Experience‐dependent regulation of adult hippocampal neurogenesis: Effects of long‐term stimulation and stimulus withdrawal

Exposure to an enriched environment has been shown to cause an increase in neurogenesis in the dentate gyrus of adult mice. In this study we examined how this experience‐dependent response in adult hippocampal neurogenesis of C57BL/6 mice is modulated under the conditions of long‐term stimulation and of withdrawal from the enriched environment. We found that a group which experienced withdrawal from the enriched environment 3 months earlier, had more than twice as many proliferating cells in the subgranular zone as controls and mice experiencing long‐term stimulation. We propose that the greater number of proliferating cells after withdrawal reflects a survival‐promoting effect on the dividing neuronal stem and progenitor cells during the earlier period of stimulation. No differences between the groups were observed in the number of surviving progeny or their phenotypes. Therefore, the existence of more dividing cells in the withdrawal group did not translate into a significant net increase in neurogenesis in the absence of continued stimulation. Similarly, the finding in the group experiencing long‐term stimulation showing no clear benefit over controls could be interpreted as a diminished efficiency of continued environmental stimuli to elicit a neurogenic response. Thus, we propose as a working hypothesis that: 1) stimulation early in life may preserve the neurogenic potential in the dentate gyrus, and 2) the novelty of complex stimuli rather than simply continued exposure to complex stimuli elicits the environmental effects on adult hippocampal neurogenesis. Hippocampus 1999;9:321–332. © 1999 Wiley‐Liss, Inc.     

Age‐dependent role for Ras‐GRF1 in the late stages of adult neurogenesis in the dentate gyrus

The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover, the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RAS‐GRF1 (GRF1), a calcium‐dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis. We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (～2 months of age), when wild‐type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2‐month‐old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age‐dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts. © 2013 Wiley Periodicals, Inc.     

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.     

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.     

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 impoverishment and aging alter object recognition,spatial learning,and dentate gyrus astrocytes

Environmental and age‐related effects on learning and memory were analysed and compared with changes observed in astrocyte laminar distribution in the dentate gyrus. Aged (20 months) and young (6 months) adult female albino Swiss mice were housed from weaning either in impoverished conditions or in enriched conditions, and tested for episodic‐like and water maze spatial memories. After these behavioral tests, brain hippocampal sections were immunolabeled for glial fibrillary acid protein to identify astrocytes. The effects of environmental enrichment on episodic‐like memory were not dependent on age, and may protect water maze spatial learning and memory from declines induced by aging or impoverished environment. In the dentate gyrus, the number of astrocytes increased with both aging and enriched environment in the molecular layer, increased only with aging in the polymorphic layer, and was unchanged in the granular layer. We suggest that long‐term experience‐induced glial plasticity by enriched environment may represent at least part of the circuitry groundwork for improvements in behavioral performance in the aged mice brain.     

Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus

Increased neurogenesis in the dentate gyrus (DG) after brain insults such as excitotoxic lesions, seizures, or stroke is a well known phenomenon in the young hippocampus. This plasticity reflects an innate compensatory response of neural stem cells (NSCs) in the young hippocampus to preserve function or minimize damage after injury. However, injuries to the middle‐aged and aged hippocampi elicit either no or dampened neurogenesis response, which could be due to an altered plasticity of NSCs and/or the hippocampus with age. We examined whether the plasticity of NSCs to increase neurogenesis in response to a milder injury such as partial deafferentation is preserved during aging. We quantified DG neurogenesis in the hippocampus of young, middle‐aged, and aged F344 rats after partial deafferentation. A partial deafferentation of the left hippocampus without any apparent cell loss was induced via administration of Kainic acid (0.5 μg in 1.0 μl) into the right lateral ventricle of the brain. In this model, degeneration of CA3 pyramidal neurons and dentate hilar neurons in the right hippocampus results in loss of commissural axons which leads to partial deafferentation of the dendrites of dentate granule cells and CA1‐CA3 pyramidal neurons in the left hippocampus. Quantification of newly born cells that are added to the dentate granule cell layer at postdeafferentation days 4–15 using 5′‐bromodeoxyuridine (BrdU) labeling revealed greatly increased addition of newly born cells (～three fold increase) in the deafferented young and middle‐aged hippocampi but not in the deafferented aged hippocampus. Measurement of newly born neurons using doublecortin (DCX) immunostaining also revealed similar findings. Analyses using BrdU‐DCX dual immunofluorescence demonstrated no changes in neuronal fate‐choice decision of newly born cells after deafferentation, in comparison to the age‐matched naive hippocampus in all age groups. Thus, the plasticity of hippocampal NSCs to increase DG neurogenesis in response to a milder injury such as partial hippocampal deafferentation is preserved until middle age but lost at old age. © 2010 Wiley‐Liss, Inc.     

