Decline in adult neurogenesis during aging follows a topographic pattern in the mouse hippocampus

In the rodent brain, diverse functions are topographically distributed within the hippocampus. For instance, the dorsal (septal) hippocampus is involved in spatial memory, whereas the ventral (temporal) hippocampus is related to emotion and anxiety. Accumulating evidence shows that age-dependent decline in hippocampal neurogenesis is associated with impairments of these functions. However, little is known about whether the decline in dentate granule cell production during aging follows a topographic pattern. Here we quantitatively estimated specific populations of adult-born cells in young adult and middle-aged mice by using endogenous markers and determined whether age-dependent reductions in adult neurogenesis exhibited topographic differences. The numerical densities (NDs) of putative primary progenitors, intermediate neuronal progenitors, and neuronal lineages were higher in the dorsal dentate gyrus (DG) than in the ventral DG both in young adult and in middle-aged mice, but the ratios of the NDs in the dorsal DG to the NDs in the ventral DG noticeably increased with age. The age-related reductions in the numbers of these populations were larger in the ventral DG than in the dorsal DG. By contrast, the NDs of glial lineages were higher in the ventral DG than in the dorsal DG during life, and the numbers of glial lineages showed no significant age-related changes. Our findings suggest that neurogenesis, but not gliogenesis, wanes faster in the ventral hippocampus than in the dorsal hippocampus during aging. Such age-related topographic changes in hippocampal neurogenesis might be implicated in memory and affective impairments in older people.     

Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats

Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague–Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5-bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal ketamine exposure.     

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.     

Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model

The accumulation of alpha-synuclein in Lewy bodies and Lewy neurites of different neuronal populations is one of the neuropathological hallmarks in Parkinson disease (PD). Overexpression of human wildtype or mutant alpha-synuclein affects the generation of new neurons in the adult dentate gyrus (DG) of the hippocampus in models of PD. Hippocampal dysfunction with reduced neurogenesis plays an important role in the pathogenesis of depression, an important non-motor symptom in PD. Moreover, effective antidepressant treatment is still an unmet need in PD. The present study explored if impaired hippocampal neurogenesis in the A53T transgenic animal model of PD may be restored by chronic oral application of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. First, we determined the expression pattern of transgenic mutant A53T synuclein in developing DG neurons and showed early expression of the transgene linked to a severely impaired neurogenesis. After chronic fluoxetine treatment we observed an increased adult neurogenesis in the hippocampus of more than threefold in treated A53T mice compared with controls. The pro-neurogenic effect of chronic fluoxetine application is predominantly related to an increased proliferation of neural precursor cells in the DG, and to a lesser extent by induction of differentiation into mature neurons. Analysis of the underlying mechanisms revealed an induction of brain-derived and glial cell-derived neurotrophic factor levels as a result of fluoxetine treatment. This study underlines the large potential of SSRI-dependent mechanisms to stimulate adult hippocampal neurogenesis in alpha-synuclein models and may lead to novel means to improve neuropsychiatric symptoms in PD.     

Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice

Early life stress (ES) increases vulnerability to psychopathology and impairs cognition in adulthood. These ES‐induced deficits are associated with lasting changes in hippocampal plasticity. Detailed information on the neurobiological basis, the onset, and progression of such changes and their sex‐specificity is currently lacking but is required to tailor specific intervention strategies. Here, we use a chronic ES mouse model based on limited nesting and bedding material from postnatal day (P) 2–9 to investigate; (1) if ES leads to impairments in hippocampus‐dependent cognitive function in adulthood and (2) if these alterations are paralleled by changes in developmental and/or adult hippocampal neurogenesis. ES increased developmental neurogenesis (proliferation and differentiation) in the dentate gyrus (DG) at P9, and the number of immature (NeurD1⁺) cells migrating postnatally from the secondary dentate matrix, indicating prompt changes in DG structure in both sexes. ES lastingly reduced DG volume and the long‐term survival of developmentally born neurons in both sexes at P150. In adult male mice only, ES reduced survival of adult‐born neurons (BrdU/NeuN⁺ cells), while proliferation (Ki67⁺) and differentiation (DCX⁺) were unaffected. These changes correlated with impaired performance in all learning and memory tasks used here. In contrast, in female mice, despite early alterations in developmental neurogenesis, no lasting changes were present in adult neurogenesis after ES and the cognitive impairments were less prominent and only apparent in some cognitive tasks. We further show that, although neurogenesis and cognition correlate positively, only the hippocampus‐dependent functions depend on changes in neurogenesis, whereas cognitive functions that are not exclusively hippocampus‐dependent do not. This study indicates that chronic ES has lasting consequences on hippocampal structure and function in mice and suggests that male mice are more susceptible to ES than females. Unraveling the mechanisms that underlie the persistent ES‐induced effects may have clinical implications for treatments to counteract ES‐induced deficits. © 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.     

