Odor-enriched environment rescues long-term social memory, but does not improve olfaction in social isolated adult mice

Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S-LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction.     

Effects of social isolation and enriched environment on behavior of adult Swiss mice do not require hippocampal neurogenesis

Housing conditions are important determinants of animal behavior. Their impact on behavioral output depends on the behavior of interest, species, strain, and age of the animal evaluated. In the present study, male Swiss mice reared from weaning up to 8 weeks in social isolation (SI8), in enriched environment (EE8) or in standard environment (SE8) were evaluated in the elevated plus-maze (EPM), open-field (OFT) and tail-suspension (TST) tests. The effect of housing for 6 weeks in EE followed by 2 weeks in SI (EE6SI2) and the opposite condition (SI6EE2) was also studied. Housing conditions are reported to affect hippocampal neurogenesis; therefore, the expression of doublecortin (DCX) in the dentate gyrus of the hippocampus (DG) of these mice was monitored. Data showed that SI8, EE8 and EE6SI2 reduced the stretching-attend postures in the EPM and explored more the center of the apparatus when compared to SE8. The time and the number of entries in the closed arms of the EPM was not affected indicating that effects of housing conditions in the EPM were not consequence of motor activity alteration. Accordingly, EE8 mice exploration of the OFT was similar to SE8. However, the SI8 mice explored the OFT more than the EE8 mice, suggesting hyperactivity induced by isolation. Behavior of Swiss mice in the TST was not altered, indicating that this test was not sensitive to the environmental changes in this mice strain. Compared to SE8, EE8 did not affect the number of DCX cells, whereas SI8, EE6SI2, and SI6EE2 decreased it. Taken together, our data suggest that the behavior of adult Swiss mice in the EPM and OFT was affected by environmental changes but that these changes seem to be independent of hippocampal neurogenesis.     

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.     

Enriched environments influence depression-related behavior in adult mice and the survival of newborn cells in their hippocampi

Major depression is a highly prevalent mental disorder and environmental factors have been strongly implicated in its pathophysiology. Clinical studies have demonstrated that stress or depression can lead to atrophy and cell loss in the hippocampus. Studies of animal models of depression have suggested that reduced neurogenesis in the adult hippocampus might contribute to such structural changes and to the behavior of these animals. On the other hand, increased hippocampal neurogenesis can be induced by the administration of antidepressants or electroconvulsive seizure, suggesting that increased neurogenesis might be related to the treatment of depression. Thus, an enriched environment (EE), which also enhances neurogenesis, is expected to have therapeutic effects on depression-related behaviors. To investigate the effects of an EE during adulthood on these behaviors, we subjected adult mice housed in an EE for five weeks to behavioral tests. In an open field test, EE mice exhibited a decrease in the distance traveled and an increase in the amount of time spent in the center. The startle response was smaller in EE mice than in control mice. EE mice also showed reduced immobility time in a forced swim test. The immobility time in EE mice was approximately half that observed in mice treated with a tricyclic antidepressant, imipramine. In our experimental condition, increased survival of newborn cells was observed in EE mice by 5-bromo-2'-deoxyuridine (BrdU)-labeled immunohistochemistry. Double-staining of BrdU and a mature neuron marker, NeuN, revealed that the majority of surviving cells were neurons. Our results suggest that EE, which enhanced the survival of newborn neurons, shows beneficial effects on behavioral despair and habituation to a novel environment.     

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.     

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.     

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.     

