Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity,anxiety, and memory deficits

Exposure to prolonged stress results in structural and functional alterations in the hippocampus including reduced long‐term potentiation (LTP), neurogenesis, spatial learning and working memory impairments, and enhanced anxiety‐like behavior. On the other hand, enriched environment (EE) has beneficial effects on hippocampal structure and function, such as improved memory, increased hippocampal neurogenesis, and progressive synaptic plasticity. It is unclear whether exposure to short‐term EE for 10 days can overcome restraint stress–induced cognitive deficits and impaired hippocampal plasticity. Consequently, the present study explored the beneficial effects of short‐term EE on chronic stress–induced impaired LTP, working memory, and anxiety‐like behavior. Male Wistar rats were subjected to chronic restraint stress (6 hr/day) over a period of 21 days, and then they were exposed to EE (6 hr/day) for 10 days. Restraint stress reduced hippocampal CA1‐LTP, increased anxiety‐like symptoms in elevated plus maze, and impaired working memory in T‐maze task. Remarkably, EE facilitated hippocampal LTP, improved working memory performance, and completely overcame the effect of chronic stress on anxiety behavior. In conclusion, exposure to EE can bring out positive effects on synaptic plasticity in the hippocampus and thereby elicit its beneficial effects on cognitive functions. © 2016 Wiley Periodicals, Inc.     

Chronic retinoic acid treatment suppresses adult hippocampal neurogenesis,in close correlation with depressive‐like behavior

Clinical studies have highlighted an association between retinoid treatment and depressive symptoms. As we had shown before that chronic application of all‐trans retinoic acid (RA) potently activated the hypothalamus‐pituitary‐adrenal (HPA) stress axis, we here questioned whether RA also induced changes in adult hippocampal neurogenesis, a form of structural plasticity sensitive to stress and implicated in aspects of depression and hippocampal function. RA was applied intracerebroventricularly (i.c.v.) to adult rats for 19 days after which animals were subjected to tests for depressive‐like behavior (sucrose preference) and spatial learning and memory (water maze) performance. On day 27, adult hippocampal neurogenesis and astrogliosis was quantified using BrdU (newborn cell survival), PCNA (proliferation), doublecortin (DCX; neuronal differentiation), and GFAP (astrocytes) as markers. RA was found to increase retinoic acid receptor‐α (RAR‐α) protein expression in the hippocampus, suggesting an activation of RA‐induced signaling mechanisms. RA further potently suppressed cell proliferation, newborn cell survival as well as neurogenesis, but not astrogliosis. These structural plasticity changes were significantly correlated with scores for anhedonia, a core symptom of depression, but not with water maze performance. Our results suggest that RA‐induced impairments in hippocampal neurogenesis correlate with depression‐like symptoms but not with spatial learning and memory in this design. Thus, manipulations aimed to enhance neurogenesis may help ameliorate emotional aspects of RA‐associated mood disorders. © 2016 Wiley Periodicals, Inc.     

Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation

Radiation therapy is a widely used treatment for brain tumors but it can cause delayed progressive cognitive decline and memory deficits. Previous studies suggested that this neurocognitive dysfunction might be linked to the impairment of hippocampal neurogenesis. However, little is known regarding how to reduce the cognitive impairment caused by radiation therapy. To investigate whether environmental enrichment (EE) promotes neurogenesis and cognitive function after irradiation, irradiated gerbils were housed in EE for 2 months and evaluated by neurobehavioral testing for learning and memory function, and immunohistochemical analysis for neurogenesis. Our results demonstrated that even relatively low doses (5-10 Gy) of irradiation could acutely abolish precursor cell proliferation in the dentate gyrus by more than 90%. This reduction in precursor proliferation was persistent and led to a significant decline in the granule cell population 9 months later. EE housing enhanced the number of newborn neurons and increased residual neurogenesis. EE also significantly increased the total number of immature neurons in the dentate gyrus. Furthermore, irradiated animals after EE housing showed a significant improvement in spatial learning and memory during the water-maze test and in rotorod motor learning over a 5-day training paradigm. In conclusion, EE has a positive impact on hippocampal neurogenesis and functional recovery in irradiated adult gerbils. Our data suggest that there is still a considerable amount of plasticity remaining in the hippocampal progenitor cells in adult animals after radiation injury, which can become a target of therapeutic intervention for radiation-induced cognitive dysfunction.     

