. However, it is equivocal that these newborn neurons migrate to the pyramidal layer and account for the reappearance of neurons at this location in these rats. This study provides further evidence for a role of melatonin in promoting neurogenesis, adding another role to its already remarkably pleiotropic profile. The scope and significance of this newly discovered role remains to be determined.     

Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis

Neurogenesis occurs within the adult dentate gyrus of the hippocampal formation and it has been proposed that the newly born neurons, recruited into the preexistent neuronal circuits, might be involved in hippocampal-dependent learning processes. Age-dependent spatial memory impairments have been related to an alteration in hippocampal plasticity. The aim of the current study was to examine whether cognitive functions in aged rats are quantitatively correlated with hippocampal neurogenesis. To this end, we took advantage of the existence of spontaneous individual differences observed in aged subjects in a hippocampal-dependent task, the water maze. We expected that the spatial memory capabilities of aged rats would be related to the levels of hippocampal neurogenesis. Old rats were trained in the water maze, and, 3 weeks after training, rats were injected with 5-bromo-2'-deoxyuridine (BrdUrd, 50 or 150 mg/kg) to label dividing cells. Cell proliferation was examined one day after the last BrdUrd injection, whereas cell survival and differentiation were determined 3 weeks later. It is shown that a quantitative relationship exists between learning and the number of newly generated neurons. Animals with preserved spatial memory, i.e., the aged-unimpaired rats, exhibited a higher level of cell proliferation and a higher number of new neurons in comparison with rats with spatial memory impairments, i.e., the aged-impaired rats. In conclusion, the extent of memory dysfunction in aged rats is quantitatively related to the hippocampal neurogenesis. These data reinforce the assumption that neurogenesis is involved in memory processes and aged-related cognitive alterations.