Long‐term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis

Neurogenesis is a well‐characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of chronic inflammation remains controversial. In this study the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis was used to investigate the long‐term effects of T cell–mediated central nervous system inflammation on hippocampal neurogenesis. 5‐Bromodeoxyuridine (BrdU)‐labeled subpopulations of hippocampal cells in EAE and control mice (coexpressing GFAP, doublecortin, NeuN, calretinin, and S100) were quantified at the recovery phase, 21 days after BrdU administration, to estimate alterations on the rate and differentiation pattern of the neurogenesis process. The core features of EAE mice DG are (i) elevated number of newborn (BrdU+) cells indicating vigorous proliferation, which in the long term subsided; (ii) enhanced migration of newborn cells into the granule cell layer; (iii) increased level of immature neuronal markers (including calretinin and doublecortin); (iv) trending decrease in the percentage of newborn mature neurons; and (v) augmented gliogenesis and differentiation of newborn neural precursor cells (NPCs) to mature astrocytes (BrdU+/S100+). Although the inflammatory environment in the brain of EAE mice enhances the proliferation of hippocampal NPCs, in the long term neurogenesis is progressively depleted, giving prominence to gliogenesis. The discrepancy between the high number of immature cells and the low number of mature newborn cells could be the result of a caused defect in the maturation pathway. © 2016 Wiley Periodicals, Inc.     

Ras‐GRF2 mediates long‐term potentiation,survival, and response to an enriched environment of newborn neurons in the hippocampus

Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including contextual discrimination. This is due, at least in part, to the unique form of plasticity that new neurons display at a specific stage of their development when compared with the surrounding principal neurons. In addition, the contribution that newborn neurons make to dentate function can be enhanced by an increase in their numbers induced by a stimulating environment. However, signaling mechanisms that regulate these properties of newborn neurons are poorly understood. Here, we show that Ras‐GRF2 (GRF2), a calcium‐regulated exchange factor that can activate Ras and Rac GTPases, contributes to both of these properties of newborn neurons. Using Ras‐GRF2 knockout mice and wild‐type mice stereotactically injected with retrovirus containing shRNA against the exchange factor, we demonstrate that GRF2 promotes the survival of newborn neurons of the DG at approximately 1–2 weeks after their birth. GRF2 also controls the distinct form of long‐term potentiation that is characteristic of new neurons of the hippocampus through its effector Erk MAP kinase. Moreover, the enhancement of neuron survival that occurs after mice are exposed to an enriched environment also involves GRF2 function. Consistent with these observations, GRF2 knockout mice display defective contextual discrimination. Overall, these findings indicate that GRF2 regulates both the basal level and environmentally induced increase of newborn neuron survival, as well as in the induction of a distinct form of synaptic plasticity of newborn neurons that contributes to distinct features of hippocampus‐derived learning and memory. © 2014 Wiley Periodicals, Inc.     

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.     

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.     

Inducible and conditional activation of ERK5 MAP kinase rescues mice from cadmium-induced olfactory memory deficits

Cadmium (Cd) is a heavy metal that is one of the most toxic environmental pollutants throughout the world. We previously reported that Cd exposure impairs olfactory memory in mice. However, the underlying mechanisms for its neurotoxicity for olfactory function are not well understood. Since adult Subventricular zone (SVZ) and Olfactory Bulb (OB) neurogenesis contributes to olfaction, olfactory memory defects caused by Cd may be due to inhibition of neurogenesis. In this study, using bromodeoxyuridine (BrdU) labeling and immunohistochemistry, we found that 0.6 mg/L Cd exposure through drinking water impaired adult SVZ/OB neurogenesis in C57BL/6 mice. To determine if the inhibition of olfactory memory by Cd can be reversed by stimulating adult neurogenesis, we utilized the transgenic caMEK5 mouse strain to conditional stimulate of adult neurogenesis by activating the endogenous ERK5 MAP kinase signaling pathway. This was accomplished by conditionally induced expression of active MEK5 (caMEK5) in adult neural stem/progenitor cells. The caMEK5 mice were exposed to 0.6 mg/L Cd for 38 weeks, and tamoxifen was administered to induce caMEK5 expression and stimulate adult SVZ/OB neurogenesis during Cd exposure. Short-term olfactory memory test and sand-digging based, odor-cued olfactory learning and memory test were conducted after Cd and tamoxifen treatments to examine their effects on olfaction. Here we report that Cd exposure impaired short-term olfactory memory and odor-cued associative learning and memory in mice. Furthermore, the Cd-impaired olfactory memory deficits were rescued by the tamoxifen-induction of caMEK5 expression. This suggests that Cd exposure impairs olfactory function by affecting adult SVZ/OB neurogenesis in mice.     