New neurons restore structural and behavioral abnormalities in a rat model of PTSD

Post‐traumatic stress disorder (PTSD) has been associated with anxiety, memory impairments, enhanced fear, and hippocampal volume loss, although the relationship between these changes remain unknown. Single‐prolonged stress (SPS) is a model for PTSD combining three forms of stress (restraint, swim, and anesthesia) in a single session that results in prolonged behavioral effects. Using pharmacogenetic ablation of adult neurogenesis in rats, we investigated the role of new neurons in the hippocampus in the long‐lasting structural and behavioral effects of SPS. Two weeks after SPS, stressed rats displayed increased anxiety‐like behavior and decreased preference for objects in novel locations regardless of the presence or absence of new neurons. Chronic stress produced by daily restraint for 2 or 6 hr produced similar behavioral effects that were also independent of ongoing neurogenesis. At a longer recovery time point, 1 month after SPS, rats with intact neurogenesis had normalized, showing control levels of anxiety‐like behavior. However, GFAP‐TK rats, which lacked new neurons, continued to show elevated anxiety‐like behavior and enhanced serum corticosterone response to anxiogenic experience. Volume loss in ventral CA1 region of the hippocampus paralleled increases in anxiety‐like behavior, occurring in all rats exposed to SPS at the early time point and only rats lacking adult neurogenesis at the later time point. In chronic stress experiments, volume loss occurred broadly throughout the dentate gyrus and CA1 after 6‐hr daily stress but was not apparent in any hippocampal subregion after 2‐hr daily stress. No effect of SPS was seen on cell proliferation in the dentate gyrus, but the survival of young neurons born a week after stress was decreased. Together, these data suggest that new neurons are important for recovery of normal behavior and hippocampal structure following a strong acute stress and point to the ventral CA1 region as a potential key mediator of stress‐induced anxiety‐like behavior.     

Hippocampal brain‐derived neurotrophic factor mediates recovery from chronic stress‐induced spatial reference memory deficits

Chronic restraint stress impairs hippocampal‐mediated spatial learning and memory, which improves following a post‐stress recovery period. Here, we investigated whether brain‐derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress‐induced spatial memory deficits. Adult male Sprague‐Dawley rats were infused into the dorsal hippocampal cornu ammonis (CA)3 region with an adeno‐associated viral vector containing the sequence for a short hairpin RNA (shRNA) directed against BDNF or a scrambled sequence (Scr). Rats were then chronically restrained (wire mesh, 6 h/day for 21 days) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str‐Imm) or following a 21‐day post‐stress recovery period (Str‐Rec). All groups learned the RAWM task similarly, but differed on the memory retention trials. Rats in the Str‐Imm group, regardless of adeno‐associated viral contents, committed more errors in the spatial reference memory domain on the single retention trial during day 3 than did the non‐stressed controls. Importantly, the typical improvement in spatial memory following the recovery from chronic stress was blocked with the shRNA against BDNF, as Str‐Rec‐shRNA performed worse on the RAWM compared with the non‐stressed controls or Str‐Rec‐Scr. The stress effects were specific for the reference memory domain, but knockdown of hippocampal BDNF in unstressed controls briefly disrupted spatial working memory as measured by repeated entry errors on day 2 of training. These results demonstrated that hippocampal BDNF was necessary for the recovery from stress‐induced hippocampal‐dependent spatial memory deficits in the reference memory domain.     

