Can the effects of environmental enrichment modulate BDNF expression in hippocampal plasticity? A systematic review of animal studies

Background and aim: Environmental enrichment (EE) can be related to changes in the expression of brain‐derived neurotrophic factor (BDNF) in the hippocampus of adult rodents. Exposure to EE may also induce neurogenesis in the dentate gyrus (DG). The aim of this systematic review was to analyze the current literature on the correlation between neurogenesis and BDNF expression in the hippocampal DG region resulting from exposure to EE, which is associated with changes in memory, in rodents. Methods: Bibliographic searches of the Medline/PubMed and ScienceDirect databases were carried out, and 334 studies were found. A predefined protocol was used and registered on PROSPERO, and 32 studies were included for qualitative synthesis. The PRISMA was used to report this systematic review. Results: Most of the included studies showed that there is little evidence in the literature demonstrating that memory changes resulting from EE are dependent on BDNF expression and that there is an induction of neurogenesis in the hippocampal DG. However, the observed increase in molecular expression levels and cell proliferation is dependent on the age, the timing and duration of exposure to EE. Regarding the methodological quality of the studies, the majority presented a risk of bias due to the high variability in the age of the animals. Conclusion: There are few studies in the literature that correlate the molecular and cellular mechanisms involved in neurogenesis in the hippocampal DG with BDNF expression in this region in rodents exposed to EE; however, there are other factors that can modulate this neurogenesis.     

Stress differentially regulates the effects of voluntary exercise on cell proliferation in the dentate gyrus of mice

It has been well-established that cell proliferation and neurogenesis in the adult mouse dentate gyrus (DG) can be regulated by voluntary exercise. Recent evidence has suggested that the effects of voluntary exercise can in turn be influenced by environmental factors that regulate the amount of stress an animal is exposed to. In this study, we use bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemistry to show that voluntary exercise produces a significant increase in cell proliferation in the adult mouse DG in both isolated and socially housed mice. This effect on proliferation translates into an increase in neurogenesis and neuronal branching of new neurons in the mice that exercised. Although social condition did not regulate proliferation in young adult mice, an effect of social housing could be observed in mice exposed to acute restraint stress. Surprisingly, only exercising mice housed in isolated conditions showed an increase in cellular proliferation following restraint stress, whereas socially housed, exercising mice, failed to show a significant increase in proliferation. These findings indicate that social housing may increase the effects of any stressful episodes on hippocampal neurogenesis in the mouse DG.     

Enrichment rescues contextual discrimination deficit associated with immediate shock

Adult animals continue to modify their behavior throughout life, a process that is highly influenced by past experiences. To shape behavior, specific mechanisms of neural plasticity to learn, remember, and recall information are required. One of the most robust examples of adult plasticity in the brain occurs in the dentate gyrus (DG) of the hippocampus, through the process of adult neurogenesis. Adult neurogenesis is strongly upregulated by external factors such as voluntary wheel running (RUN) and environmental enrichment (EE); however, the functional differences between these two factors remain unclear. Although both manipulations result in increased neurogenesis, RUN dramatically increases the proliferation of newborn cells and EE promotes their survival. We hypothesize that the method by which these newborn neurons are induced influences their functional role. Furthermore, we examine how EE‐induced neurons may be primed to encode and recognize features of novel environments due to their previous enrichment experience. Here, we gave mice a challenging contextual fear‐conditioning (FC) procedure to tease out the behavioral differences between RUN‐induced neurogenesis and EE‐induced neurogenesis. Despite the robust increases in neurogenesis seen in the RUN mice, we found that only EE mice were able to discriminate between similar contexts in this task, indicating that EE mice might use a different cognitive strategy when processing contextual information. Furthermore, we showed that this improvement was dependent on EE‐induced neurogenesis, suggesting a fundamental functional difference between RUN‐induced neurogenesis and EE‐induced neurogenesis. © 2014 Wiley Periodicals, Inc.     

Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus

Both vitamin A deficiency and high doses of retinoids can result in learning and memory impairments, depression as well as decreases in cell proliferation, neurogenesis and cell survival. Physical activity enhances hippocampal neurogenesis and can also exert an antidepressant effect. Here we elucidate a putative link between running, retinoid signaling, and neurogenesis in hippocampus. Adult transgenic reporter mice designed to detect ligand-activated retinoic acid receptors (RAR) or retinoid X receptors (RXR) were used to localize the distribution of activated RAR or RXR at the single-cell level in the brain. Two months of voluntary wheel-running induced an increase in hippocampal neurogenesis as indicated by an almost two-fold increase in doublecortin-immunoreactive cells. Running activity was correlated with neurogenesis. Under basal conditions a distinct pattern of RAR-activated cells was detected in the granule cell layer of the dentate gyrus (DG), thalamus, and cerebral cortex layers 3-4 and to a lesser extent in hippocampal pyramidal cell layers CA1-CA3. Running did not change the number of RAR-activated cells in the DG. There was no correlation between running and RAR activation or between RAR activation and neurogenesis in the DG of hippocampus. Only a few scattered activated retinoid X receptors were found in the DG under basal conditions and after wheel-running, but RXR was detected in other areas such as in the hilus region of hippocampus and in layer VI of cortex cerebri. RAR agonists affect mood in humans and reduce neurogenesis, learning and memory in animal models. In our study, long-term running increased neurogenesis but did not alter RAR ligand activation in the DG in individually housed mice. Thus, our data suggest that the effects of exercise on neurogenesis and other plasticity changes in the hippocampal formation are mediated by mechanisms that do not involve retinoid receptor activation.     

Gonadal hormone modulation of hippocampal neurogenesis in the adult

Gonadal hormones modulate neurogenesis in the dentate gyrus (DG) of adult rodents in complex ways. Estradiol, the most potent estrogen, initially enhances and subsequently suppresses cell proliferation in the dentate gryus of adult female rodents. Much less is known about how estradiol modulates neurogenesis in the adult male rodent; however, recent evidence suggests that estradiol may have a moderate effect on cell proliferation but enhances cell survival in the DG of newly synthesized cells but only when estradiol is administered during a specific stage in the cell maturation cycle in the adult male rodent. Testosterone likely plays a role in adult neurogenesis, although there have been no direct studies to address this. However, pilot studies from our laboratory suggest that testosterone up-regulates cell survival but not cell proliferation in the DG of adult male rats. Progesterone appears to attenuate the estradiol-induced enhancement of cell proliferation. Neurosteroids such as allopregnalone decrease neurogenesis in adult rodents, while pregnancy and motherhood differentially regulate adult neurogenesis in the adult female rodent. Very few studies have investigated the effects of gonadal hormones on male rodents; however, studies have indicated that there is a gender difference in the response to hormone-regulated hippocampal neurogenesis in the adult. Clearly, more work needs to be done to elucidate the effects of gonadal hormones on neurogenesis in the DG of both male and female rodents.     

Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.     

Gender and endogenous levels of estradiol do not influence adult hippocampal neurogenesis in mice

In several species, including rat and vole, the proliferation of new neurons in the adult dentate gyrus (DG) subgranular zone (SGZ) is influenced by both gender and endogenous levels of the gonadotropic steroid hormone estradiol. However, little is known about how adult neurogenesis is regulated by these factors in the mouse. We report here that adult C57BL/6 mice do not have gender differences in hippocampal proliferation or neurogenesis. In addition, the production of new SGZ cells in female mice was not influenced by estrous cycle or after ovariectomy, suggesting that fluctuations in endogenous estradiol levels do not alter adult neurogenesis in the mouse. Both male and female mice had a greater number of BrdU-immunoreactive SGZ cells following chronic treatment with fluoxetine. This demonstrates a parallel proliferation response in both genders, and opens avenues for addressing the neurogenesis hypothesis of depression in female rodents. These findings underscore a distinct regulation of adult neurogenesis in mice vs. other rodents, and are discussed in regard to their implications for the study of adult hippocampal neurogenesis.     

Retinoic acid and environmental enrichment alter subventricular zone and striatal neurogenesis after stroke

Neurogenesis increases in the adult rodent forebrain subventricular zone (SVZ) after experimental stroke. Newborn neurons migrate to the injured striatum, but few survive long-term and little evidence exists to suggest that they integrate or contribute to functional recovery. One potential strategy to improve stroke recovery is to stimulate neurogenesis and integration of adult-born neurons by using treatments that enhance neurogenesis. We examined the influence of retinoic acid (RA), which stimulates neonatal SVZ and adult hippocampal neurogenesis, and environmental enrichment (EE), which enhances survival of adult-born hippocampal neurons. We hypothesized that the combination of RA and EE would promote survival of adult-generated SVZ-derived neurons and improve functional recovery after stroke. Adult rats underwent middle cerebral artery occlusion, received BrdU on days 5-11 after stroke and were treated with RA/EE, RA alone, EE/vehicle or vehicle alone and were killed 61 days after stroke. Rats underwent repeated MRI and behavioral testing. We found that RA/EE treatment preserved striatal and hemisphere tissue and increased SVZ neurogenesis as demonstrated by Ki67 and doublecortin (DCx) immunolabeling. All treatments influenced the location of BrdU- and DCx-positive cells in the post-stroke striatum. RA/EE increased the number of BrdU/NeuN-positive cells in the injured striatum but did not lead to improvements in behavioral function. These results demonstrate that combined pharmacotherapy and behavioral manipulation enhances post-stroke striatal neurogenesis and decreases infarct volume without promoting detectable functional recovery. Further study of the integration of adult-born neurons in the ischemic striatum is necessary to determine their restorative potential.     