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.     

Increased neurogenesis after hypoxic-ischemic encephalopathy in humans is age related

The leading cause of morbidity and mortality after successful resuscitation is hypoxic-ischemic encephalopathy (HIE), which results in neuronal loss within the neocortex and the hippocampal formation. This study focuses on the impact of HIE on adult neurogenesis in the human hippocampal dentate gyrus as a potential intrinsic regenerative mechanism in response to neuronal damage. Brain sections of 22 autopsy cases with HIE and of 19 age-matched controls without neuropathological abnormalities were investigated by means of immunohistochemistry. The densities of immature granule cells during axon guidance and outgrowth (assessed by TUC-4 immunohistochemistry) and of young calretinin-expressing postmitotic neurons were increased in the granule cell layer of cases who had suffered from HIE (P = 0.0002 and P = 0.0001, respectively). Similarly, the density of apoptotic granule cells, as detected by in situ tailing and morphological criteria, was increased in HIE (P = 0.014). In cases with HIE, the increase in the density of TUC-4-labeled cells inversely correlated with age (P = 0.027). In contrast, neither the density of proliferating nor that of apoptotic cells was substantially influenced by age within the control group. Taken together, both an increase in adult neurogenesis and in neuronal apoptosis was observed in the human dentate gyrus in response to HIE. The data suggest a decrease of adult neurogenesis in older-aged cases. Whether neurogenesis can contribute to recovery after HIE remains to be determined. The stimulation of adult neurogenesis may be less efficient in older victims of HIE. W.-R. C. Mattiesen and S. C. Tauber have equally contributed to this work.     

Avoidance and escape conditioning adjust adult neurogenesis to conserve a fit hippocampus in adult male rodents

In this study, the connection between cognitive behaviors and the adult rodent hippocampus was investigated. Recording field potentials at performant pathway (PP)–hippocampal dentate gyrus (DG) synapses in transverse slices from the dorsal (d), intermediate (i), and ventral (v) hippocampus showed differences in paired-pulse responses and long-term potentiation in rats. The Barnes maze (BM) and passive avoidance (PA) tests indicated a decrease in escape latency and step-through latency in both rats and mice over training days. A decrease in the use of random or sequential strategy while an increase in the use of direct strategy to search for an escape box occurred in both groups. Evaluation of the levels of neurogenesis markers (Ki67 and BrdU/NeuN) by immunofluorescence assay in the dDG, iDG, and vDG revealed a long-axis disparity in the hippocampal dentate baseline cell proliferation and exposure to the BM and PA task changed the profile of baseline cell proliferation along the DG in both rats and mice. Also, these learning experiences changed the profile of BrdU⁺/NeuN⁺ cells along the DG of rats. Quantitation of hippocampal BDNF protein levels using ELISA exhibited no changes in BDNF levels due to learning experiences in rats. We demonstrate that PP–DG synaptic efficacy and neurogenesis are organized along a gradient. Avoidance and escape conditioning themselves are sufficient to change and calibrate adult neurogenesis along the hippocampal long axis in rodents. Further research will be required to determine the precise mechanisms underlying the role of experience-derived neuroplasticity in cognitive function and decline.     