Acute nicotine treatment prevents rem sleep deprivation‐induced learning and memory impairment in rat

Rapid eye movement (REM) sleep deprivation (SD) is implicated in impairment of spatial learning and memory and hippocampal long‐term potentiation (LTP). An increase in nicotine consumption among habitual smokers and initiation of tobacco use by nonsmokers was observed during SD. Although nicotine treatment was reported to attenuate the impairment of learning and memory and LTP associated with several mental disorders, the effect of nicotine on SD‐induced learning and memory impairment has not been studied. Modified multiple platform paradigm was used to induce SD for 24 or 48 h during which rats were injected with saline or nicotine (1 mg kg^?1 s.c.) twice a day. In the radial arm water maze (RAWM) task, 24‐ or 48‐h SD significantly impaired learning and short‐term memory. In addition, extracellular recordings from CA1 and dentate gyrus (DG) regions of the hippocampus in urethane anesthetized rats showed a significant impairment of LTP after 24‐ and 48‐h SD. Treatment of normal rats with nicotine for 24 or 48 h did not enhance spatial learning and memory or affect magnitude of LTP in the CA1 and DG regions. However, concurrent, acute treatment of rats with nicotine significantly attenuated SD‐induced impairment of learning and STM and prevented SD‐induced impairment of LTP in the CA1 and DG regions. These results show that acute nicotine treatment prevented the deleterious effect of sleep loss on cognitive abilities and synaptic plasticity. © 2010 Wiley‐Liss, Inc.     

Enriched environment fails to increase meningitis‐induced neurogenesis and spatial memory in a mouse model of pneumococcal meningitis

An increase in adult neurogenesis was observed after exposure to enriched environment (EE) and during reconvalescence from experimental pneumococcal meningitis. This study investigated neurogenesis and spatial learning performance 5 weeks after bacterial meningitis and exposure to EE. C57BL/6 mice were infected by intracerebral injection of Streptococcus pneumoniae and treated with ceftriaxone for 5 days. Forty‐eight hours after infection, one group (n = 22) was exposed to EE and the other group (n = 23) housed under standard conditions. Another set of mice was kept under either enriched (n = 16) or standard (n = 15) conditions without bacterial meningitis. Five weeks later, the Morris water maze was performed, and neurogenesis was evaluated by means of immunohistochemistry. Mice housed in EE without prior bacterial infection displayed both increased neurogenesis and improved water maze performance in comparison with uninfected control animals. Bacterial meningitis stimulated neurogenesis in the granular cell layer of the dentate gyrus: with standard housing conditions, we observed a higher density of BrdU‐immunolabeled and TUC‐4‐expressing cells 5 weeks after induction of bacterial meningitis than in the noninfected control group. EE did not further increase progenitor cell proliferation and neuronal differentiation in the subgranular cell layer of the dentate gyrus after bacterial meningitis in comparison with infected mice housed under standard conditions. Moreover, the Morris water maze showed no significant differences between survivors of meningitis exposed to EE and animals kept in standard housing. In summary, exposure to EE after pneumococcal meningitis did not further increase meningitis‐induced neurogenesis or improve spatial learning. © 2009 Wiley‐Liss, Inc.     

Progranulin promotes hippocampal neurogenesis and alleviates anxiety‐like behavior and cognitive impairment in adult mice subjected to cerebral ischemia

