Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.     

Early‐life stress diminishes the increase in neurogenesis after exercise in adult female mice

Exposure to early‐life stress (ES) has long‐lasting consequences for later cognition and hippocampal plasticity, including adult hippocampal neurogenesis (AHN), i.e., the generation of new neurons from stem/progenitor cells in the adult hippocampal dentate gyrus. We had previously demonstrated a sex‐specific vulnerability to ES exposure; female mice exposed to ES from P2‐P9 exhibited only very mild cognitive changes and no reductions in AHN as adult, whereas ES‐exposed male mice showed impaired cognition closely associated with reductions in AHN. Given the apparent resilience of AHN to ES in females, we here questioned whether ES has also altered the capacity to respond to positive stimuli for neurogenesis. We therefore investigated whether exercise, known for its strong pro‐neurogenic effects, can still stimulate AHN in adult female mice that had been earlier exposed to ES. We confirm a strong pro‐neurogenic effect of exercise in the dorsal hippocampus of 8‐month‐old control female mice, but this positive neurogenic response is less apparent in female ES mice. These data provide novel insights in the lasting consequences of ES on hippocampal plasticity in females and also indicate that ES might lastingly reduce the responsiveness of the hippocampal stem cell pool, to exercise, in female mice.     

Distinct stages of adult hippocampal neurogenesis are regulated by running and the running environment

Hippocampal neurogenesis continues into adulthood in mammalian vertebrates, and in experimental rodent models it is powerfully stimulated by exposure to a voluntary running wheel. In this study, we demonstrate that exposure to a running wheel environment, in the absence of running, is sufficient to regulate specific aspects of hippocampal neurogenesis. Adult mice were provided with standard housing, housing enriched with a running wheel or housing enriched with a locked wheel (i.e., an environment comparable to that of running animals, without the possibility of engaging in running). We found that mice in the running wheel and locked wheel groups exhibited equivalent increases in proliferation within the neurogenic niche of the dentate gyrus; this included comparable increases in the proliferation of radial glia‐like stem cells and the number of proliferating neuroblasts. However, only running animals displayed increased numbers of postmitotic neuroblasts and mature neurons. These results demonstrate that the running wheel environment itself is sufficient for promoting proliferation of early lineage hippocampal precursors, while running per se enables newly generated neuroblasts to survive and mature into functional hippocampal neurons. Thus, both running‐independent and running‐dependent stimuli are integral to running wheel‐induced hippocampal neurogenesis. © 2010 Wiley Periodicals, Inc.     

Repetitive noxious neonatal stimuli increases dentate gyrus cell proliferation and hippocampal brain‐derived neurotrophic factor levels

Neonatal noxious stimulation has been proposed to model pain triggered by diagnostic/therapeutic invasive procedures in premature infants. Previous studies have shown that hippocampal neurogenesis rate and the behavioral repertoire of adult rats may be altered by neonatal noxious stimuli. The purpose of this study was to evaluate whether noxious stimulation during neonatal period alters the nociceptive response and dentate gyrus neurogenesis when compared to rats subjected to a single noxious stimulus in late infancy. Plasma corticosterone and hippocampal brain‐derived neurotrophic factor (BDNF) levels were measured. Neurogenesis in the dentate gyrus was evaluated in adolescent rats (postnatal day 40; P40) exposed twice to intra‐plantar injections of Complete Freund's adjuvant (CFA) on P1 and P21 (group P1P21) or P8 and P21 (P8P21) or exposed once on P21 (pubertal). On P21, one subset of animals received 5‐bromo‐2′‐deoxyuridine (BrdU) and was euthanized on P40 for identification of proliferating cells in the dentate gyrus. Another subset was sampled for thermal response or plasma corticosterone measurement and hippocampal BDNF levels. Proliferative cell rate in dentate gyrus was the highest in all re‐exposed groups (P < 0.001), except for P8 females (P8P21F), revealing also a sex difference, where P8P21 males showed higher rate than females (P < 0.001). Stimulated groups took longer than CTL animals to lick the paws (P < 0.001), regardless of the age when the noxious stimulus was applied. Re‐exposed groups had lower corticosterone plasma level (P1P21 M and F, P8P21M) than controls. On the contrary, hippocampal BDNF was increased in males from both re‐exposed groups. These results show that infant noxious stimulation in neonatally previously stimulated rats is related to high proliferation in the DG and this association seems to be modified by the animal's sex. The new generated dentate granule cells in the hippocampus may have a role in the long‐term behavioral responses to neonatal nociceptive stimulation. Noxious stimulation in the neonatal period results in sex‐dependent neurogenic response. © 2013 Wiley Periodicals, Inc.     

Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long‐term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long‐term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long‐term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum, Lieberman, Briner, Leonardo, & Dranovsky, 2014 ), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.     