CXCR4 prevents dispersion of granule neuron precursors in the adult dentate gyrus

Neurogenesis in the adult dentate gyrus (DG) generates new granule neurons that differentiate in the inner one‐third of the granule cell layer (GCL). The migrating precursors of these neurons arise from neural stem cells (NSCs) in the subgranular zone (SGZ). Although it is established that pathological conditions, including epilepsy and stroke, cause dispersion of granule neuron precursors, little is known about the factors that regulate their normal placement. Based on the high expression of the chemokine CXCL12 in the adult GCL and its role in guiding neuronal migration in development, we addressed the function of the CXCL12 receptor CXCR4 in adult neurogenesis. Using transgenic reporter mice, we detected Cxcr4‐GFP expression in NSCs, neuronal‐committed progenitors, and immature neurons of adult and aged mice. Analyses of hippocampal NSC cultures and hippocampal tissue by immunoblot and immunohistochemistry provided evidence for CXCL12‐promoted phosphorylation/activation of CXCR4 receptors in NSCs in vivo and in vitro. Cxcr4 deletion in NSCs of the postnatal or mature DG using Cre technology reduced neurogenesis. Fifty days after Cxcr4 ablation in the mature DG, the SGZ showed a severe reduction of Sox2‐positive neural stem/early progenitor cells, NeuroD‐positive neuronal‐committed progenitors, and DCX‐positive immature neurons. Many immature neurons were ectopically placed in the hilus and inner molecular layer, and some developed an aberrant dendritic morphology. Only few misplaced cells survived permanently as ectopic neurons. Thus, CXCR4 signaling maintains the NSC pool in the DG and specifies the inner one‐third of the GCL as differentiation area for immature granule neurons. © 2013 Wiley Periodicals, Inc.     

Positive Controls in Adults and Children Support That Very Few,If Any,New Neurons Are Born in the Adult Human Hippocampus

Adult hippocampal neurogenesis was originally discovered in rodents. Subsequent studies identified the adult neural stem cells and found important links between adult neurogenesis and plasticity, behavior, and disease. However, whether new neurons are produced in the human dentate gyrus (DG) during healthy aging is still debated. We and others readily observe proliferating neural progenitors in the infant hippocampus near immature cells expressing doublecortin (DCX), but the number of such cells decreases in children and few, if any, are present in adults. Recent investigations using dual antigen retrieval find many cells stained by DCX antibodies in adult human DG. This has been interpreted as evidence for high rates of adult neurogenesis, even at older ages. However, most of these DCX-labeled cells have mature morphology. Furthermore, studies in the adult human DG have not found a germinal region containing dividing progenitor cells. In this Dual Perspectives article, we show that dual antigen retrieval is not required for the detection of DCX in multiple human brain regions of infants or adults. We review prior studies and present new data showing that DCX is not uniquely expressed by newly born neurons: DCX is present in adult amygdala, entorhinal and parahippocampal cortex neurons despite being absent in the neighboring DG. Analysis of available RNA-sequencing datasets supports the view that DG neurogenesis is rare or absent in the adult human brain. To resolve the conflicting interpretations in humans, it is necessary to identify and visualize dividing neuronal precursors or develop new methods to evaluate the age of a neuron at the single-cell level.     

Anatomical gradients of adult neurogenesis and activity: Young neurons in the ventral dentate gyrus are activated by water maze training

Hippocampal function varies in a subregion‐specific fashion: spatial processing is thought to rely on the dorsal hippocampus, whereas anxiety‐related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus (DG) proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion‐specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in DG subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c‐fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral DG. In contrast, c‐fos expression in adult‐born granule cells, identified by PSA‐NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral DG. Interestingly, c‐fos expression in the entire granule cell population was equivalent in water maze‐trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally‐relevant experience activates young and mature neurons in different DG subregions and with different experiential specificity, and suggest that adult‐born neurons may play a specific role in anxiety‐related behavior or other nonspatial aspects of hippocampal function. © 2008 Wiley‐Liss, Inc.     

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.     