AimsCerebral ischemia can lead to anxiety and cognitive impairment due to the loss of hippocampal neurons. Facilitation of endogenous neurogenesis in the hippocampus is a potential therapeutic strategy for alleviating ischemia‐induced anxiety and cognitive impairment. Progranulin (PGRN), a secretory glycoprotein, has been reported to have a mitogentic effect on many cell types. However, it is not clear whether PGRN enhances hippocampal neurogenesis and promotes functional recovery.MethodsAdult male C57BL/6 mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and injected intracerebroventricularly with recombinant mouse PGRN 30 min after pMCAO. Anxiety‐like behavior was detected by the open field and the elevated plus maze tests, and spatial learning and memory abilities were evaluated by Morris water maze. Neurogenesis was examined by double labeling of BrdU and neural stem cells or neurons markers. For mechanism studies, the level of ERK1/2 and AKT phosphorylation were assessed by western blotting.ResultsProgranulin significantly alleviated anxiety‐like behavior and spatial learning and memory impairment induced by cerebral ischemia in mice. Consistent with the functional recovery, PGRN promoted neural stem cells (NSCs) proliferation and neuronal differentiation in the dentate gyrus (DG) after cerebral ischemia. PGRN upregulated the expression of phosphorylated ERK1/2 and Akt in the DG after cerebral ischemia.ConclusionsProgranulin alleviates ischemia‐induced anxiety‐like behavior and spatial learning and memory impairment in mice, probably via stimulation of hippocampal neurogenesis mediated by activation of MAPK/ERK and PI3K/Akt pathways. PGRN might be a promising candidate for coping with ischemic stroke‐induced mood and cognitive impairment in clinic.     

Sex‐dependent regulation of hippocampal neurogenesis under basal and chronic stress conditions in rats

Sex differences in basal as well as in stress‐induced hippocampal neurogenesis processes have been reported in the literature. However, studies directly comparing sex differences on multiple neurogenesis processes under such conditions are lacking to date. Therefore, the aim of the present study was to directly compare cell proliferation and survival, neuronal and astroglial differentiation as well as stem cells quiescence in male and female Wistar rats under both basal and chronic stress conditions (12 days of 2 h restraint stress (RS)). In addition, corticosterone (CORT) levels and spatial working memory were assessed. Under baseline conditions, only the number of immature neurons within the hippocampal dentate gyrus was higher in males compared with females. In contrast, chronic stress resulted in a number of sex‐specific alterations. Thus, stress exposure reduced cell proliferation in males with a concurrent increase in stem cell quiescence, while it did not alter either parameter in females but decreased cell survival. Analysis of astroglial and neuronal differentiation patterns revealed that chronic stress specifically diminished the number of mature neurons in females, with no effect in males. Despite the observed sex differences in adult hippocampal neurogenesis, spatial working memory was not altered by stress exposure in either sex. While basal CORT levels were higher, chronic stress exposure did not affect this parameter in either sex across the initial stress period. This study presents the first direct and detailed evaluation of sex‐dependent and chronic stress‐induced changes in adult hippocampal neurogenesis not only showing changes in cell proliferation and survival, but moreover immature neuron production, differentiation patterns, stem cell quiescence and therefore contributes to a better understanding of sex differences in neurogenesis processes. © 2013 Wiley Periodicals, Inc.     

Hippocampal cell genesis does not correlate with spatial learning ability in aged rats

Aging in rodents is known to lead to deficits in spatial learning and memory, including decreased performance on the Morris water maze. Recent attention has focused on the possible role of adult hippocampal neurogenesis in regulating spatial learning and memory. Therefore, in this study, we have examined levels of hippocampal cell proliferation in relation to water maze performance in aged and young male Fischer 344 rats. Aged rats (24 months old) were divided into aged-unimpaired and aged-impaired groups based on comparison with performance of young animals. Animals received five daily injections of the thymidine-analog bromodeoxyuridine (BrdU) and were killed 1 week later. Total numbers of BrdU-labeled cells were quantified in the hippocampal dentate gyrus and hilus and were related to behavioral performance. Whereas aging was associated with a significant reduction in the number of BrdU-labeled cells, behavioral impairment with aging was not associated with a further reduction in BrdU labeling. In the context of aging, these finding do not support a direct relationship of adult hippocampal neurogenesis with learning and memory capability.     