The role of seizure-induced neurogenesis in epileptogenesis and brain repair

Data accumulated over the past four decades have led to the widespread recognition that neurogenesis, the birth of new neurons, persists in the hippocampal dentate gyrus and rostral forebrain subventricular zone (SVZ) of the adult mammalian brain. Neural precursor cells located more caudally in the forebrain SVZ are thought to also give rise to glia throughout life. The continued production of neurons and glia suggests that the mature brain maintains an even greater potential for plasticity after injury than was previously recognized. Underscoring this idea are recent findings that seizures induced by various experimental manipulations increase neurogenesis in the adult rodent dentate gyrus. Although neurogenesis and gliogenesis in persistent germinative zones are altered in adult rodent models of temporal lobe epilepsy (TLE), the effects of seizure-induced neurogenesis in the epileptic brain, in terms of either a pathological or reparative role, are only beginning to be explored. Emerging data suggest that altered neurogenesis in the epileptic dentate gyrus may be pathological and promote abnormal hyperexcitability. However, the presence of endogenous neural progenitors in other proliferative regions may offer potential strategies for the development of anti-epileptogenic or neuronal replacement therapies.     

Functional recruitment of newborn hippocampal neurons after experimental stroke

The adult brain responds to diverse pathologies such as stroke with increased generation of neurons in the dentate gyrus of the hippocampus. However, only little is known regarding the functional integration of newborn neurons into pre-existing neuronal circuits. In this study, we investigated whether newborn neurons generated after experimental stroke are recruited for different behavioral tasks. Adult mice received photochemical cortical infarcts in the sensorimotor cortex and proliferating cells were labeled using the proliferation marker, bromodeoxyuridine. Eight weeks after stroke induction, the animals were trained to perform either a spatiotemporal task or a sensorimotor task. Immediate early gene expression (c-fos, Zif268) in newborn neurons was analyzed directly after the last session. Using this approach, we demonstrate that post-stroke generated neurons are recruited within the hippocampal networks. The sensorimotor task activates significantly more newborn neurons compared to the spatiotemporal task. Further experiments employing the two well-established stimulators of neurogenesis, enriched environment and voluntary wheel running, both significantly increase post-stroke neurogenesis in the dentate gyrus but do not affect the percentage of recruited neurons compared to controls. Significantly, the spatiotemporal task leads to a higher portion of activated newborn neurons in the granule cell layer, suggesting a specific spatial activation pattern of new neurons in the dentate gyrus.     

Short‐term environmental enrichment,in the absence of exercise,improves memory,and increases NGF concentration,early neuronal survival,and synaptogenesis in the dentate gyrus in a time‐dependent manner

Environmental manipulations can enhance neuroplasticity in the brain, with enrichment‐induced cognitive improvements being linked to increased expression of growth factors, such as neurotrophins, and enhanced hippocampal neurogenesis. There is, however, a great deal of variation in environmental enrichment protocols used in the literature, making it difficult to assess the role of particular aspects of enrichment upon memory and the underlying associated mechanisms. This study sought to evaluate the efficacy of environmental enrichment, in the absence of exercise, as a cognitive enhancer and assess the role of Nerve Growth Factor (NGF), neurogenesis and synaptogenesis in this process. We report that rats housed in an enriched environment for 3 and 6 weeks (wk) displayed improved recognition memory, while rats enriched for 6 wk also displayed improved spatial and working memory. Neurochemical analyses revealed significant increases in NGF concentration and subgranular progenitor cell survival (as measured by BrdU+ nuclei) in the dentate gyrus of rats enriched for 6 wk, suggesting that these cellular changes may mediate the enrichment‐induced memory improvements. Further analysis revealed a significant positive correlation between recognition task performance and BrdU+ nuclei. In addition, rats enriched for 6 wk showed a significant increase in expression of synaptophysin and synapsin I in the dentate gyrus, indicating that environmental enrichment can increase synaptogenesis. These data indicate a time‐dependent cognitive‐enhancing effect of environmental enrichment that is independent of physical activity. These data also support a role for increased concentration of NGF in dentate gyrus, synaptogenesis, and neurogenesis in mediating this effect. © 2013 Wiley Periodicals, Inc.     