Doublecortin (DCX) immunoreactivity in hippocampus of chronic refractory temporal lobe epilepsy patients with hippocampal sclerosis

IntroductionStatus epilepticus increases the production of new neurons (hippocampal neurogenesis) and promotes aberrant migration. However chronic experimental models of epilepsy and studies performed in human epilepsy showed controversial results suggesting a reduction in hippocampal neurogenesis in late stages of the disease. Doublecortin (DCX) has been validated to determine alterations in the production of new neurons in the human hippocampus.ObjectivesDetermine DCX expression in human hippocampal sclerosis (HS) from patients who underwent epilepsy surgery for refractory temporal lobe epilepsy (TLE).MethodsHippocampal sections of 9 patients with HS and TLE who underwent surgery, were processed using immunoperoxidase for DCX. Archival material from 5 normal post-mortem hippocampus were simultaneously processed.ResultsSignificantly lower staining intensity was observed in DCX-positive neurons localized in dentate gyrus (DG) and in CA1 of epileptic hippocampus; lower DCX reactive area was observed in pyramidal layers of CA1; and a reduced in the mean number of DCX-positive neurons were determined in DG compared to normal hippocampus (p < 0.05).ConclusionsThis study found a decrease in DCX expression in hippocampus of patients with HS and chronic and refractory TLE suggesting alterations in NG and hippocampal synaptogenesis with potential cognitive and emotional repercussion.     

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.     

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.     

Inverse relationship between adult hippocampal cell proliferation and synaptic rewiring in the dentate gyrus

Adult neurogenesis is a key feature of the hippocampal dentate gyrus (DG). Neurogenesis is accompanied by synaptogenesis as new cells become integrated into the circuitry of the hippocampus. However, little is known to what extent the embedding of new neurons rewires the pre-existing network. Here we investigate synaptic rewiring in the DG of gerbils (Meriones unguiculatus) under different rates of adult cell proliferation caused by different rearing conditions as well as juvenile methamphetamine treatment. Surprisingly, we found that an increased cell proliferation reduced the amount of synaptic rewiring. To help explain this unexpected finding, we developed a novel model of dentate network formation incorporating neurogenesis and activity-dependent synapse formation and remodelling. In the model, we show that homeostasis of neuronal activity can account for the inverse relationship between cell proliferation and synaptic rewiring.     

p21Cip restrains hippocampal neurogenesis and protects neuronal progenitors from apoptosis during acute systemic inflammation

Altered neurogenesis in adult hippocampus is implicated in cognition impairment and depression. Inflammation is a potent inhibitor of neurogenesis. The cyclin‐dependent kinase inhibitor p21^Cip1 (p21) restrains cell cycle progression and arrests the cell in the G1 phase. We recently showed that p21 is expressed in neuronal progenitors and regulates proliferation of these cells in the subgranular zone of the dentate gyrus of hippocampus where adult neurogenesis occurs. The current study suggests that p21 is induced in vivo in the hippocampus of WT mice in response to acute systemic inflammation caused by LPS injections, restrains neuronal progenitor proliferation and protects these cells from inflammation‐induced apoptosis. In intact p21^?/? hippocampus, neuronal progenitors proliferate more actively as assessed by BrdU incorporation, and give rise to increased number of DCX positive neuroblasts. However, when mice were treated with LPS, the number of neuroblasts decreased due to induced subgranular zone apoptosis. In vitro, differentiating Tuj‐1 positive neuroblasts isolated from p21^?/? hippocampus exhibited increased proliferation rate, measured by Ki‐67 staining, as compared to WT cells (p<0.05). In WT neuronal progenitors treated with IL‐6, the number of p21‐positive cells was increased (p<0.05), and this led to Tuj‐1⁺ cell proliferation restraint, whereas the number of proliferating GFAP⁺ astrocytes was increased ～ 2‐fold. Thus, when p21 is intact, inflammation might divert neuronal progenitors towards astrogliogenesis by inducing p21. At the same time, when p21 is lacking, no effects of IL‐6 on proliferation of Tuj‐1⁺ cells or GFAP⁺ cells are detected in differentiating p21^?/? neuronal progenitors. These results underscore the important role of p21 controlling hippocampal neuronal differentiation during inflammation. © 2013 Wiley Periodicals, Inc.