IRF-8 is Involved in Amyloid-β<Subscript>1–40</Subscript> (Aβ<Subscript>1–40</Subscript>)-induced Microglial Activation: a New Implication in Alzheimer’s Disease

Using microarray analysis, we detected microRNA-124 (miR-124) to be abundantly expressed in the olfactory bulb (OB). miR-124 regulates adult neurogenesis in the subventricular zone (SVZ). However, much less is known about its role in newborn OB neurons. Here, using both gain-of-function and loss-of-function approaches, we demonstrate that brain-specific miR-124 affects dendritic morphogenesis and spine density in newborn OB neurons. Functional Annotation Clustering of miR-124 targets was enriched in “cell morphogenesis involved in neuron differentiation.”     

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.     

Synergistic and additive effects of enriched environment and lithium on the generation of new cells in adult mouse hippocampus

Hippocampal atrophy is reported in several neuropathological disorders. The hippocampal dentate gyrus (DG) is a brain region where adult neurogenesis constitutively occurs. There are some reports suggesting the ability of endogenous neurogenesis to initiate neuronal repair in the hippocampus in response to neuropathological conditions, but its capacity to compensate for neuronal loss is limited. Among strategies to enhance adult hippocampal neurogenesis are enriched environment and lithium. This study aimed to assess whether both strategies could interact to potentiate the generation of new cells in the adult DG. Healthy adult male C57BL/6 mice were divided into four treatment groups for 28 days: control, lithium, enriched environment, enriched environment plus lithium. The animals were injected with BrdU (cell proliferation marker) shortly before the start of the treatments and killed 28 days later for analysis of newly generated cells. Two-way ANOVA followed by post hoc test revealed a significant synergistic interaction between enriched environment and lithium in the total number of BrdU⁺ cells in the entire DG (p = 0.019), a trend towards significant synergistic interaction in the dorsal DG (p = 0.075), and a significant additive effect in the ventral DG (p = 0.001). These findings indicate that the combination of enriched environment and lithium has both synergistic and additive effects on the generation of new cells in the healthy adult DG (these effects being possibly segregated along the dorso-ventral axis of the hippocampus), and suggest that it might be worth investigating whether this combination would have a similar effect in neuropathological conditions.     

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.     

Enriched Environment Promotes Adult Hippocampal Neurogenesis through FGFRs

The addition of new neurons to existing neural circuits in the adult brain remains of great interest to neurobiology because of its therapeutic implications. The premier model for studying this process has been the hippocampal dentate gyrus in mice, where new neurons are added to mature circuits during adulthood. Notably, external factors such as an enriched environment (EE) and exercise markedly increase hippocampal neurogenesis. Here, we demonstrate that EE acts by increasing fibroblast growth factor receptor (FGFR) function autonomously within neurogenic cells to expand their numbers in adult male and female mice. FGFRs activated by EE signal through their mediators, FGFR substrate (FRS), to induce stem cell proliferation, and through FRS and phospholipase Cγ to increase the number of adult-born neurons, providing a mechanism for how EE promotes adult neurogenesis.SIGNIFICANCE STATEMENT How the environment we live in affects cognition remains poorly understood. In the current study, we explore the mechanism underlying the effects of an enriched environment on the production of new neurons in the adult hippocampal dentate gyrus, a brain area integral in forming new memories. A mechanism is provided for how neural precursor cells in the adult mammalian dentate gyrus respond to an enriched environment to increase their neurogenic output. Namely, an enriched environment acts on stem and progenitor cells by activating fibroblast growth factor receptor signaling through phospholipase Cγ and FGF receptor substrate proteins to expand the pool of precursor cells.     