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.     

Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology

Alzheimer's disease (AD) is accompanied by hippocampal neuronal loss and abnormal neurogenesis, both of which probably contributing to AD-related cognitive deficits. Mounting evidence indicates that cognitive and physical stimulation provided by environmental enrichment improves neurogenesis in healthy animals and counteracts beta-amyloid pathology in mouse models of AD. Here, we hypothesized that environmental enrichment has also an impact on hippocampal neurogenesis in mice with AD-like pathology. Therefore, TgCRND8 mice and wild type littermates were either housed under standard conditions or in an enriched environment for 4 months. Standard housed TgCRND8 mice revealed diminished hippocampal cell proliferation and reduced number of mature newborn neurons compared to wild type littermates under the same housing condition. However, environmental enrichment reversed this genotype effect. Here, we show that cognitive and physical stimulation is capable of increasing the number of newborn mature hippocampal neurons in transgenic mice to wild type levels. Moreover, the expression of various plasticity associated molecules was enhanced in transgenic mice due to enriched housing. This study identifies that environmental enrichment improves diminished cellular plasticity in AD brain, probably enhancing the brain capacity to better compensate for neurodegeneration.     

The Novel Antidepressant Agomelatine Normalizes Hippocampal Neuronal Activity and Promotes Neurogenesis in Chronically Stressed Rats

Agomelatine is a novel antidepressant which acts as a melatonergic (MT1/MT2) receptor agonist and serotonergic (5‐HT_2C) receptor antagonist. The antidepressant properties of agomelatine have been demonstrated in animal models as well as in clinical studies. Several preclinical studies reported agomelatine‐induced effects on brain plasticity, mainly under basal conditions in healthy animals. Yet, it is important to unravel agomelatine‐mediated changes in the brain affected by psychopathology or exposed to conditions that might predispose to mood disorders. Since stress is implicated in the etiology of depression, it is valid to investigate antidepressant‐induced effects in animals subjected to chronic stress. In this context, we sought to determine changes in the brain after agomelatine treatment in chronically stressed rats. Adult male rats were subjected to footshock stress and agomelatine treatment for 21 consecutive days. Rats exposed to footshock showed a robust increase in adrenocorticotropic hormone (ACTH) and corticosterone. Chronic agomelatine treatment did not markedly influence this HPA‐axis response. Whereas chronic exposure to daily footshock stress reduced c‐Fos expression in the hippocampal dentate gyrus, agomelatine treatment reversed this effect and normalized neuronal activity to basal levels. Moreover, chronic agomelatine administration was associated with enhanced hippocampal cell proliferation and survival in stressed but not in control rats. Furthermore, agomelatine reversed the stress‐induced decrease in doublecortin expression in the dentate gyrus. Taken together, these data show a beneficial action of agomelatine in the stress‐compromised brain, where it restores stress‐affected hippocampal neuronal activity and promotes adult hippocampal neurogenesis.     

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.     

Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occured before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146–156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.     

Monday July 3, 200612:00–13:30Hall 3DPlatform SessionBasic Science I: Molecules and Networks for Epileptogenesis

¹ M. Kokaia (   ¹ Wallenberg Neuroscience Center, Lund University Hospital, Sweden )
Purpose: Neural stem cells in the adult mammalian brain (including humans) continue to produce new functional granule cells in the dentate gyrus subgranular zone and new olfactory bulb neurons in the subventricular zone during an entire life. In the hippocampus, neurogenesis has been proposed to play a role in learning and memory and mood regulation. The new cells develop electrophysiological characteristics and synaptic inputs very similar to those of the rest of the cell population. The purpose of the study was to explore whether tissue environment in an epileptic brain influences properties of afferent synapses formed on newborn granule cells.
Method: Rats were exposed to either a physiological stimulus, i.e., running, or status epilepticus, which gives rise to neuronal death, inflammation, increased network excitability and recurrent spontaneous seizures. Both treatments increase neurogenesis in the dentate gyrus. We labelled newborn cells by GFP-retroviral vector injections right after these treatments to identify the cells and apply whole-cell patch-clamp recordings in live hippocampal slices.
Results: Granule cells formed after running and status epilepticus exhibited similar intrinsic membrane properties. However, new neurons born into the epileptic environment differed with respect to tonic drive and short-term plasticity of both excitatory and inhibitory afferent synapses. The new granule cells formed after status epilepticus exhibited functional connectivity consistent with reduced synaptic network excitability of the dentate gyrus, i.e., decreased excitatory and increased inhibitory input activity.
Conclusion: We demonstrate for the first time a high degree of plasticity in synaptic inputs to the new neurons, which could mitigate pathological activity in the epileptic brain.     