Fibroblast growth factor-2 deficiency causes defects in adult hippocampal neurogenesis, which are not rescued by exogenous fibroblast growth factor-2

Neurogenesis within the adult brain is restricted to selected areas, one of which is the dentate gyrus (DG). Several growth factors have been reported to affect neurogenesis in the adult DG. However, a role of fibroblast growth factor-2 (FGF-2) in adult hippocampal neurogenesis has not been firmly established. We have analyzed neurogenesis in the DG using in vivo and in vitro approaches. FGF-2(-/-) mice revealed no alterations in the number of proliferating cells but a significant decrease in the numbers of newly generated neurons. Moreover, FGF-2 added to hippocampal slice cultures from FGF-2(-/-) mice was unable to rescue the phenotype. Although an increase in death of neurogenic cells in the FGF-2-deficient DG could not be specifically demonstrated, there was a massive increase in global cell death in FGF-2(-/-) hippocampal slice cultures compared with slices from wild-type mice. Cell death could not be prevented by addition of FGF-2. Neutralization of endogenous FGF-2 in hippocampal slices did not interfere with neurogenesis in a short-term paradigm. Together, our data suggest that FGF-2 is essentially required for maturation of new neurons in adult hippocampal neurogenesis but is likely to operate synergistically in combination with other mechanisms/growth factors.     

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.     

Maternal experience and adult neurogenesis in mammals: Implications for maternal care,cognition, and mental health

The transition to motherhood encompasses physiological and behavioral adaptations essential for the initiation and maintenance of offspring care and feeding and includes widespread changes throughout the brain. The growth of new neurons occurs across the lifespan in distinct regions of mammalian brains and changes dynamically across reproductive events in female mammals. The subventricular zone (SVZ) and dentate gyrus (DG) of the hippocampus undergo high rates of neurogenesis in adulthood and are sensitive to hormonal fluctuations. Pregnancy and the postpartum period are associated with increased cell proliferation in the SVZ and interneuron survival in the olfactory bulb. In mice, peripartum prolactin signaling mediates SVZ neurogenesis and is important for enhanced olfactory recognition of offspring and maternal care. In contrast, cell proliferation and immature neuron survival decrease in the DG during the postpartum period. High baseline glucocorticoid concentrations suppress hippocampal neurogenesis, potentially representing an energetic trade-off accompanying a reduced need for spatial navigation early postpartum. In women, hippocampal volume decline during pregnancy and partial recovery during the postpartum period could contribute to the risk of psychiatric illness. New evidence indicates that the dorsal raphe nucleus (DR) is an additional site for adult neurogenesis sensitive to reproductive experience and offspring contact. In this review, we discuss the initial and lasting impact of maternal experience on adult neurogenesis. Because neurogenesis has been implicated in a variety of psychiatric and neurodegenerative illnesses, understanding how reproductive experience alters new neuron production in maternal mammals has far-reaching implications for women's health and wellness across the lifespan.     

Characterization of the neurogenesis quiescent zone in the rodent brain: Effects of age and exercise

Although it is accepted that new neurons continue to be generated in the hippocampal dentate gyrus (DG) throughout adulthood, it has recently become apparent that this process is not homogeneous, and that a small region of the DG lacks neurogenesis. Here, we show that the relative area of this neurogenesis quiescent zone (NQZ) did not vary after the peak in hippocampal postnatal neurogenesis and until animals reached adulthood, although the ratio between its actual volume and the total volume of the DG doubled during this time. However, we were able to identify a few mitotic cells that reside within this subregion in early adolescent rats. Furthermore, these cells can be activated, and 1 week of voluntary exercise was enough to significantly increase the number of mitotic cells within the NQZ of adolescent rats. There was, however, no corresponding increase in the number of new neurons in this subregion of the DG, suggesting that some factor necessary to allow these cells to develop into a mature phenotype is missing. Moreover, the same intervention was ineffective in increasing either proliferation or neurogenesis in older adult rats. Surprisingly, we found no evidence for the existence of an NQZ in the mouse DG, suggesting that the neurogenic process in these two rodent species is differently regulated. Understanding the molecular mechanisms underlying the existence of the NQZ in the rat DG might shed light on the processes that regulate adult neurogenesis and its modulation by factors such as aging and exercise.     

Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent motor seizures (SRMS), learning and memory impairments, and depression, is associated with neurodegeneration, abnormal reorganization of the circuitry, and loss of functional inhibition in the hippocampal and extrahippocampal regions. Over the last decade, abnormal neurogenesis in the dentate gyrus (DG) has emerged as another hallmark of TLE. Increased DG neurogenesis and recruitment of newly born neurons into the epileptogenic hippocampal circuitry is a characteristic phenomenon occurring during the early phase after the initial precipitating injury such as status epilepticus. However, the chronic phase of the disease displays substantially declined DG neurogenesis, which is associated with SRMS, learning and memory impairments, and depression. This review focuses on DG neurogenesis in the chronic phase of TLE and first confers the extent and mechanisms of declined DG neurogenesis in chronic TLE. The available data on production, survival and neuronal fate choice decision of newly born cells, stability of hippocampal stem cell numbers, and changes in the hippocampal microenvironment in chronic TLE are considered. The next section discusses the possible contribution of declined DG neurogenesis to the pathophysiology of chronic TLE, which includes its potential effects on spontaneous recurrent seizures, cognitive dysfunction, and depression. The subsequent section considers strategies that may be useful for augmenting DG neurogenesis in chronic TLE, which encompass stem cell grafting, administration of distinct neurotrophic factors, physical exercise, exposure to enriched environment, and antidepressant therapy. The final section suggests possible ramifications of increasing the DG neurogenesis in chronic epilepsy.     

Essential role of tau phosphorylation in adult hippocampal neurogenesis

An increased hippocampal neurogenesis has been observed in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with accumulation of β‐amyloid (Aβ) and hyperphosphorylated tau (p‐tau). Studies in transgenic mouse models suggest that the amyloidosis suppresses adult neurogenesis. Although emerging evidence links tau to neurodevelopment, the direct data regarding tau phosphorylation in adult neurogenesis is missing. Here, we found that the immature neurons, identified by doublecortin (DCX) and neurogenic differentiation factor (neuroD), were only immunoreactive to p‐tau but not to the non‐p‐tau in adult rat brain and human patients with AD, and the p‐tau was coexpressed temporally and spatially with DCX and neuroD in the hippocampal dentate gyrus (DG) of the rat brains during postnatal development. A correlative increase of immature neuron markers and tau phosphorylation was induced in rat hippocampal DG by upregulating glycogen synthase kinase‐3 (GSK‐3), a crucial tau kinase, and the increased neurogenesis was due to an enhanced proliferation but not survival or differentiation of the newborn neurons. The hippocampal neurogenesis was severely impaired in tau knockout mice and activation of GSK‐3 in these mice did not rescue the deficits. These results reveal an essential role of tau phosphorylation in adult hippocampal neurogenesis. It suggests that spatial/temporal manipulation of tau phosphorylation may be compensatory for the neuron loss in neurological disorders, including AD. © 2009 Wiley‐Liss, Inc.     

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.     

Plasticity of hippocampus following perinatal asphyxia: effects on postnatal apoptosis and neurogenesis

Asphyxia during delivery produces long-term deficits in brain development, including hippocampus. We investigated hippocampal plasticity after perinatal asphyxia, measuring postnatal apoptosis and neurogenesis. Asphyxia was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 20 min. Caesarean-delivered pups were used as controls. The animals were euthanized 1 week or 1 month after birth. Apoptotic nuclear morphology and DNA breaks were assessed by Hoechst and TUNEL assays. Neurogenesis was estimated by bromodeoxyuridine/MAP-2 immunocytochemistry, and the levels and expression of proteins related to apoptosis and cell proliferation were measured by Western blots and in situ hybridization, respectively. There was an increase of apoptosis in CA1, CA3, and dentate gyrus (DG) and cell proliferation and neurogenesis in CA1, DG, and hilus regions of hippocampus 1 week after asphyxia. The increase of apoptosis in CA3 and cell proliferation in the suprapyramidal band of DG was still observed 1 month following asphyxia. There was an increase of BAD, BCL-2, ERK2, and bFGF levels in whole hippocampus and bFGF expression in CA1 and CA2 and hilus at P7 and P30. There was a concomitant decrease of phosphorylated-BAD (Ser112) levels. The increase of BAD levels supports the idea of delayed cell death after perinatal asphyxia, whereas the increases of BCL-2, ERK2, and bFGF levels suggest the activation of neuroprotective and repair pathways. In conclusion, perinatal asphyxia induces short- and long-term regionally specific plastic changes, including delayed cell death and neurogenesis, involving pro- and antiapoptotic as well as mitogenic proteins, favoring hippocampal functional recovery.     