In vivo contribution of nestin‐ and GLAST‐lineage cells to adult hippocampal neurogenesis

Radial glia‐like cells (RGCs) are the hypothesized source of adult hippocampal neurogenesis. However, the current model of hippocampal neurogenesis does not fully incorporate the in vivo heterogeneity of RGCs. In order to better understand the contribution of different RGC subtypes to adult hippocampal neurogenesis, we employed widely used transgenic lines (Nestin‐CreER^T2 and GLAST::CreER^T2 mice) to explore how RGCs contribute to neurogenesis under basal conditions and after stimulation and depletion of neural progenitor cells. We first used these inducible fate‐tracking transgenic lines to define the similarities and differences in the contribution of nestin‐ and GLAST‐lineage cells to basal long‐term hippocampal neurogenesis. We then explored the ability of nestin‐ and GLAST‐lineage RGCs to contribute to neurogenesis after experimental manipulations that either ablate neurogenesis (i.c.v. application of the anti‐mitotic AraC, cytosine‐β‐D‐arabinofuranoside) or stimulate neurogenesis (wheel running). Interestingly, in both ablation and stimulation experiments, labeled RGCs in GLAST::CreER^T2 mice appear to contribute to neurogenesis, whereas RGCs in Nestin‐CreER^T2 mice do not. Finally, using NestinGFP reporter mice, we expanded on previous research by showing that not all RGCs in the adult dentate gyrus subgranular zone express nestin, and therefore RGCs are antigenically heterogeneous. These findings are important for the field, as they allow appropriately conservative interpretation of existing and future data that emerge from these inducible transgenic lines. These findings also raise important questions about the differences between transgenic driver lines, the heterogeneity of RGCs, and the potential differences in progenitor cell behavior between transgenic lines. As these findings highlight the possible differences in the contribution of cells to long‐term neurogenesis in vivo, they indicate that the current models of hippocampal neurogenesis should be modified to include RGC lineage heterogeneity. © 2013 Wiley Periodicals, Inc.     

Sexual experience restores age‐related decline in adult neurogenesis and hippocampal function

Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age‐related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle‐aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle‐aged rats. Following continuous long‐term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle‐aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown. © 2013 Wiley Periodicals, Inc.     

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.     

Prolonged voluntary wheel‐running stimulates neural precursors in the hippocampus and forebrain of adult CD1 mice

Voluntary wheel‐running induces a rapid increase in proliferation and neurogenesis by neural precursors present in the adult rodent hippocampus. In contrast, the responses of hippocampal and other central nervous system neural precursors following longer periods of voluntary physical activity are unclear and are an issue of potential relevance to physical rehabilitation programs. We investigated the effects of a prolonged, 6‐week voluntary wheel‐running paradigm on neural precursors of the CD1 mouse hippocampus and forebrain. Examination of the hippocampus following 6 weeks of running revealed two to three times as many newly born neurons and 60% more proliferating cells when compared with standard‐housed control mice. Among running mice, the number of newly born neurons correlated with the total running distance. To establish the effects of wheel‐running on hippocampal precursors dividing during later stages of the prolonged running regime, BrdU was administered after 3 weeks of running and the BrdU‐retaining cells were analyzed 18 days later. Quantifications revealed that the effects of wheel‐running were maintained in late‐stage proliferating cells, as running mice had two to three times as many BrdU‐retaining cells within the hippocampal dentate gyrus, and these yielded greater proportions of both mature neurons and proliferative cells. The effects of prolonged wheel‐running were also detected beyond the hippocampus. Unlike short‐term wheel‐running, prolonged wheel‐running was associated with higher numbers of proliferating cells within the ventral forebrain subventricular region, a site of age‐associated decreases in neural precursor proliferation and neurogenesis. Collectively, these findings indicate that (i) prolonged voluntary wheel‐running maintains an increased level of hippocampal neurogenesis whose magnitude is linked to total running performance, and (ii) that it influences multiple neural precursor populations of the adult mouse brain. © 2009 Wiley‐Liss, Inc.     

Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment

Neurons are continually born from endogenous stem cells and added to the dentate gyrus throughout life, but adult hippocampal neurogenesis declines precipitously with age. Short‐term exposure to an enriched environment leads to a striking increase in new neurons, along with a substantial improvement in behavioral performance. Could this plastic response be relevant for explaining the beneficial effects of leading “an active life” on brain function and pathology? Adult hippocampal neurogenesis in mice living in an enriched environment from the age of 10 to 20 months was fivefold higher than in controls. Relatively, the increase in neuronal phenotypes was entirely at the expense of newly generated astrocytes. This cellular plasticity occurred in the context of significant improvements of learning parameters, exploratory behavior, and locomotor activity. Enriched living mice also had a reduced lipofuscin load in the dentate gyrus, indicating decreased nonspecific age‐dependent degeneration. Therefore, in mice signs of neuronal aging can be diminished by a sustained active and challenging life, even if this stimulation started only at medium age. Activity exerts not only an acute but also a sustained effect on brain plasticity.     

Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment

Neurogenesis continues to occur in the adult mammalian hippocampus and is regulated by both genetic and environmental factors. It is known that exposure to an enriched environment enhances the number of newly generated neurons in the dentate gyrus. However, the mechanisms by which enriched housing produces these effects are poorly understood. To test a role for neurotrophins, we used heterozygous knockout mice for brain-derived neurotrophic factor (BDNF+/-) and mice lacking neurotrophin-4 (NT-4-/-) together with their wild-type littermates. Mice were either reared in standard laboratory conditions or placed in an enriched environment for 8 weeks. Animals received injections of the mitotic marker bromodeoxyuridine (BrdU) to label newborn cells. Enriched wild-type and enriched NT-4-/- mice showed a two-fold increase in hippocampal neurogenesis as assessed by stereological counting of BrdU-positive cells in the dentate gyrus and double labelling for BrdU and the neuronal marker NeuN. Remarkably, this enhancement of hippocampal neurogenesis was not seen in enriched BDNF+/- mice. Failure to up-regulate BDNF accompanied the lack of a neurogenic response in enriched BDNF heterozygous mice. We conclude that BDNF but not NT-4 is required for the environmental induction of neurogenesis.     

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.     

Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis

Kainate-induced seizures increase hippocampal neurogenesis. Glial fibrillary acidic protein-positive astrocytes with radial processes in the dentate gyrus share many of the characteristics of radial glia and appear to act as precursor cells for adult dentate neurogenesis. Using the chemoconvulsant kainate and transgenic mice with human glial-fibrillary acidic protein (hGFAP) promoter-controlled enhanced green fluorescent protein (EGFP) expression, we examined the proliferation, morphology and electrophysiological properties of astrocytes in the neurogenic subgranular zone of the dentate gyrus in control animals and upon the induction of seizure-induced cell proliferation, three days post-kainate. EGFP-positive cells with and without radial processes could easily be distinguished. Kainate treatment caused a significant increase in the total number of proliferating EGFP-positive cells, particularly a tenfold elevation in the number of proliferating radial glia-like astrocytes, and also caused a preferential shift in the dividing cell population towards cells expressing EGFP. Immunohistochemical analysis revealed a surprisingly low proportion of cells coexpressing the astroglial marker S100beta and EGFP. Kainate increased the number of EGFP-positive, S100beta-positive and S100beta-positive-EGFP-positive astrocytes in the subgranular zone. We also report a subset of faintly EGFP-positive cells expressing markers of early neuronal differentiation. Patch-clamp analysis revealed the presence of three functionally different populations of EGFP-positive cells in both kainate and control tissue. We conclude that there is an early increase in proliferating radial glia-like astrocytes in the dentate after kainate-induced seizures, consistent with a recruitment of precursors for seizure-induced neurogenesis.     

Activity‐regulated gene expression in immature neurons in the dentate gyrus following re‐exposure to a cocaine‐paired environment

Intense craving for drug and relapse are observed in addicts who are exposed to environmental stimuli associated with drug‐taking behavior even after long periods of abstinence. The hippocampus is a brain region known to be involved in contextual processing, taking place predominantly in the septal hippocampus, and emotional processing, taking place predominantly in the temporal hippocampus. Conditioned place preference is an animal model of context‐conditioned reward. The dentate gyrus is a hippocampal sub‐region particularly important for the acquisition of cocaine‐induced place preference and is a site of continuous neurogenesis, which has been implicated in the vulnerability to drug‐taking behavior. Therefore, these experiments explored the role of newly generated neurons in drug reward‐context association by examining the activation, as determined by expression of the immediate early gene cfos, of young and mature granule cells in the septal and temporal dentate gyrus of adult rats that were re‐exposed to a drug‐paired environment following the development of cocaine place preference. The overall level of cfos expression was increased in both the septal and temporal dentate gyrus of animals that developed place preference and were re‐exposed to the drug paired environment compared with re‐exposure to a neutral environment. Overall level of neurogenesis, as detected by the S‐phase marker 5′‐bromo‐2′‐deoxyuridine (BrdU) and the immature neuron marker doublecortin (DCX), was unaltered by cocaine conditioning. However, the number of activated new neurons (DCX + cfos) was greater in the temporal dentate gyrus of cocaine‐conditioned rats re‐exposed to the drug‐paired environment as compared to those re‐exposed to a neutral environment. Further understanding of the role of dentate gyrus neurogenesis on the conditioned effects of drugs of abuse may provide new insights into the role of this process in the expression of addictive behaviors. © 2014 Wiley Periodicals, Inc.     