Environmental enrichment and social isolation modulate inhibitory transmission and plasticity in hippocampal area CA2

Environmental factors are well-accepted to play a complex and interdependent role with genetic factors in learning and memory. The goal of this study was to examine how environmental conditions altered synaptic plasticity in hippocampal area CA2. To do this, we housed adult mice for 3 weeks in an enriched environment (EE) consisting of a larger cage with running wheel, and regularly changed toys, tunnels and treats. We then performed whole-cell or extracellular field recordings in hippocampal area CA2 and compared the synaptic plasticity from EE-housed mice with slices from littermate controls housed in standard environment (SE). We found that the inhibitory transmission recruited by CA3 input stimulation in CA2 was significantly less plastic in EE conditions as compared to SE following an electrical tetanus. We demonstrate that delta-opioid receptor (DOR) mediated plasticity is reduced in EE conditions by direct application of DOR agonist. We show that in EE conditions the overall levels of GABA transmission is reduced in CA2 cells by analyzing inhibition of ErbB4 receptor, spontaneous inhibitory currents and paired-pulse ratio. Furthermore, we report that the effect of EE of synaptic plasticity can be rapidly reversed by social isolation. These results demonstrate how the neurons in hippocampal area CA2 are sensitive to environment and may lead to promising therapeutic targets.     

Environmental enrichment alters glial antigen expression and neuroimmune function in the adult rat hippocampus

Neurogenesis is a well-characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Environmental enrichment (EE) in rodents increases neurogenesis, enhances cognition, and promotes recovery from injury. However, little is known about the effects of EE on glia (astrocytes and microglia). Given their importance in neural repair, we predicted that EE would modulate glial phenotype and/or function within the hippocampus. Adult male rats were housed either 12 h/day in an enriched environment or in a standard home cage. Rats were injected with BrdU at 1 week, and after 7 weeks, half of the rats from each housing group were injected with lipopolysaccharide (LPS), and cytokine and chemokine expression was assessed within the periphery, hippocampus and cortex. Enriched rats had a markedly blunted pro-inflammatory response to LPS within the hippocampus. Specifically, expression of the chemokines Ccl2, Ccl3 and Cxcl2, several members of the tumor necrosis factor (TNF) family, and the pro-inflammatory cytokine IL-1β were all significantly decreased following LPS administration in EE rats compared to controls. EE did not impact the inflammatory response to LPS in the cortex. Moreover, EE significantly increased both astrocyte (GFAP+) and microglia (Iba1+) antigen expression within the DG, but not in the CA1, CA3, or cortex. Measures of neurogenesis were not impacted by EE (BrdU and DCX staining), although hippocampal BDNF mRNA was significantly increased by EE. This study demonstrates the importance of environmental factors on the function of the immune system specifically within the brain, which can have profound effects on neural function.     

The role of postnatal neurogenesis in supporting remote memory and spatial metric processing

In this study, we determined the contribution of juvenile neurogenesis to the performance of mice on a remote memory for temporally based association task and in a novelty based spatial pattern separation task. This was accomplished by mating homozygous DNMT1‐loxP mice with heterozygous GFAP‐Cre mice and comparing Cre+ (no postnatal neurogenesis) to Cre? (wild type) littermate offspring. The results indicate that Cre+ mice are impaired relative to Cre? mice in the remote memory for a temporal based association task and in a novelty based spatial pattern separation task. These results support the temporal integration model of Aimone et al., [(2006) Nat Neurosci 9:723–727] and provide further support for an important role for postnatally born neurons in spatial pattern separation. In contrast, Cre+ mice are not impaired relative to Cre? mice in an object‐context recognition task and a spatial location recognition task. These latter data suggest that postnatally derived neurons in the dentate gyrus (DG) do not support all spatial and object recognition functions of the DG. © 2014 Wiley Periodicals, Inc.