Lactation‐induced reduction in hippocampal neurogenesis is reversed by repeated stress exposure

The peripartum period is a time of high susceptibility for mood and anxiety disorders, some of which have recently been associated with alterations in hippocampal neurogenesis. Several factors including stress, aging, and, perhaps unexpectedly, lactation have been shown to decrease hippocampal neurogenesis. Intriguingly, lactation is also a time of reduced stress responsivity suggesting that the effect of stress on neurogenic processes may differ during this period. Therefore, the aim of the present study was to assess the effect of repeated stress during lactation [2 h restraint stress from lactation day (LD) 2 to LD13] on brain weight, hippocampal volume, cell proliferation and survival, and on neuronal and astroglial differentiation. In addition to confirming the known lactation‐associated decrease in cell proliferation and survival, we could reveal that stress reversed the lactation‐induced decrease in cell proliferation, while it did not affect survival of newly born cells, nor the number of mature neurons , nor did it alter immature neuron production or the number of astroglial cells in lactation. Stress exposure increased relative brain weight and hippocampal volume mirroring the observed changes in neurogenesis. Interestingly, hippocampal volume and relative brain weight were lower in lactation as compared to nulliparous females under nonstressed conditions. This study assessed the effect of stress during lactation on hippocampal neurogenesis and indicates that stress interferes with important peripartum adaptations at the level of the hippocampus. © 2014 Wiley Periodicals, Inc.     

Enriched environment prevents memory deficits in type 1 diabetic rats

Studies have shown that an enriched environmental (EE) enhances hippocampal neurogenesis and dendritic branching in rodents, improving the performance in learning and memory task. Diabetes, however, is associated with memory deficits and decreasing in cell proliferation in the hippocampal dentate gyrus (DG), possibly related with higher glucocorticoid levels. Thus, our objective was to investigate the influence of EE on the memory deficits and cell proliferation of diabetic rats. For this, we reared rats for 2 months during early stages of life in standard environments (control rats) or EE. At adulthood, control and EE groups were divided and half of them induced to diabetes by a single injection of streptozotocin, 60 mg/kg, via i.p. Memory deficit was evaluated in these groups in the novel object-placement recognition task 11 days after diabetes induction. BrdU label cells were detected by immunohistochemistry after 3 days of administration to correlate cell proliferation in the DG area and performance in the memory task. Our results showed that EE decreased memory deficits in diabetic-induced rats (p < 0.05). Although cell proliferation in the DG was lower in the diabetic rats, enriched environment did not interfere in this parameter. These findings suggest that enriched environment is able to prevent or delay the development of memory deficits caused by diabetes in rats.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.     

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits,biochemical changes,and hippocampal synaptic plasticity in an animal model of depression

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression‐associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression‐associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression‐induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long‐term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight‐arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression‐associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments. © 2014 Wiley Periodicals, Inc.     

Persistent behavioral impairments and neuroinflammation following global ischemia in the rat

Cognitive deficits associated with cardiac arrest have been well documented; however, the corresponding deficits in animal models of global ischemia have not been comprehensively assessed, particularly after long‐term, clinically relevant survival times. We exposed male Sprague–Dawley rats to 10 min of bilateral carotid artery occlusion + systemic hypotension (40–45 mmHg) or sham surgery, and used histopathological assessments for short‐term survival animals (16 days) and both behavioral and histopathological assessments for long‐term survival animals (270 days). Analyses revealed significant long‐term deficits in ischemic animals’ learning, memory (T‐maze, radial arm maze), working memory (radial arm maze), and reference memory (Morris water maze, radial arm maze) abilities that were not associated with a general cognitive decline. Histological results showed significant increases in glial fibrillary acidic protein, neuron glia 2, OX‐42 and ED‐1 staining, as well as significant decreases in microtubule‐associated protein 2 staining and cornu ammonis area 1 (CA1) cell counts 16 days post‐ischemia. The pattern at 270 days was similar, but notably there was a persistent elevation of ED‐1 staining, suggesting recent cell death as well as significant atrophy of CA1. Whereas previous work has primarily reported transient changes in behavior after global ischemia, this study describes disturbances in several different functional domains following CA1 cell loss at clinically relevant survival times. Moreover, the histopathological outcome is suggestive of a spontaneous repopulation of CA1, but this was not sufficient to offset the behavioral impairments arising from the ischemic insult.     