Activation of local inhibitory circuits in the dentate gyrus by adult‐born neurons

Robust incorporation of new principal cells into pre‐existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult‐born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult‐born GCs (0 to 7 weeks post‐mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging—to decrease it—and housing in an enriched environment—to increase it—strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult‐born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult‐born hippocampal neurons. © 2015 Wiley Periodicals, Inc.     

Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) affects cognitive modalities that are known to be regulated by adult neurogenesis, such as hippocampal‐ and olfactory‐dependent learning and memory. However, the relationship between AD‐associated pathologies and alterations in adult neurogenesis has remained contentious. In the present study, we performed a detailed investigation of adult neurogenesis in the triple transgenic (3xTg) mouse model of AD, a unique model that generates both amyloid plaques and neurofibrillary tangles, the hallmark pathologies of AD. In both neurogenic niches of the brain, the hippocampal dentate gyrus and forebrain subventricular zone, we found that 3xTg mice had decreased numbers of (i) proliferating cells, (ii) early lineage neural progenitors, and (iii) neuroblasts at middle age (11 months old) and old age (18 months old). These decreases correlated with major reductions in the addition of new neurons to the respective target areas, the dentate granule cell layer and olfactory bulb. Within the subventricular zone niche, cytological alterations were observed that included a selective loss of subependymal cells and the development of large lipid droplets within the ependyma of 3xTg mice, indicative of metabolic changes. Temporally, there was a marked acceleration of age‐related decreases in 3xTg mice, which affected multiple stages of neurogenesis and was clearly apparent prior to the development of amyloid plaques or neurofibrillary tangles. Our findings indicate that AD‐associated mutations suppress neurogenesis early during disease development. This suggests that deficits in adult neurogenesis may mediate premature cognitive decline in AD.     

Blockade of 2‐arachidonoylglycerol hydrolysis produces antidepressant‐like effects and enhances adult hippocampal neurogenesis and synaptic plasticity

The endocannabinoid ligand 2‐arachidonoylglycerol (2‐AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant‐ and anxiolytic‐like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive‐like behaviors and decreased the number of bromodeoxyuridine‐labeled neural progenitor cells and doublecortin‐positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long‐term potentiation (LTP) in the DG known to be neurogenesis‐dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS‐exposed mice. These results suggest that enhanced adult neurogenesis and long‐term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant‐ and anxiolytic‐like behavioral effects of JZL184. © 2014 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.     

Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

Dentate gyrus adult neurogenesis is implicated in the formation of hippocampal‐dependent contextual associations. However, the role of adult neurogenesis during reward‐based context‐dependent paradigms—such as conditioned place preference (CPP)—is understudied. Therefore, we used image‐guided, hippocampal‐targeted X‐ray irradiation (IG‐IR) and morphine CPP to explore whether dentate gyrus adult neurogenesis plays a role in reward memories created in adult C57BL/6J male mice. In addition, as adult neurogenesis appears to participate to a greater extent in retrieval and extinction of recent (<48 hr posttraining) versus remote (>1 week posttraining) memories, we specifically examined the role of adult neurogenesis in reward‐associated contextual memories probed at recent and remote timepoints. Six weeks post‐IG‐IR or Sham treatment, mice underwent morphine CPP. Using separate groups, retrieval of recent and remote reward memories was found to be similar between IG‐IR and Sham treatments. Interestingly, IG‐IR mice showed impaired extinction—or increased persistence—of the morphine‐associated reward memory when it was probed 24‐hr (recent) but not 3‐weeks (remote) postconditioning relative to Sham mice. Taken together, these data show that hippocampal‐directed irradiation and the associated decrease in dentate gyrus adult neurogenesis affect the persistence of recently—but not remotely—probed reward memory. These data indicate a novel role for adult neurogenesis in reward‐based memories and particularly the extinction rate of these memories. Consideration of this work may lead to better understanding of extinction‐based behavioral interventions for psychiatric conditions characterized by dysregulated reward processing.     

Adult interleukin-6 knockout mice show compromised neurogenesis

Interleukin-6 (IL-6) is a proinflammatory cytokine known to modulate neurogenesis. We presently evaluated neural progenitor proliferation, survival, and phenotypic maturation in the hippocampal dentate gyrus, subventricular zone, and the posterior periventricle in the brains of IL-6 knockout mice and their wild-type littermates. In all the three neurogenic regions of the IL-6 mice there was a significant decrease in the number of 5-bromo-2-deoxyuridine positive (BrdU) proliferating progenitors compared with the IL-6 mice. The IL-6 mice also showed a significantly lower progenitor cell survival in the dentate gyrus and subventricular zone compared with the IL-6 mice. In conclusion, a complete lack of IL-6 might be detrimental to neurogenesis in the adult brain.