Exogenous neuropeptide Y promotes in vivo hippocampal neurogenesis

Adult neurogenesis mainly occurs in two brain regions, the subventricular zone and the dentate gyrus (DG) of the hippocampus. Neuropeptide Y (NPY) is widely expressed throughout the brain and is known to enhance in vitro hippocampal cell proliferation. Mice lacking either NPY or the Y1 receptor display lower levels of cell proliferation, thereby suggesting a role for NPY in basal in vivo neurogenesis. Here, we investigated whether exogenous NPY stimulates DG progenitors proliferation in vivo. We show that intracerebroventricular administration of NPY increases DG cell proliferation and promotes neuronal differentiation in C57BL/6 adult mice. In these mice, the proliferative effect of NPY is mediated by the Y1 and not the Y2 receptor, as a Y1 ([Leu³¹,Pro³⁴]), but not a Y2 (NPY_3–36), receptor agonist enhanced proliferation. In addition, no NPY‐induced DG cellular proliferation is observed following NPY injection when coadministered with a Y1 antagonist or in the Y1 receptor knockout mouse. These results are in line with data obtained in Y1^?/? mice, demonstrating that NPY regulates in vivo hippocampal neurogenesis. © 2010 Wiley‐Liss, Inc.     

Enriched environment and spatial learning enhance hippocampal neurogenesis and salvages ischemic penumbra after focal cerebral ischemia

Enriched environment (EE) has been shown to increase neurogenesis in the adult brain. The aim of this study is to determine the effect of EE and spatial learning on neurogenesis following ischemic stroke. Male adult SD rats were subjected to sham surgery or distal middle cerebral artery occlusion (MCAO). MCAO induced a transient increase followed by a sustained depression of progenitor cell proliferation and neuroblast production below baseline level in both ipsilateral and contralateral DG compared to sham. Increased neuronal differentiation and neurogenesis in the DG were observed in both sham and MCAO rats following 8 weeks in the EE combined with spatial learning, compared to rats housed in the standard environment. EE/Learning also restored the total number of neuroblasts in the DG after MCAO compared to sham. Furthermore, EE/learning enhanced the density of NeuN positive cells in the ischemic penumbra, though no new neurons were detected in this region.     

Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice

Social memory consists of the information necessary to identify and recognize cospecifics and is essential to many forms of social interaction. Social memory persistence is strongly modulated by the animal's experiences. We have shown in previous studies that social isolation (SI) in adulthood impairs social memory persistence and that an enriched environment (EE) prevents this impairment. However, the mechanisms involved in the effects of SI and EE on social memory persistence remain unknown. We hypothesized that the mechanism by which SI and EE affect social memory persistence is through their modulation of neurogenesis. To investigate this hypothesis, adult mice were submitted to 7 days of one of the following conditions: group‐housing in a standard (GH) or enriched environment (GH+EE); social isolation in standard (SI) or enriched environment (SI+EE). We observed an increase in the number of newborn neurons in the dentate gyrus of the hippocampus (DG) and glomerular layer of the olfactory bulb (OB) in both GH+EE and SI+EE mice. However, this increase of newborn neurons in the granule cell layer of the OB was restricted to the GH+EE group. Furthermore, both SI and SI+EE groups showed less neurogenesis in the mitral layer of the OB. Interestingly, the performance of the SI mice in the buried food‐finding task was inferior to that of the GH mice. To further analyze whether increased neurogenesis is in fact the mechanism by which the EE improves social memory persistence in SI mice, we administered the mitotic inhibitor AraC or saline directly into the lateral ventricles of the SI+EE mice. We found that the AraC treatment decreased cell proliferation in both the DG and OB, and impaired social memory persistence in the SI+EE mice. Taken together, our results strongly suggest that neurogenesis is what supports social memory persistence in socially isolated mice. © 2013 Wiley Periodicals, Inc.