Fibroblast growth factor receptor-1 is required for long-term potentiation, memory consolidation, and neurogenesis.

BACKGROUND: Although substantial evidence supports the view that adult neurogenesis is involved in learning and memory, how newly generated neurons contribute to the cognitive process remains unknown. Fibroblast growth factor 2 (FGF-2) is known to stimulate the proliferation of neuronal progenitor cells (NPCs) in adult brain. Using conditional knockout mice that lack brain expression of FGFR1, a major receptor for FGF-2, we have investigated the role of adult neurogenesis in hippocampal synaptic plasticity and learning and memory. METHODS: The Fgfr1 conditional knockout mice were generated by crossing the Fgfr1-null line, the Fgfr1-flox line, and the Nestin-Cre transgenic mice. Bromodeoxyuridine (BrdU) labeling, slice electrophysiology, and Morris Water Maze experiments were performed with the Fgfr1 conditional mutant mice. RESULTS: Bromodeoxyuridine labeling experiments demonstrate that FGFR1 is required for the proliferation of NPCs as well as generation of new neurons in the adult dentate gyrus (DG). Moreover, deficits in neurogenesis in Fgfr1 mutant mice are accompanied by a severe impairment of long-term potentiation (LTP) at the medial perforant path (MPP)-granule neuron synapses in the hippocampal dentate. Moreover, the Fgfr1 mutant mice exhibit significant deficits in memory consolidation but not spatial learning. CONCLUSIONS: Our study suggests a critical role of FGFR1 in adult neurogenesis in vivo, provides a potential link between proliferative neurogenesis and dentate LTP, and raises the possibility that adult neurogenesis might contribute to memory consolidation.     

Fluoxetine induces input‐specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age

Fluoxetine, a selective serotonin‐reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input‐specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase‐67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle‐aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle‐aged hippocampus shows greater sensitivity to fluoxetine‐induced input‐specific synaptic remodeling than the hippocampus in adulthood with the stratum‐oriens of CA1 exhibiting heightened structural plasticity. The input‐specific changes and circuit‐level modifications in middle‐age were associated with modest enhancement in contextual fear memory precision, anxiety‐like behavior and antidepressant‐like behavioral responses. © 2015 Wiley Periodicals, Inc.     

Transgenic expression of human wild‐type amyloid precursor protein decreases neurogenesis in the adult hippocampus

Besides its role in Alzheimer's disease, the amyloid precursor protein (APP) is implicated in several physiological functions in neuronal tissue such as cell survival, neurite outgrowth, synaptic formation, and neuronal plasticity. The present study analyzed effects of human wild‐type APP (hAPP) overexpression on adult hippocampal neurogenesis in transgenic mice. Mice were housed under either standard or enriched conditions, the latter to boost neurogenetic activity. Different aspects of neurogenesis including proliferation, survival, and differentiation were assessed by employing the BrdU‐incorporation method and, in parallel, immunohistochemistry for the neuronal and glial markers NeuN and S100b, respectively. Overexpression of hAPP caused a significant decrease in cell proliferation under standard housing conditions. The relative increase in the proliferation rate following housing in enriched environment was not different to that observed in wild‐type mice. Overexpression of hAPP, on the other hand, promoted the survival of newly generated cells, but just under conditions of standard housing. Findings further suggest that overexpression of hAPP suppresses the phenotypic shift toward neuronal differentiation under conditions of enriched environment. In summary, the results reveal a dual effect of APP on adult hippocampal neurogenesis, comprising antiproliferative and prosurvival activities. © 2009 Wiley‐Liss, Inc.