Region‐dependent and stage‐specific effects of stress,environmental enrichment,and antidepressant treatment on hippocampal neurogenesis

Chronic stress and depression are associated with decreased levels of hippocampal neurogenesis. On the other hand, antidepressants as well as environmental enrichment may rely in part on their pro‐neurogenic effects to improve cognition and mood. Because a functional heterogeneity has been consistently reported along the septo‐temporal axis of the hippocampus, regional changes in neurogenesis could differentially contribute to these effects and affect distinct hippocampal functions. Mapping these regional changes could therefore provide a better understanding of the function of newborn neurons. While some studies report region‐specific effects of stress and antidepressants on neurogenesis, it is unclear whether these changes affect distinct populations of newborn neurons according to their developmental stage in a region‐specific manner. By using endogenous markers and BrdU labeling we quantified the regional changes in cell proliferation and survival as well as in the number of neuronal progenitors and immature neurons following unpredictable chronic mild stress (UCMS), environmental enrichment (EE) and chronic fluoxetine (20 mg/kg/day) treatment along the septo‐temporal axis of the hippocampus. EE promoted cell proliferation and survival of 4‐week‐old newborn cells as well as increased the number and proportion of post‐mitotic immature neurons specifically within the septal hippocampus. By contrast, UCMS uniformly decreased cell proliferation, survival and immature newborn neurons but differentially affected progenitor cells with a decrease restricted to the temporal regions of the hippocampus. Whereas fluoxetine treatment in control mice affected proliferation and survival specifically in the temporal hippocampus, it reversed most of the UCMS‐induced alterations all along the septo‐temporal axis. These results highlight that different factors known for exerting a mood improving effect differentially regulate neurogenesis along the septo‐temporal axis of the hippocampus. Such region and stage specific effects may correlate to distinct functional properties of newborn neurons along the septo‐temporal axis of the hippocampus which may contribute differently to the pathophysiology of affective disorders. © 2013 Wiley Periodicals, Inc.     

Time‐dependent enhancement of hippocampus‐dependent memory after treatment with memantine: Implications for enhanced hippocampal adult neurogenesis

Adult hippocampal neurogenesis has been suggested to play modulatory roles in learning and memory. Importantly, previous studies have shown that newborn neurons in the adult hippocampus are integrated into the dentate gyrus circuit and are recruited more efficiently into the hippocampal memory trace of mice when they become 3 weeks old. Interestingly, a single high‐dose treatment with the N‐methyl‐d ‐aspartate receptor antagonist memantine (MEM) has been shown to increase hippocampal neurogenesis dramatically by promoting cell proliferation. In the present study, to understand the impact of increased adult neurogenesis on memory performance, we examined the effects of a single treatment of MEM on hippocampus‐dependent memory in mice. Interestingly, mice treated with MEM showed an improvement of hippocampus‐dependent spatial and social recognition memories when they were trained and tested at 3–6 weeks, but not at 3 days or 4 months, after treatment with MEM. Importantly, we observed a significant positive correlation between the scores for spatial memory (probe trial in the Morris water maze task) and the number of young mature neurons (3 weeks old) in MEM‐treated mice, but not saline‐treated mice. We also observed that the young mature neurons generated by treatment with MEM were recruited into the trace of spatial memory similarly to those generated through endogenous neurogenesis. Taken together, our observations suggest that treatment with MEM temporally improves hippocampus‐dependent memory formation and that the newborn neurons increased by treatment with MEM contribute to this improvement when they become 3 weeks old. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Environmental enrichment and physical exercise revert behavioral and electrophysiological impairments caused by reduced adult neurogenesis

It is well known that adult neurogenesis occurs in two distinct regions, the subgranular zone of the dentate gyrus and the subventricular zone along the walls of the lateral ventricles. Until now, the contribution of these newly born neurons to behavior and cognition is still uncertain. The current study tested the functional impacts of diminished hippocampal neurogenesis on emotional and cognitive functions in transgenic Gfap‐tk mice. Our results showed that anxiety‐related behavior evaluated both in the elevated plus maze as well as in the open field, social interaction in the sociability test, and spatial working memory in the spontaneous alternation test were not affected. On the other hand, recognition and emotional memory in the object recognition test and contextual fear conditioning, and hippocampal long‐term potentiation were impaired in transgenic mice. Furthermore, we evaluated whether environmental enrichment together with physical exercise could improve or even restore the level of adult neurogenesis, as well as the behavioral functions. Our results clearly demonstrated that environmental enrichment together with physical exercise successfully elevated the overall number of progenitor cells and young neurons in the dentate gyrus of transgenic mice. Furthermore, it led to a significant improvement in object recognition memory and contextual fear conditioning, and reverted impairments in hippocampal long‐term potentiation. Thus, our results confirm the importance of adult neurogenesis for learning and memory processes and for hippocampal circuitry in general. Environmental enrichment and physical exercise beneficially influenced adult neurogenesis after it had been disrupted and most importantly recovered cognitive functions and long‐term potentiation. © 2016 Wiley Periodicals, Inc.     

Age‐dependent effects of hippocampal neurogenesis suppression on spatial learning

Reducing hippocampal neurogenesis sometimes, but not always, disrupts hippocampus‐dependent learning and memory. Here, we tested whether animal age, which regulates rate of hippocampal neurogenesis, is a factor that influences whether deficits in spatial learning are observed after reduction of neurogenesis. We found that suppressing the generation of new hippocampal neurons via treatment with temozolomide, an antiproliferation agent, impaired learning the location of a hidden platform in the water maze in juvenile mice (1–2 months old) but not in adult mice (2–3 months old) or middle‐aged mice (11–12 months old). These findings suggest that during juvenility, suppression of neurogenesis may alter hippocampal development, whereas during adulthood and aging, pre‐existing neurons may compensate for the lack of new hippocampal neurons. © 2012 Wiley Periodicals, Inc.     

Effect of food deprivation during early development on cognition and neurogenesis in the rat

Food deprivation has been recognized as having pronounced beneficial effects in adult animals, increasing longevity, reducing seizure susceptibility, and enhancing resistance to neurotoxins. It is not known whether food deprivation in developing animals is neuroprotective or harmful. To evaluate the effects of food deprivation on brain development, we evaluated visual-spatial learning and memory and neurogenesis in the dentate gyrus of the hippocampus in food-deprived (FD) and well-fed (WF) rats. To induce food deprivation, pups were removed from their dams for 12 hours per day from Postnatal Day (P) 2 to P19. FD and WF rat pups were then subjected to status epilepticus (SE) induced by lithium-pilocarpine at P20. After SE, neurogenesis was measured, while in another group of P38 rats, learning and memory were evaluated using the Morris water maze. Food deprivation was found to reduce neurogenesis when assessed after the period of food deprivation. Although SE reduced neurogenesis in the WF animals, it had little effect additional to food deprivation on neurogenesis in the FD rats. Compared with the WF group, FD rats had a mild impairment in memory in the water maze testing after SE. Our study demonstrates that food deprivation during the neonatal period in rats is associated with a decrease in neurogenesis and mild impairment of visual-spatial memory. Although SE decreased neurogenesis in the WF group, in FD animals, SE did not reduce neurogenesis more than what was seen with food deprivation alone. Our results suggest that although food deprivation during early development reduces dentate gyrus neurogenesis, the reduced neurogenesis is not a major factor in cognitive impairment after SE in FD rats.